Format

Send to:

Choose Destination

Cerebellar ataxia

MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
Synonyms: Ataxia, Cerebellar; Ataxias, Cerebellar; Cerebellar Ataxia; Cerebellar Ataxias; Cerebellar Incoordination; Cerebellar Incoordinations; Incoordination, Cerebellar; Incoordinations, Cerebellar
SNOMED CT: Cerebellar ataxia (85102008); Cerebellar ataxia (loss of muscle coordination) (85102008)
 
HPO: HP:0001251

Definition

Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly). [from HPO]

Conditions with this feature

Abetalipoproteinaemia
MedGen UID:
1253
Concept ID:
C0000744
Disease or Syndrome
Abetalipoproteinemia and familial hypobetalipoproteinemia (FBHL; 615558) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy, and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein B-containing particles. Obligate heterozygous parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, whereas obligate heterozygous parents of FBHL patients typically have half normal levels of apoB-containing lipoproteins consistent with autosomal codominant inheritance (summary by Lee and Hegele, 2014).
Ataxia-telangiectasia syndrome
MedGen UID:
439
Concept ID:
C0004135
Congenital Abnormality
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
Celiac disease
MedGen UID:
3291
Concept ID:
C0007570
Disease or Syndrome
Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, weight loss, abdominal pain, anorexia, lactose intolerance, abdominal distention, and irritability) and/or highly variable non-gastrointestinal findings (iron deficiency anemia, dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms.
Cerebelloparenchymal disorder v
MedGen UID:
2956
Concept ID:
C0007761
Disease or Syndrome
A condition marked by progressive CEREBELLAR ATAXIA combined with MYOCLONUS usually presenting in the third decade of life or later. Additional clinical features may include generalized and focal SEIZURES, spasticity, and DYSKINESIAS. Autosomal recessive and autosomal dominant patterns of inheritance have been reported. Pathologically, the dentate nucleus and brachium conjunctivum of the CEREBELLUM are atrophic, with variable involvement of the spinal cord, cerebellar cortex, and basal ganglia. (From Joynt, Clinical Neurology, 1991, Ch37, pp60-1)
Facial hemiatrophy
MedGen UID:
8761
Concept ID:
C0015458
Disease or Syndrome
A syndrome characterized by slowly progressive unilateral atrophy of facial subcutaneous fat, muscle tissue, skin, cartilage, and bone. The condition typically progresses over a period of 2-10 years and then stabilizes.
Pigmentary pallidal degeneration
MedGen UID:
6708
Concept ID:
C0018523
Disease or Syndrome
Pantothenate kinase-associated neurodegeneration (PKAN) is a form of neurodegeneration with brain iron accumulation, or NBIA (formerly called Hallervorden-Spatz syndrome). PKAN is characterized by progressive dystonia and basal ganglia iron deposition with onset that usually occurs before age ten years. Commonly associated features include dysarthria, rigidity, and pigmentary retinopathy. Approximately 25% of affected individuals have an 'atypical' presentation with later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease.
Kearns Sayre syndrome
MedGen UID:
9618
Concept ID:
C0022541
Disease or Syndrome
A mitochondrial disorder featuring the triad of chronic progressive EXTERNAL OPHTHALMOPLEGIA, cardiomyopathy (CARDIOMYOPATHIES) with conduction block (HEART BLOCK), and RETINITIS PIGMENTOSA. Disease onset is in the first or second decade. Elevated CSF protein, sensorineural deafness, seizures, and pyramidal signs may also be present. Ragged-red fibers are found on muscle biopsy. (Adams et al., Principles of Neurology, 6th ed, p984)
Adult neuronal ceroid lipofuscinosis
MedGen UID:
7230
Concept ID:
C0022797
Disease or Syndrome
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Laurence-Moon syndrome
MedGen UID:
44078
Concept ID:
C0023138
Disease or Syndrome
Laurence-Moon syndrome has a clinical presentation similar to that of Oliver-McFarlane syndrome (275400), including chorioretinopathy and pituitary dysfunction, but with childhood onset of ataxia, peripheral neuropathy, and spastic paraplegia and without trichomegaly. Historically, Laurence-Moon syndrome has been associated with Bardet-Biedl syndrome (see BBS, 209900) (summary by Hufnagel et al., 2015). Oliver-McFarlane syndrome is an allelic disorder.
Leigh syndrome
MedGen UID:
44095
Concept ID:
C0023264
Disease or Syndrome
Leigh syndrome is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation (Dahl, 1998). Leigh syndrome may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (252010), complex II deficiency (252011), complex III deficiency (124000), complex IV deficiency (cytochrome c oxidase; 220110), or complex V deficiency (604273).
Metachromatic leukodystrophy
MedGen UID:
6071
Concept ID:
C0023522
Disease or Syndrome
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD (50%-60% of cases); juvenile MLD (20%-30% of cases); and adult MLD (15%-20% of cases). Age of onset within a family is usually similar. The disease course may be from three to ten or more years in the late-infantile form and up to 20 years or more in the juvenile and adult forms. Late-infantile MLD. Onset is between ages one and two years. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and slurred speech. Later signs include inability to stand, difficulty with speech, deterioration of mental function, increased muscle tone, pain in the arms and legs, generalized or partial seizures, compromised vision and hearing, and peripheral neuropathy. In the final stages children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD. Onset is between age four years and sexual maturity (age 12-14 years). Initial manifestations include decline in school performance and emergence of behavioral problems, followed by clumsiness, gait problems, slurred speech, incontinence, and bizarre behaviors. Seizures may occur. Progression is similar to but slower than the late-infantile form. Adult MLD. Onset occurs after sexual maturity, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, alcohol or drug abuse, poor money management, and emotional lability; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures predominate initially. Peripheral neuropathy is common. Disease course is variable, with periods of stability interspersed with periods of decline, and may extend over two to three decades. The final stage is similar to that for the earlier-onset forms.
Azorean disease
MedGen UID:
9841
Concept ID:
C0024408
Disease or Syndrome
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. Neurologic findings tend to evolve as the disease progresses.
Maple syrup urine disease
MedGen UID:
6217
Concept ID:
C0024776
Disease or Syndrome
Maple syrup urine disease (MSUD) is classified as classic or intermediate. Twelve hours after birth, untreated neonates with classic MSUD have a maple syrup odor in cerumen; by 12-24 hours, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios; by age two to three days, ketonuria, irritability, and poor feeding; by age four to five days, deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling." By age seven to ten days, coma and central respiratory failure may supervene. Individuals with intermediate MSUD have partial BCKAD enzyme deficiency that only manifests intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy during sufficient catabolic stress.
Neuroblastoma
MedGen UID:
18012
Concept ID:
C0027819
Neoplastic Process
ALK-related neuroblastic tumor susceptibility results from heterozygosity for a germline ALK activating pathogenic variant in the tyrosine kinase domain that predisposes to neuroblastic tumors. The spectrum of neuroblastic tumors includes neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. At present there are no data regarding the lifetime risk to an individual with a germline ALK pathogenic variant of developing a neuroblastic tumor. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest that the overall penetrance is around 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.
Neurofibromatosis, type 2
MedGen UID:
18014
Concept ID:
C0027832
Neoplastic Process
Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Posterior subcapsular lens opacities that rarely progress to a visually significant cataract are the most common ocular findings and may be the first sign of NF2. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy, a squint (third nerve palsy), or hand/foot drop.
Polyarteritis nodosa
MedGen UID:
14681
Concept ID:
C0031036
Disease or Syndrome
Childhood-onset polyarteritis nodosa is an autosomal recessive systemic vascular inflammatory disorder characterized mainly by involvement of the skin, nervous system, kidney, and gastrointestinal tract. There is considerable variability in the severity and age at onset, although most patients have onset of symptoms in the first decade. Features include recurrent ischemic stroke affecting the small vessels of the brain and resulting in neurologic dysfunction, recurrent fever, elevated acute-phase proteins, myalgias, and livedo racemosa or reticularis with an inflammatory vasculitis on biopsy. Some patients develop hypertension, aneurysms, or ischemic necrosis of the digits (summary by Zhou et al., 2014 and Navon Elkan et al., 2014). Some patients present with clinical immunodeficiency van Eyck et al., 2014).
Phytanic acid storage disease
MedGen UID:
11161
Concept ID:
C0034960
Disease or Syndrome
Refsum disease is characterized by anosmia and early-onset retinitis pigmentosa, which are both universal findings with variable combinations of neuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems which develop later in life.
Sandhoff disease
MedGen UID:
11313
Concept ID:
C0036161
Disease or Syndrome
Sandhoff disease is a progressive neurodegenerative disorder characterized by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease (272800).
Shy-Drager syndrome
MedGen UID:
20740
Concept ID:
C0037019
Disease or Syndrome
Multiple system atrophy (MSA) is a distinct clinicopathologic entity that manifests as a progressive adult-onset neurodegenerative disorder causing parkinsonism, cerebellar ataxia, and autonomic, urogenital, and pyramidal dysfunction in various combinations. Two main subtypes are recognized: 'subtype C,' characterized predominantly by cerebellar ataxia, and 'subtype P,' characterized predominantly by parkinsonism. MSA is characterized pathologically by the degeneration of striatonigral and olivopontocerebellar structures and glial cytoplasmic inclusions that consist of abnormally phosphorylated alpha-synuclein (SNCA; 163890) or tau (MAPT; 157140) (Gilman et al., 1998; Gilman et al., 2008; Scholz et al., 2009). 'Subtype C' of MSA has been reported to be more prevalent than 'subtype P' in the Japanese population (65-67% vs 33-35%), whereas 'subtype P' has been reported to be more prevalent than 'subtype C' in Europe (63% vs 34%) and North America (60% vs 13%, with 27% of cases unclassified) (summary by the The Multiple-System Atrophy Research Collaboration, 2013). MSA is similar clinically and pathologically to Parkinson disease (PD; 168600) and Lewy body dementia (127750). See also PARK1 (168601), which is specifically caused by mutation in the SNCA gene. Pure autonomic failure manifests as orthostatic hypotension and other autonomic abnormalities without other neurologic involvement. Although there is some phenotypic overlap, the relationship of pure autonomic failure to MSA is unclear (Vanderhaeghen et al., 1970; Schatz, 1996).
Diabetes mellitus AND insipidus with optic atrophy AND deafness
MedGen UID:
21923
Concept ID:
C0043207
Disease or Syndrome
WFS1-related disorders range from Wolfram syndrome (WFS) to WFS1-related low-frequency sensory hearing loss (also known as DFNA6/14/38 low-frequency sensorineural hearing loss [LFSNHL]). WFS is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 16 years, and typically associated with sensorineural hearing loss, progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony), and other endocrine abnormalities. Median age at death is 30 years. WFS-like disease is characterized by sensorineural hearing loss, diabetes mellitus, psychiatric illness, and variable optic atrophy. WFS1-related LFSNHL is characterized by congenital, nonsyndromic, slowly progressive, low-frequency (<2000 Hz) sensorineural hearing loss.
Cyclical vomiting syndrome
MedGen UID:
57509
Concept ID:
C0152164
Disease or Syndrome
Cyclic vomiting syndrome is a disorder that causes recurrent episodes of nausea, vomiting, and tiredness (lethargy). This condition is diagnosed most often in young children, but it can affect people of any age.The episodes of nausea, vomiting, and lethargy last anywhere from an hour to 10 days. An affected person may vomit several times per hour, potentially leading to a dangerous loss of fluids (dehydration). Additional symptoms can include unusually pale skin (pallor), abdominal pain, diarrhea, headache, fever, and an increased sensitivity to light (photophobia) or to sound (phonophobia). In most affected people, the signs and symptoms of each attack are quite similar. These attacks can be debilitating, making it difficult for an affected person to go to work or school.Episodes of nausea, vomiting, and lethargy can occur regularly or apparently at random, or can be triggered by a variety of factors. The most common triggers are emotional excitement and infections. Other triggers can include periods without eating (fasting), temperature extremes, lack of sleep, overexertion, allergies, ingesting certain foods or alcohol, and menstruation.If the condition is not treated, episodes usually occur four to 12 times per year. Between attacks, vomiting is absent, and nausea is either absent or much reduced. However, many affected people experience other symptoms during and between episodes, including pain, lethargy, digestive disorders such as gastroesophageal reflux and irritable bowel syndrome, and fainting spells (syncope). People with cyclic vomiting syndrome are also more likely than people without the disorder to experience depression, anxiety, and panic disorder. It is unclear whether these health conditions are directly related to nausea and vomiting.Cyclic vomiting syndrome is often considered to be a variant of migraines, which are severe headaches often associated with pain, nausea, vomiting, and extreme sensitivity to light and sound. Cyclic vomiting syndrome is likely the same as or closely related to a condition called abdominal migraine, which is characterized by attacks of stomach pain and cramping. Attacks of nausea, vomiting, or abdominal pain in childhood may be replaced by migraine headaches as an affected person gets older. Many people with cyclic vomiting syndrome or abdominal migraine have a family history of migraines.Most people with cyclic vomiting syndrome have normal intelligence, although some affected people have developmental delay or intellectual disability. Autism spectrum disorders, which affect communication and social interaction, have also been associated with cyclic vomiting syndrome. Additionally, muscle weakness (myopathy) and seizures are possible. People with any of these additional features are said to have cyclic vomiting syndrome plus.
Myoclonus with epilepsy with ragged red fibers
MedGen UID:
56486
Concept ID:
C0162672
Disease or Syndrome
A very rare mitochondrial abnormality characterized by myoclonic epilepsy and the microscopic finding of ragged-red fibers in muscle tissues.
Citrullinemia type I
MedGen UID:
104491
Concept ID:
C0175683
Disease or Syndrome
Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset form, a form without symptoms or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum. Distinction between the clinical forms is based on clinical findings and is not clear-cut. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. The late-onset form may be milder than that seen in the acute neonatal form, for unknown reasons. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals.
Progressive sclerosing poliodystrophy
MedGen UID:
60012
Concept ID:
C0205710
Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. These phenotypes exemplify the diversity that can result from mutation of a given gene. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life up to about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, Parkinsonism, hypogonadism, and cataracts (in what has been called “chronic progressive external ophthalmoplegia plus,” or “CPEO+”).
Pelizaeus-Merzbacher disease
MedGen UID:
61440
Concept ID:
C0205711
Disease or Syndrome
PLP1-related disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Female carriers may manifest mild to moderate signs of the disease.
Fatal familial insomnia
MedGen UID:
104768
Concept ID:
C0206042
Disease or Syndrome
Genetic prion diseases generally manifest with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. Familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI) represent the core phenotypes of genetic prion disease. Note: A fourth clinical phenotype, known as Huntington disease like-1 (HDL-1) has been proposed, but this is based on a single report, and the underlying pathologic features would categorize it as GSS. Although it is clear that these four subtypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset ranges from the third to ninth decade of life. The course ranges from a few months to several years (typically 5-7 years; in rare instances, >10 years).
Biotinidase deficiency
MedGen UID:
66323
Concept ID:
C0220754
Disease or Syndrome
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Hereditary acrodermatitis enteropathica
MedGen UID:
66355
Concept ID:
C0221036
Disease or Syndrome
severe human skin and gastrointestinal disease inherited as a recessive autosomal trait that is characterized by the symptoms of zinc deficiency and clears up when zinc is added to the diet.
Abortive cerebellar ataxia
MedGen UID:
66358
Concept ID:
C0221061
Disease or Syndrome
'Behr syndrome' is a clinical term that refers to the constellation of early-onset optic atrophy accompanied by neurologic features, including ataxia, pyramidal signs, spasticity, and mental retardation (Behr, 1909; Thomas et al., 1984). Patients with mutations in genes other than OPA1 can present with clinical features reminiscent of Behr syndrome. Mutations in one of these genes, OPA3 (606580), result in type III 3-methylglutaconic aciduria (MGCA3; 258501). Lerman-Sagie (1995) noted that the abnormal urinary pattern in MGCA3 may not be picked up by routine organic acid analysis, suggesting that early reports of Behr syndrome with normal metabolic features may actually have been 3-methylglutaconic aciduria type III.
Cholestanol storage disease
MedGen UID:
116041
Concept ID:
C0238052
Disease or Syndrome
Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Chronic diarrhea from infancy may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show cognitive impairment from early infancy, whereas the majority have normal or only slightly impaired intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the 20s in more than 50% of individuals. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs almost invariably become evident between ages 20 and 30 years. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration, decreased chenodeoxycholic acid, increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid.
De Sanctis-Cacchione syndrome
MedGen UID:
75550
Concept ID:
C0265201
Congenital Abnormality
A rare autosomal recessive inherited syndrome. It is characterized by xeroderma pigmentosum, mental retardation, dwarfism, hypogonadism, and neurologic abnormalities.
Congenital cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Underdevelopment of the cerebellum.
Purine-nucleoside phosphorylase deficiency
MedGen UID:
75653
Concept ID:
C0268125
Disease or Syndrome
Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment (review by Aust et al., 1992).
Xeroderma pigmentosum, type 1
MedGen UID:
82775
Concept ID:
C0268135
Congenital Abnormality
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, and marked freckle-like pigmentation of the face before age 2 years in most affected individuals); Ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Xeroderma pigmentosum, group D
MedGen UID:
75656
Concept ID:
C0268138
Congenital Abnormality
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, and marked freckle-like pigmentation of the face before age 2 years in most affected individuals); Ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Xeroderma pigmentosum, group F
MedGen UID:
120612
Concept ID:
C0268140
Congenital Abnormality
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, and marked freckle-like pigmentation of the face before age 2 years in most affected individuals); Ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Xeroderma pigmentosum, group G
MedGen UID:
75657
Concept ID:
C0268141
Congenital Abnormality
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, and marked freckle-like pigmentation of the face before age 2 years in most affected individuals); Ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Deficiency of cytochrome-b5 reductase
MedGen UID:
75661
Concept ID:
C0268193
Disease or Syndrome
Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by Percy and Lappin, 2008). There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979).
Cytochrome-c oxidase deficiency
MedGen UID:
75662
Concept ID:
C0268237
Congenital Abnormality
Complex IV (cytochrome c oxidase; EC 1.9.3.1) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase complex are the actual catalytic subunits that carry out the electron transport function (Saraste, 1983). See 123995 for discussion of some of the nuclear-encoded subunits. Shoubridge (2001) provided a comprehensive review of cytochrome c oxidase deficiency and noted that most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare.
Triglyceride storage disease with ichthyosis
MedGen UID:
82780
Concept ID:
C0268238
Disease or Syndrome
Chanarin-Dorfman syndrome is a condition in which fats (lipids) are stored abnormally in the body. Affected individuals cannot break down certain fats called triglycerides, and these fats accumulate in organs and tissues, including skin, liver, muscles, intestine, eyes, and ears. People with this condition also have dry, scaly skin (ichthyosis), which is usually present at birth. Additional features of this condition include an enlarged liver (hepatomegaly), clouding of the lens of the eyes (cataracts), difficulty with coordinating movements (ataxia), hearing loss, short stature, muscle weakness (myopathy), involuntary movement of the eyes (nystagmus), and mild intellectual disability.The signs and symptoms vary greatly among individuals with Chanarin-Dorfman syndrome. Some people may have ichthyosis only, while others may have problems affecting many areas of the body.
Subacute neuronopathic Gaucher disease
MedGen UID:
78653
Concept ID:
C0268251
Disease or Syndrome
Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.
Multiple sulfatase deficiency
MedGen UID:
75664
Concept ID:
C0268263
Disease or Syndrome
Multiple sulfatase deficiency is an autosomal recessive inborn error of metabolism resulting in tissue accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates. The enzymatic defect affects the whole family of sulfatase enzymes; thus, the disorder combines features of metachromatic leukodystrophy (250100) and of various mucopolysaccharidoses (see, e.g., MPS6; 253200). Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and ichthyosis. Different types of MSD can be distinguished according to the age of onset: neonatal, late infantile (0 to 2 years), and juvenile (2 to 4 years). Neonatal MSD is the most severe form with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. Late-infantile MSD, which includes the majority of cases, resembles late-infantile metachromatic leukodystrophy with progressive loss of mental and motor abilities and skeletal changes. There is also an attenuated form of late-infantile MSD with onset beyond the second year of life. Rare cases of juvenile-onset MSD have been reported with onset of symptoms in late childhood and slower progression (Blanco-Aguirre et al., 2001) (summary by Schlotawa et al., 2011).
Juvenile GM>1< gangliosidosis
MedGen UID:
120625
Concept ID:
C0268272
Disease or Syndrome
GM1-gangliosidosis type II is an autosomal recessive lysosomal storage disease characterized by slowly progressive generalized neurodegeneration and mild skeletal changes, with onset between 7 months and 3 years of age. Unlike the severe infantile type I, type II is usually not associated with macular cherry-red spots or organomegaly. Within type II, those with somewhat earlier onset and earlier death are considered to have the 'late-infantile' form, whereas those with slightly later onset and survival into late childhood are referred to as having the 'juvenile' form (Caciotti et al., 2003). However, there is no strict age marker to distinguish between these 2 type II forms. GLB1 enzyme activity in type II ranges from approximately 1 to 4% of control values (Nishimoto et al., 1991; Yoshida et al., 1991).
Sepiapterin reductase deficiency
MedGen UID:
120642
Concept ID:
C0268468
Disease or Syndrome
SPR deficiency results in neurologic deterioration due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Clinically, affected individuals show an L-DOPA-responsive, diurnally fluctuating movement disorder usually associated with cognitive delay and severe neurologic dysfunction. BH4 is a required cofactor for the synthesis of the neurotransmitters dopamine and serotonin. BH4 is also a required cofactor for phenylalanine hydroxylase (PAH; 612349), but patients with SPR deficiency do not exhibit overt hyperphenylalaninemia. The lack of hyperphenylalaninemia distinguishes SPR deficiency from other disorders of BH4 synthesis (see, e.g., HPABH4A, 261640). However, the neurologic phenotype of SPR deficiency resembles the other BH4-deficient disorders (summary by Bonafe et al., 2001 and Friedman et al., 2012). Another form of dopa-responsive dystonia (DTY5; 128230) is caused by mutation in the gene encoding GTP cyclohydrolase I (GCH1; 600225), which is also a component of the biopterin synthetic pathway.
Tryptophanuria with dwarfism
MedGen UID:
78680
Concept ID:
C0268473
Disease or Syndrome
Urocanate hydratase deficiency
MedGen UID:
120644
Concept ID:
C0268514
Disease or Syndrome
An increased concentration of urocanic acid in the urine.
Argininosuccinate lyase deficiency
MedGen UID:
78687
Concept ID:
C0268547
Disease or Syndrome
Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, is characterized by a severe neonatal onset form and a late onset form. The severe neonatal onset form, which is indistinguishable from that of other urea cycle disorders, is characterized by hyperammonemia within the first few days after birth accompanied by vomiting, lethargy, hypothermia, and poor feeding. In the absence of treatment, lethargy, seizures, and coma worsen, resulting in death. In contrast, the late onset form ranges from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency that appear to be unrelated to the severity or duration of hyperammonemic episodes include: (1) neurocognitive deficiencies (attention deficit hyperactivity disorder [ADHD], developmental disability, seizures, and learning disability); (2) liver disease (hepatitis, cirrhosis); (3) trichorrhexis nodosa (coarse brittle hair that breaks easily); and (4) systemic hypertension.
Sulfite oxidase deficiency
MedGen UID:
78695
Concept ID:
C0268624
Disease or Syndrome
Abnormally reduced sulfite oxidase activity.
Succinate-semialdehyde dehydrogenase deficiency
MedGen UID:
124340
Concept ID:
C0268631
Disease or Syndrome
Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by psychomotor retardation, childhood-onset hypotonia, and ataxia. Seizures occur in more than 50% of affected individuals. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all patients, and are common in older individuals. Basal ganglia signs such as choreoathetosis, dystonia, and myoclonus have been reported in a few individuals with earlier-onset, more severe disease. Involvement beyond the central nervous system has not been described.
Infantile neuroaxonal dystrophy
MedGen UID:
82852
Concept ID:
C0270724
Disease or Syndrome
PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: Classic infantile neuroaxonal dystrophy (INAD). Atypical neuroaxonal dystrophy (atypical NAD). PLA2G6-related dystonia-parkinsonism. INAD usually begins between ages six months and three years with developmental regression, hypotonia, progressive psychomotor delay, and progressive spastic tetraparesis. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid. Many affected children never learn to walk or lose the ability shortly after attaining it. Severe spasticity, progressive cognitive decline, and visual impairment typically result in death during the first decade. Atypical NAD shows more phenotypic variability than INAD. In general, onset is in early childhood but can be as late as the end of the second decade. The presenting signs may be gait instability or ataxia (as in the classic form) or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years. PLA2G6-related dystonia-parkinsonism presents with subacute onset of dystonia-parkinsonism in late adolescence/early adulthood. Other findings are eye movement abnormalities, pyramidal tract signs, and marked cognitive decline.
Alexander disease
MedGen UID:
78724
Concept ID:
C0270726
Disease or Syndrome
Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children and has variable life expectancy. The later-onset forms present with a slower clinical course. The infantile form comprises about 42% of affected individuals, the juvenile form about 22%, and the adult form about 33%. A neonatal form is also recognized. The neonatal form leads to severe disability or death within two years. Characteristics include seizures, hydrocephalus, severe motor and intellectual disability, and elevated CSF protein concentration. MRI shows severe white matter abnormalities with involvement of the basal ganglia and cerebellum. The infantile form presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly, frontal bossing, and seizures. Other findings include hyperreflexia and pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis. Affected children survive weeks to several years. The juvenile form usually presents between ages four and ten years, occasionally in the mid-teens. Findings can include bulbar/pseudobulbar signs, ataxia, gradual loss of intellectual function, seizures, normocephaly or megalencephaly, and breathing problems. Survival ranges from the early teens to the 20s-30s. The adult form is the most variable.
Leucine-induced hypoglycemia
MedGen UID:
82888
Concept ID:
C0271714
Disease or Syndrome
Glucocorticoid deficiency with achalasia
MedGen UID:
82889
Concept ID:
C0271742
Disease or Syndrome
Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).People with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.People with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.Alacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.
Familial hemophagocytic lymphohistiocytosis
MedGen UID:
78797
Concept ID:
C0272199
Pathologic Function
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Dominant hereditary optic atrophy
MedGen UID:
137902
Concept ID:
C0338508
Disease or Syndrome
Optic atrophy type 1 (OPA1, or Kjer type optic atrophy) is characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity (usually between ages 4 and 6 years), visual field defects, and color vision defects. Visual impairment is usually moderate (6/10 to 2/10), but ranges from mild or even insignificant to severe (legal blindness with acuity <1/20). The visual field defect is typically centrocecal, central, or paracentral; it is often large in those with severe disease. The color vision defect is often described as acquired blue-yellow loss (tritanopia). Other findings can include auditory neuropathy resulting in sensorineural hearing loss that ranges from severe and congenital to subclinical (i.e., identified by specific audiologic testing only). Visual evoked potentials are typically absent or delayed; pattern electroretinogram shows an abnormal N95:P50 ratio. Tritanopia is the classic feature of color vision defect, but more diffuse nonspecific dyschromatopsia is not uncommon. Ophthalmoscopic examination discloses temporal or diffuse pallor of the optic discs, sometimes associated with optic disc excavation. The neuroretinal rim shows some pallor in most cases, sometimes associated with a temporal pigmentary gray crescent.
Muscular atrophy, ataxia, retinitis pigmentosa, and diabetes mellitus
MedGen UID:
137966
Concept ID:
C0342281
Congenital Abnormality
Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness
MedGen UID:
83338
Concept ID:
C0342287
Congenital Abnormality
Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia is between infancy and adolescence. The anemia is corrected with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day). However, the red cells remain macrocytic. The anemia can recur when thiamine is withdrawn. Progressive sensorineural hearing loss has generally been early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence.
Transcobalamin II deficiency
MedGen UID:
137976
Concept ID:
C0342701
Disease or Syndrome
Transcobalamin II deficiency is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities (summary by Haberle et al., 2009). Hall (1981) gave a clinically oriented review of congenital defects of vitamin B12 transport, and Frater-Schroder (1983) gave a genetically oriented review.
Congenital defect of folate absorption
MedGen UID:
83348
Concept ID:
C0342705
Disease or Syndrome
Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system (CNS). Findings include poor feeding and failure to thrive, anemia often accompanied by leukopenia and/or thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections with unusual organisms. Neurologic manifestations include developmental delays, cognitive and motor impairment, behavioral disorders and, frequently, seizures.
3-Methylglutaconic aciduria
MedGen UID:
90994
Concept ID:
C0342727
Disease or Syndrome
3-methylglutaconyl-CoA hydratase deficiency is an inherited condition that causes neurological problems. Beginning in infancy to early childhood, children with this condition often have delayed development of mental and motor skills (psychomotor delay), speech delay, involuntary muscle cramping (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis). Affected individuals can also have optic atrophy, which is the degeneration (atrophy) of nerve cells that carry visual information from the eyes to the brain.In some cases, signs and symptoms of 3-methylglutaconyl-CoA hydratase deficiency begin in adulthood, often in a person's twenties or thirties. These individuals have damage to a type of brain tissue called white matter (leukoencephalopathy), which likely contributes to progressive problems with speech (dysarthria), difficulty coordinating movements (ataxia), stiffness (spasticity), optic atrophy, and a decline in intellectual function (dementia).Affected individuals who show symptoms of 3-methylglutaconyl-CoA hydratase deficiency in childhood often go on to develop leukoencephalopathy and other neurological problems in adulthood.All people with 3-methylglutaconyl-CoA hydratase deficiency accumulate large amounts of a substance called 3-methylglutaconic acid in their body fluids. As a result, they have elevated levels of acid in their blood (metabolic acidosis) and excrete large amounts of acid in their urine (aciduria). 3-methylglutaconyl-CoA hydratase deficiency is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels 3-methylglutaconic acid in urine (3-methylglutaconic aciduria). People with 3-methylglutaconyl-CoA hydratase deficiency also have high urine levels of another acid called 3-methylglutaric acid.
Flynn-Aird syndrome
MedGen UID:
91009
Concept ID:
C0343108
Congenital Abnormality
Korsakoff psychosis
MedGen UID:
83883
Concept ID:
C0349464
Mental or Behavioral Dysfunction
behavior disorder caused by thiamine deficiency, most commonly due to chronic alcohol abuse; Wernicke's encephalopathy involves confusion, ataxia, nystagmus and ophthalmoplegia and is generally reversible by thiamine administration; Korsakoff's syndrome, involving severe anterograde and retrograde amnesia, may appear later and complete recovery is less frequent.
Carbohydrate-deficient glycoprotein syndrome type I
MedGen UID:
138111
Concept ID:
C0349653
Disease or Syndrome
PMM2-CDG (CDG-Ia) (previously known as congenital disorder of glycosylation type 1a), the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three types: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. The three types notwithstanding, clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. Clinical presentations tend to be similar in siblings. In the infantile multisystem type, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, failure to thrive, and impaired growth are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical presentations are observed: (1) a non-fatal neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade and (2) a neurologic-multivisceral form with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia-intellectual disability type, with onset between age three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability type, intellectual ability is stable; peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed; females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur. An increased risk for deep venous thrombosis is present.
Gluthathione synthetase deficiency
MedGen UID:
97988
Concept ID:
C0398746
Disease or Syndrome
Glutathione synthetase deficiency, or 5-oxoprolinuria, is an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The metabolic defect results in decreased levels of cellular glutathione, which overstimulates the synthesis of gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline (Larsson and Anderson, 2001).
Kohlschutter syndrome
MedGen UID:
98036
Concept ID:
C0406740
Congenital Abnormality
Kohlschutter-Tonz syndrome is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Intellectual disability is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (summary by Schossig et al., 2012 and Mory et al., 2012).
Familial aplasia of the vermis
MedGen UID:
98464
Concept ID:
C0431399
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Aniridia, cerebellar ataxia, and mental retardation
MedGen UID:
96563
Concept ID:
C0431401
Disease or Syndrome
Gillespie syndrome is a disorder that involves eye abnormalities, problems with balance and coordinating movements (ataxia), and mild to moderate intellectual disability.Gillespie syndrome is characterized by aniridia, which is the absence of the colored part of the eye (the iris). In most affected individuals, only part of the iris is missing (partial aniridia) in both eyes, but in some affected individuals, partial aniridia affects only one eye, or the entire iris is missing (complete aniridia) in one or both eyes. The absence of all or part of the iris can cause blurry vision (reduced visual acuity) and increased sensitivity to light (photophobia). Rapid, involuntary eye movements (nystagmus) can also occur in Gillespie syndrome.The balance and movement problems in Gillespie syndrome result from underdevelopment (hypoplasia) of a part of the brain called the cerebellum. This abnormality can cause delayed development of motor skills such as walking. In addition, difficulty controlling the muscles in the mouth can lead to delayed speech development. The difficulties with coordination generally become noticeable in early childhood when the individual is learning these skills. People with Gillespie syndrome usually continue to have an unsteady gait and speech problems. However, the problems do not get worse over time, and in some cases they improve slightly.Other features of Gillespie syndrome can include abnormalities in the bones of the spine (vertebrae) and malformations of the heart.
Chiari malformation type II
MedGen UID:
108222
Concept ID:
C0555206
Congenital Abnormality
Chiari malformation type II (CM2), also known as the Arnold-Chiari malformation, consists of elongation and descent of the inferior cerebellar vermis, cerebellar hemispheres, pons, medulla, and fourth ventricle through the foramen magnum into the spinal canal. CM2 is uniquely associated with myelomeningocele (open spina bifida; see 182940) and is found only in this population (Stevenson, 2004). It is believed to be a disorder of neuroectodermal origin (Schijman, 2004). For a general phenotypic description of the different forms of Chiari malformations, see Chiari malformation type I (CM1; 118420).
Deficiency of guanidinoacetate methyltransferase
MedGen UID:
154356
Concept ID:
C0574080
Disease or Syndrome
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.
3-Methylglutaconic aciduria type 3
MedGen UID:
108273
Concept ID:
C0574084
Disease or Syndrome
OPA3-related 3-methylglutaconic aciduria is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive, decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. Although most individuals develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.
Cockayne syndrome, type B
MedGen UID:
155487
Concept ID:
C0751038
Disease or Syndrome
Cockayne syndrome (referred to as CS in this GeneReview) spans a phenotypic spectrum that includes: CS type I, the "classic" or “moderate” form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal syndrome (COFS) or Pena-Shokeir syndrome type II; CS type III, a milder form; Xeroderma pigmentosum-Cockayne syndrome (XP-CS). CS type I (moderate CS) is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II (severe CS or early-onset CS) is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age seven years. CS type III (mild CS or late-onset CS) is characterized by essentially normal growth and cognitive development or by late onset. Xeroderma pigmentosum-Cockayne syndrome (XP-CS) includes facial freckling and early skin cancers typical of XP and some features typical of CS, including intellectual disability, spasticity, short stature, and hypogonadism. XP-CS does not include skeletal involvement, the facial phenotype of CS, or CNS dysmyelination and calcifications.
Cockayne syndrome type A
MedGen UID:
155488
Concept ID:
C0751039
Disease or Syndrome
Cockayne syndrome (referred to as CS in this GeneReview) spans a phenotypic spectrum that includes: CS type I, the "classic" or “moderate” form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal syndrome (COFS) or Pena-Shokeir syndrome type II; CS type III, a milder form; Xeroderma pigmentosum-Cockayne syndrome (XP-CS). CS type I (moderate CS) is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II (severe CS or early-onset CS) is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age seven years. CS type III (mild CS or late-onset CS) is characterized by essentially normal growth and cognitive development or by late onset. Xeroderma pigmentosum-Cockayne syndrome (XP-CS) includes facial freckling and early skin cancers typical of XP and some features typical of CS, including intellectual disability, spasticity, short stature, and hypogonadism. XP-CS does not include skeletal involvement, the facial phenotype of CS, or CNS dysmyelination and calcifications.
Severe myoclonic epilepsy in infancy
MedGen UID:
148243
Concept ID:
C0751122
Disease or Syndrome
SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome (also known as severe myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]) are usually associated with progressive dementia. Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A-related seizure disorders can vary even within the same family.
Congenital hyperammonemia, type I
MedGen UID:
199727
Concept ID:
C0751753
Disease or Syndrome
Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by Klaus et al., 2009). Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800).
Dentatorubral pallidoluysian atrophy
MedGen UID:
155630
Concept ID:
C0751781
Disease or Syndrome
Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive disorder of ataxia, choreoathetosis, and dementia or character changes in adults and ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children. The age of onset is from one to 62 years with a mean age of onset of 30 years. The clinical presentation varies depending on the age of onset. The cardinal features in adults are ataxia, choreoathetosis, and dementia. Cardinal features in children are progressive intellectual deterioration, behavioral changes, myoclonus, and epilepsy.
Unverricht-Lundborg syndrome
MedGen UID:
155923
Concept ID:
C0751785
Disease or Syndrome
Unverricht-Lundborg disease (EPM1) is a neurodegenerative disorder characterized by onset from age six to 15 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Some years after the onset, ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time.
Bardet-Biedl syndrome
MedGen UID:
156019
Concept ID:
C0752166
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Allan-Herndon-Dudley syndrome
MedGen UID:
208645
Concept ID:
C0795889
Disease or Syndrome
MCT8-specific thyroid hormone cell-membrane transporter deficiency is characterized by severe cognitive deficiency, infantile hypotonia, diminished muscle mass and generalized muscle weakness, progressive spastic quadriplegia, joint contractures, and dystonic and/or athetoid movement with characteristic paroxysms or kinesigenic dyskinesias. Seizures occur in about 25% of cases. Most affected males never sit or walk independently or lose these abilities over time; most never speak or have severely dysarthric speech. Brain MRI obtained in the first few years of life shows transient delayed myelination, which improves by age four years. Although psychomotor findings observed in affected males do not occur in heterozygous females, the latter often have thyroid test abnormalities intermediate between affected and normal individuals.
Microcephaly, hiatal hernia and nephrotic syndrome
MedGen UID:
167086
Concept ID:
C0795949
Disease or Syndrome
Galloway-Mowat syndrome is a rare autosomal recessive neurodegenerative disorder characterized by infantile onset of microcephaly and central nervous system abnormalities resulting in severely delayed psychomotor development. Brain imaging shows cerebellar atrophy and sometimes cerebral atrophy. More variable features include optic atrophy, movement disorders, seizures, and nephrotic syndrome (summary by Vodopiutz et al., 2015).
Gomez Lopez Hernandez syndrome
MedGen UID:
163201
Concept ID:
C0795959
Disease or Syndrome
Gomez-Lopez-Hernandez syndrome, also known as cerebellotrigeminal dermal dysplasia, is a rare neurocutaneous syndrome classically characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, often giving rise to corneal opacities, and bilateral parietal or parietooccipital alopecia, However, trigeminal anesthesia is an inconsistent finding (summary by Sukhudyan et al., 2010).
Arts syndrome
MedGen UID:
163205
Concept ID:
C0796028
Disease or Syndrome
Arts syndrome, which is part of the spectrum of PRPS1-related disorders, is characterized by profound congenital sensorineural hearing impairment, early-onset hypotonia, delayed motor development, mild to moderate intellectual disability, ataxia, and increased risk of infection, all of which (with the exception of optic atrophy) present before age two years. Signs of peripheral neuropathy develop during early childhood. Twelve of 15 boys from the two Dutch families reported with Arts syndrome died before age six years of complications of infection. Carrier females can show late-onset (age >20 years) hearing impairment and other findings.
Reardon Wilson Cavanagh syndrome
MedGen UID:
208659
Concept ID:
C0796045
Disease or Syndrome
Ataxia, deafness, mental retardation, and upper and lower neuron disease are the principal symptoms.
Ataxia-microcephaly-cataract syndrome
MedGen UID:
167098
Concept ID:
C0796056
Disease or Syndrome
Ataxia, microcephaly, hypotonia, cataracts, and nystagmus.
Myhre syndrome
MedGen UID:
167103
Concept ID:
C0796081
Disease or Syndrome
Myhre syndrome is a rare disorder characterized by mental retardation, dysmorphic facial features, including microcephaly, midface hypoplasia, prognathism, and blepharophimosis, as well as typical skeletal anomalies, including short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. All reported cases have been sporadic (summary by Bachmann-Gagescu et al., 2011).
Megalocornea mental retardation syndrome
MedGen UID:
162904
Concept ID:
C0796086
Disease or Syndrome
Megalocornea and iris anomalies accompanied by facial and skeletal defects, slow psychomotor development, hypotonia, and seizures. Later reports classify megalocornea-mental retardation syndrome into several types: Type 1 Synonym: Neuhauser syndrome With iris hypoplasia and minor abnormalities. Type 2 With camptodactyly, scoliosis, and growth retardation. Type 3 Synonym: Verloes type With macrocephaly, hypotonia, and other minor anomalies but no hypoplasia of the irides. Type 4 With megalocephaly,obesity, and normal irides.
Cataract ataxia deafness
MedGen UID:
163216
Concept ID:
C0796123
Disease or Syndrome
Mild mental deficiency with cataracts, ataxia, deafness, polyneuropthy, and other disorders.
Richards-Rundle syndrome
MedGen UID:
163219
Concept ID:
C0796136
Disease or Syndrome
Hearing loss, mental retardation, ataxia, hypogonadism, peripheral muscle wasting, and ketoaciduria progressing from childhood and eventually becoming static.
Spinocerebellar ataxia, X-linked 1
MedGen UID:
163229
Concept ID:
C0796205
Disease or Syndrome
SCAX1 is an X-linked recessive neurologic disorder characterized by hypotonia at birth, delayed motor development, gait ataxia, difficulty standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar ataxia (summary by Bertini et al., 2000). Genetic Heterogeneity of X-linked Spinocerebellar Ataxia X-linked recessive spinocerebellar ataxia (SCAX) is a clinically and genetically heterogeneous disorder. See also SCAX2 (302600), SCAX3 (301790), SCAX4 (301840), and SCAX5 (300703).
Brown-Vialetto-Van laere syndrome
MedGen UID:
163239
Concept ID:
C0796274
Disease or Syndrome
Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (summary by Green et al., 2010). Genetic Heterogeneity of Brown-Vialetto-Van Laere Syndrome See also BVVLS2 (614707), caused by mutation in the SLC52A2 gene (607882) on chromosome 8q.
Oculodentodigital dysplasia
MedGen UID:
167236
Concept ID:
C0812437
Disease or Syndrome
Oculodentodigital syndrome is characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding (summary by Judisch et al., 1979). Neurologic abnormalities are sometimes associated (Gutmann et al., 1991), and lymphedema has been reported in some patients with ODDD (Brice et al., 2013). See review by De Bock et al. (2013). Genetic Heterogeneity of Oculodentodigital Syndrome An autosomal recessive form of ODDD (257850) is also caused by mutation in the GJA1 gene, but the majority of cases are autosomal dominant.
6-pyruvoyl-tetrahydropterin synthase deficiency
MedGen UID:
209234
Concept ID:
C0878676
Disease or Syndrome
Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene. Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed.
Deficiency of ferroxidase
MedGen UID:
168057
Concept ID:
C0878682
Disease or Syndrome
Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 25 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.
Leber optic atrophy
MedGen UID:
182973
Concept ID:
C0917796
Disease or Syndrome
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.
Salla disease
MedGen UID:
203368
Concept ID:
C1096903
Disease or Syndrome
The allelic disorders of free sialic acid metabolism — Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) — are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. The mildest phenotype is Salla disease, which is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor retardation, spasticity, athetosis, and epileptic seizures. The most severe phenotype is ISSD, characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.
Dyskeratosis congenita X-linked
MedGen UID:
216941
Concept ID:
C1148551
Disease or Syndrome
Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. However, the classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Ichthyosis, cerebellar degeneration and hepatosplenomegaly
MedGen UID:
266150
Concept ID:
C1275088
Disease or Syndrome
Deficiency of ribose-5-phosphate isomerase
MedGen UID:
220946
Concept ID:
C1291609
Disease or Syndrome
Revesz syndrome
MedGen UID:
231230
Concept ID:
C1327916
Disease or Syndrome
Myelocerebellar disorder
MedGen UID:
230896
Concept ID:
C1327919
Disease or Syndrome
Kallmann syndrome 1
MedGen UID:
295872
Concept ID:
C1563719
Disease or Syndrome
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the setting of hypogonadism. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome [KS]) in approximately 60%. IGD can first be apparent in infancy, adolescence, or adulthood. Infant boys with congenital (i.e., present at birth) IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
Photomyoclonus, diabetes mellitus, deafness, nephropathy and cerebral dysfunction
MedGen UID:
315660
Concept ID:
C1809475
Disease or Syndrome
Familial hemiplegic migraine type 1
MedGen UID:
331389
Concept ID:
C1832894
Disease or Syndrome
Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including familial hemiplegic migraine) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. Cerebral infarction and death have rarely been associated with hemiplegic migraine.
Optic atrophy with demyelinating disease of CNS
MedGen UID:
322290
Concept ID:
C1833830
Disease or Syndrome
Olivopontocerebellar atrophy v
MedGen UID:
319015
Concept ID:
C1833995
Disease or Syndrome
Nystagmus, hereditary vertical
MedGen UID:
322336
Concept ID:
C1834078
Disease or Syndrome
Ceroid lipofuscinosis neuronal 4B autosomal dominant
MedGen UID:
320287
Concept ID:
C1834207
Disease or Syndrome
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Myoclonus, cerebellar ataxia, and deafness
MedGen UID:
331780
Concept ID:
C1834579
Disease or Syndrome
Dyssynergia cerebellaris myoclonica
MedGen UID:
331781
Concept ID:
C1834580
Disease or Syndrome
Spinocerebellar ataxia, autosomal recessive 7
MedGen UID:
324520
Concept ID:
C1836474
Disease or Syndrome
Congenital disorder of glycosylation type 1F
MedGen UID:
322968
Concept ID:
C1836669
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579).
Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease
MedGen UID:
373160
Concept ID:
C1836727
Disease or Syndrome
The neurologic variant of Waardenburg-Shah syndrome is a complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy (see 118200), central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (see 142623) (Inoue et al., 2004). Inoue et al. (2004) proposed the acronym PCWH for this disorder.
Ceroid lipofuscinosis neuronal 9
MedGen UID:
332304
Concept ID:
C1836841
Disease or Syndrome
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Leukodystrophy, hypomyelinating, 2
MedGen UID:
325157
Concept ID:
C1837355
Disease or Syndrome
Congenital disorder of glycosylation type 1E
MedGen UID:
324784
Concept ID:
C1837396
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579).
Spinocerebellar ataxia 25
MedGen UID:
373347
Concept ID:
C1837518
Disease or Syndrome
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Joubert syndrome 3
MedGen UID:
332931
Concept ID:
C1837713
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Ceroid lipofuscinosis neuronal 8
MedGen UID:
374004
Concept ID:
C1838570
Disease or Syndrome
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Ceroid lipofuscinosis neuronal 7
MedGen UID:
325457
Concept ID:
C1838571
Disease or Syndrome
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy
MedGen UID:
325051
Concept ID:
C1838577
Disease or Syndrome
CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by early-onset changes in the deep white matter of the brain observed on MRI and associated neurologic findings. The most frequent initial symptom is gait disturbance from spasticity beginning between ages 20 and 30 years. Twenty-three percent of affected individuals have stroke-like episodes before age 40 years. Mood changes (apathy and irritability), pseudobulbar palsy, and cognitive dysfunction begin between ages 20 and 50 years. The disease progresses slowly over the five to 20 years following the onset of neurologic symptoms. Scalp alopecia before age 30 years and acute mid- to lower-back pain (lumbago) with onset between ages ten and 40 years are characteristic.
Neuropathy ataxia retinitis pigmentosa syndrome
MedGen UID:
325131
Concept ID:
C1838914
Disease or Syndrome
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.
Mitochondrial complex I deficiency
MedGen UID:
374101
Concept ID:
C1838979
Disease or Syndrome
Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1 (161015), NDUFV2 (600532), NDUFS1 (157655), NDUFS2 (602985), NDUFS3 (603846), NDUFS4 (602694), NDUFS6 (603848), NDUFS7 (601825), NDUFS8 (602141), NDUFA2 (602137), NDUFA11 (612638), NDUFAF3 (612911), NDUFA10 (603835), NDUFB3 (603839), NDUFB9 (601445), and the complex I assembly genes B17.2L (609653), HRPAP20 (611776), C20ORF7 (612360), NUBPL (613621), and NDUFAF1 (606934). The disorder can also be caused by mutation in other nuclear-encoded genes, including FOXRED1 (613622), ACAD9 (611103; see 611126), and MTFMT (611766; see 256000). X-linked inheritance is observed with mutations in the NDUFA1 gene (300078). Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome (256000). Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Mitochondrial myopathy with diabetes
MedGen UID:
333236
Concept ID:
C1839028
Disease or Syndrome
Kallmann syndrome with spastic paraplegia
MedGen UID:
333437
Concept ID:
C1839911
Disease or Syndrome
GLUT1 deficiency syndrome 2
MedGen UID:
330866
Concept ID:
C1842534
Disease or Syndrome
The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1-DS) is now known to be a continuum that includes the classic phenotype as well as dystonia 9, dystonia 18, atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures begin before age two years in approximately 90% and later in approximately 10%. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continuous with fluctuations in severity influenced by environmental factors such as fasting, fever, and intercurrent infection. Symptoms often improve substantially when a ketogenic diet is started.
Joubert syndrome 2
MedGen UID:
334114
Concept ID:
C1842577
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Spinocerebellar ataxia autosomal recessive 6
MedGen UID:
334220
Concept ID:
C1842676
Disease or Syndrome
Niemann-Pick disease type C2
MedGen UID:
335942
Concept ID:
C1843366
Disease or Syndrome
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Pontocerebellar hypoplasia type 1
MedGen UID:
335969
Concept ID:
C1843504
Disease or Syndrome
Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Different types were classified based on the clinical picture and the spectrum of pathologic changes. PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA; see SMA1, 253300); death usually occurs early. In PCH type 2 (see PCH2A, 277470), there is progressive microcephaly from birth combined with extrapyramidal dyskinesias. PCH3 (608027) is characterized by hypotonia, hyperreflexia, microcephaly, optic atrophy, and seizures. PCH4 (225753) is characterized by hypertonia, joint contractures, olivopontocerebellar hypoplasia, and early death. Patients with PCH5 (610204) have cerebellar hypoplasia apparent in the second trimester and show seizures. PCH6 (611523) is associated with mitochondrial respiratory chain defects (summary by Graham et al., 2010). Also see PCH7 (614969), PCH8 (614961), PCH9 (615809), and PCH10 (615803). Genetic Heterogeneity of Pontocerebellar Hypoplasia Also see PCH1B (614678), caused by mutation in the EXOSC3 gene (606489); PCH1C (616081), caused by mutation in the EXOSC8 gene (606019); PCH2A (277470), caused by mutation in the TSEN54 gene (608755); PCH2B (612389), caused by mutation in the TSEN2 gene (608753); PCH2C (612390), caused by mutation in the TSEN34 gene (608754); PCH2D (613811), caused by mutation in the SEPSECS gene (613009); PCH3 (608027), caused by mutation in the PCLO gene (604918); PCH4 (225753), caused by mutation in the TSEN54 gene; PCH5 (610204), caused by mutation in the TSEN54 gene; PCH6 (611523), caused by mutation in the RARS2 gene (611524); PCH8 (614961), caused by mutation in the CHMP1A gene (164010); PCH9 (615809), caused by mutation in the AMPD2 gene (102771); and PCH10 (615803), caused by mutation in the CLP1 gene (608757). PCH7 (614969) has not yet been mapped.
Spastic paraplegia, ataxia, and mental retardation
MedGen UID:
336010
Concept ID:
C1843661
Disease or Syndrome
Coenzyme Q10 deficiency, primary 1
MedGen UID:
334528
Concept ID:
C1843920
Disease or Syndrome
Primary CoQ10 deficiency is a rare, clinically heterogeneous autosomal recessive disorder caused by mutation in any of the genes encoding proteins directly involved in the synthesis of coenzyme Q (review by Quinzii and Hirano, 2011). Coenzyme Q10 (CoQ10), or ubiquinone, is a mobile lipophilic electron carrier critical for electron transfer by the mitochondrial inner membrane respiratory chain (Duncan et al., 2009). The disorder has been associated with 5 major phenotypes, but the molecular basis has not been determined in most patients with the disorder and there are no clear genotype/phenotype correlations. The phenotypes include an encephalomyopathic form with seizures and ataxia (Ogasahara et al., 1989); a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure (Rotig et al., 2000); a predominantly cerebellar form with ataxia and cerebellar atrophy (Lamperti et al., 2003); Leigh syndrome with growth retardation (van Maldergem et al., 2002); and an isolated myopathic form (Lalani et al., 2005). The correct diagnosis is important because some patients may show a favorable response to CoQ10 treatment. Genetic Heterogeneity of Primary Coenzyme Q10 Deficiency See also COQ10D2 (614651), caused by mutation in the PDSS1 gene (607429) on chromosome 10p12; COQ10D3 (614652), caused by mutation in the PDSS2 gene (610564) on chromosome 6q21; COQ10D4 (612016), caused by mutation in the COQ8 gene (ADCK3; 606980) on chromosome 1q42; COQ10D5 (614654), caused by mutation in the COQ9 gene (612837) on chromosome 16q21; COQ10D6 (614650), caused by mutation in the COQ6 gene (614647) on chromosome 14q24; COQ10D7 (616276), caused by mutation in the COQ4 gene (612898) on chromosome 9q34; and COQ10D8 (616733), caused by mutation in the COQ7 gene (601683) on chromosome 16p13. Secondary CoQ10 deficiency has been reported in association with glutaric aciduria type IIC (MADD; 231680), caused by mutation in the ETFDH gene (231675) on chromosome 4q, and with ataxia-oculomotor apraxia syndrome-1 (AOA1; 208920), caused by mutation in the APTX gene (606350) on chromosome 9p13.
Charcot-Marie-Tooth peroneal muscular atrophy and Friedreich ataxia, combined
MedGen UID:
337104
Concept ID:
C1844863
Disease or Syndrome
Spinocerebellar ataxia X-linked type 2
MedGen UID:
375535
Concept ID:
C1844885
Disease or Syndrome
Spinocerebellar ataxia X-linked type 4
MedGen UID:
337122
Concept ID:
C1844933
Disease or Syndrome
Cataracts, ataxia, short stature, and mental retardation
MedGen UID:
375579
Concept ID:
C1845094
Disease or Syndrome
MECP2 duplication syndrome
MedGen UID:
337496
Concept ID:
C1846058
Mental or Behavioral Dysfunction
The MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by infantile hypotonia, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections (in ~75% of affected individuals) and seizures (in ~50%). MECP2 duplication syndrome is 100% penetrant in males. Occasionally females have been described with a MECP2 duplication and related clinical findings, often associated with concomitant X-chromosomal abnormalities that prevent inactivation of the duplicated region. Generalized tonic-clonic seizures are most often observed; atonic seizures and absence seizures have also been described. One third of affected males are never able to walk independently. Almost 50% of affected males die before age 25 years, presumably from complications of recurrent infection and/or neurologic deterioration. In addition to the core features, autistic behaviors and gastrointestinal dysfunction have been observed in several affected boys. Although interfamilial phenotypic variability is observed, severity is usually consistent within families.
Spinocerebellar ataxia autosomal recessive 4
MedGen UID:
335442
Concept ID:
C1846492
Disease or Syndrome
Spinocerebellar ataxia autosomal recessive with axonal neuropathy
MedGen UID:
337609
Concept ID:
C1846574
Disease or Syndrome
Spinocerebellar ataxia with axonal neuropathy (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia, followed by areflexia and signs of peripheral neuropathy. Gaze nystagmus and cerebellar dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation become impaired in the hands and legs; vibration sense disappears in hands and lower thigh. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent.
Joubert syndrome 4
MedGen UID:
335526
Concept ID:
C1846790
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Spinocerebellar ataxia autosomal recessive 5
MedGen UID:
376048
Concept ID:
C1847114
Disease or Syndrome
Glucose transporter type 1 deficiency syndrome
MedGen UID:
337833
Concept ID:
C1847501
Disease or Syndrome
The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1-DS) is now known to be a continuum that includes the classic phenotype as well as dystonia 9, dystonia 18, atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures begin before age two years in approximately 90% and later in approximately 10%. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continuous with fluctuations in severity influenced by environmental factors such as fasting, fever, and intercurrent infection. Symptoms often improve substantially when a ketogenic diet is started.
Lissencephaly, X-linked
MedGen UID:
336286
Concept ID:
C1848199
Disease or Syndrome
DCX-related disorders include the neuronal migration disorders classic lissencephaly (formerly also known as lissencephaly type 1), usually in males; and subcortical band heterotopia (SBH, also called double cortex), primarily in females. Males with classic DCX-related lissencephaly typically have severe and global developmental delay, infantile-onset seizures (infantile spasms, West syndrome, focal and generalized seizures), and severe intellectual disability. In individuals with SBH, cognitive abilities range from normal to learning disabilities and/or severe intellectual disability. The majority of individuals with SBH present with focal or generalized seizures. Behavior problems may also be observed. In DCX-related lissencephaly and SBH the severity of the clinical manifestation correlates with the degree of the underlying brain malformation.
Waardenburg syndrome type 4A
MedGen UID:
341244
Concept ID:
C1848519
Disease or Syndrome
Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome, is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 4A is caused by mutation in the EDNRB gene (131244). Clinical Variability of Waardenburg Syndrome Types 1-4 Waardenburg syndrome has been classified into 4 main phenotypes. Type I Waardenburg syndrome (WS1; 193500) is characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia iridis and brilliant blue eyes; congenital sensorineural hearing loss; and 'dystopia canthorum.' WS type II (WS2) is distinguished from type I by the absence of dystopia canthorum. WS type III (WS3; 148820) has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type 4 has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). Genetic Heterogeneity of Waardenburg Syndrome Type 4 Waardenburg syndrome type 4 is genetically heterogeneous. WS4B (613265) is caused by mutation in the EDN3 gene (131242) on chromosome 20q13, and WS4C (613266) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13.
Ataxia with vitamin E deficiency
MedGen UID:
341248
Concept ID:
C1848533
Disease or Syndrome
Most individuals with ataxia with vitamin E deficiency (AVED) present at puberty; common characteristics of the disease include progressive ataxia, clumsiness of the hands, loss of proprioception (especially of vibration and joint position sense), and areflexia. Other features often observed are dysdiadochokinesia, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. The phenotype and disease severity vary widely among families with different mutations; age of onset and disease course are more uniform within a given family, but symptoms and disease severity can vary even among sibs.
Thyrocerebral-retinal syndrome
MedGen UID:
341311
Concept ID:
C1848813
Disease or Syndrome
Tapetoretinal degeneration with ataxia
MedGen UID:
336461
Concept ID:
C1848932
Disease or Syndrome
Spinocerebellar degeneration and corneal dystrophy
MedGen UID:
341379
Concept ID:
C1849087
Disease or Syndrome
Spinocerebellar ataxia with dysmorphism
MedGen UID:
336495
Concept ID:
C1849088
Disease or Syndrome
Spinocerebellar ataxia autosomal recessive 3
MedGen UID:
338611
Concept ID:
C1849094
Disease or Syndrome
Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
MedGen UID:
338613
Concept ID:
C1849096
Disease or Syndrome
Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotrophic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness.
Spastic paraplegia 15
MedGen UID:
341387
Concept ID:
C1849128
Disease or Syndrome
Spastic paraplegia-15 is an autosomal recessive neurodegenerative disorder characterized by progressive spasticity primarily affecting the lower limbs. It is a complex form of spastic paraplegia, associated with other neurologic dysfunction, including variable mental retardation, hearing and visual defects, and thin corpus callosum (summary by Goizet et al., 2009).
Knobloch syndrome 1
MedGen UID:
336594
Concept ID:
C1849409
Congenital Abnormality
Knobloch syndrome is an autosomal recessive developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia (summary by Aldahmesh et al., 2011).
Renal dysplasia, retinal pigmentary dystrophy, cerebellar ataxia and skeletal dysplasia
MedGen UID:
341455
Concept ID:
C1849437
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Polymyoclonus, infantile
MedGen UID:
376647
Concept ID:
C1849731
Disease or Syndrome
Peripheral neuropathy, ataxia, focal necrotizing encephalopathy, and spongy degeneration of brain
MedGen UID:
342395
Concept ID:
C1850022
Disease or Syndrome
Pellagra like syndrome
MedGen UID:
337955
Concept ID:
C1850052
Disease or Syndrome
OLIVOPONTOCEREBELLAR ATROPHY II, AUTOSOMAL RECESSIVE
MedGen UID:
376758
Concept ID:
C1850319
Disease or Syndrome
Navajo neurohepatopathy
MedGen UID:
338045
Concept ID:
C1850406
Disease or Syndrome
MPV17-related hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome is characterized by infantile-onset liver dysfunction that typically progresses to liver failure; neurologic involvement (developmental delay, hypotonia, and muscle weakness in the majority; ataxia, seizures, and motor and sensory peripheral neuropathy in some); failure to thrive; and metabolic derangements including lactic acidosis and hypoglycemic crises. Less frequent manifestations include renal tubulopathy, hypoparathyroidism, gastrointestinal dysmotility, and corneal anesthesia. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported.
Ceroid lipofuscinosis neuronal 1
MedGen UID:
340540
Concept ID:
C1850451
Disease or Syndrome
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Elejalde disease
MedGen UID:
342508
Concept ID:
C1850466
Disease or Syndrome
Friedreich ataxia, so-called, with optic atrophy and sensorineural deafness
MedGen UID:
376920
Concept ID:
C1850982
Disease or Syndrome
Dyskeratosis congenita autosomal dominant
MedGen UID:
338831
Concept ID:
C1851970
Congenital Abnormality
Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. However, the classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Optic Atrophy Type 1
MedGen UID:
377632
Concept ID:
C1852267
Disease or Syndrome
Syndromic optic atrophy, also known as DOA+ syndrome, is a neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia (PEO), muscle cramps, hyperreflexia, and ataxia. There appears to be a wide range of intermediate phenotypes (Yu-Wai-Man et al., 2010).
Mitochondrial complex III deficiency
MedGen UID:
377658
Concept ID:
C1852372
Disease or Syndrome
Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003). Genetic Heterogeneity of Mitochondrial Complex III Deficiency Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; and MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12. See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene.
Joubert syndrome 6
MedGen UID:
342805
Concept ID:
C1853153
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Neuroferritinopathy
MedGen UID:
381211
Concept ID:
C1853578
Disease or Syndrome
Neuroferritinopathy typically presents with progressive adult-onset chorea or dystonia affecting one or two limbs, and subtle cognitive deficits. The movement disorder involves additional limbs within five to ten years and becomes more generalized within 20 years. When present, asymmetry remains throughout the course of the disorder. The majority of individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity and orolingual dyskinesia are common. Cognitive deficits and behavioral issues become major problems with time.
Mitochondrial complex II deficiency
MedGen UID:
344401
Concept ID:
C1855008
Disease or Syndrome
Mitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013).
Megalencephaly with dysmyelination
MedGen UID:
344470
Concept ID:
C1855309
Disease or Syndrome
Pyruvate dehydrogenase E3-binding protein deficiency
MedGen UID:
343383
Concept ID:
C1855553
Disease or Syndrome
Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.
Pyruvate dehydrogenase E2 deficiency
MedGen UID:
343386
Concept ID:
C1855565
Disease or Syndrome
Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.
Kuru, susceptibility to
MedGen UID:
343389
Concept ID:
C1855588
Disease or Syndrome
Genetic prion diseases generally manifest with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. Familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI) represent the core phenotypes of genetic prion disease. Note: A fourth clinical phenotype, known as Huntington disease like-1 (HDL-1) has been proposed, but this is based on a single report, and the underlying pathologic features would categorize it as GSS. Although it is clear that these four subtypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset ranges from the third to ninth decade of life. The course ranges from a few months to several years (typically 5-7 years; in rare instances, >10 years).
Joubert syndrome with oculorenal anomalies
MedGen UID:
340930
Concept ID:
C1855675
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Friedreich ataxia congenital glaucoma
MedGen UID:
344787
Concept ID:
C1856688
Disease or Syndrome
Encephalopathy with intracranial calcification, growth hormone deficiency, microcephaly, and retinal degeneration
MedGen UID:
346482
Concept ID:
C1856973
Disease or Syndrome
Diaminopentanuria
MedGen UID:
347412
Concept ID:
C1857285
Disease or Syndrome
Leigh syndrome, French Canadian type
MedGen UID:
387801
Concept ID:
C1857355
Disease or Syndrome
The French Canadian type of Leigh syndrome is an autosomal recessive severe neurologic disorder with onset in infancy. Features include delayed psychomotor development, mental retardation, mild dysmorphic facial features, hypotonia, ataxia, and the development of lesions in the brainstem and basal ganglia. Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of Leigh syndrome, see 256000.
COACH syndrome
MedGen UID:
387879
Concept ID:
C1857662
Disease or Syndrome
COACH syndrome is an autosomal recessive disorder characterized by mental retardation, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Other features, such as coloboma and renal cysts, may be variable. COACH syndrome is considered by some to be a subtype of Joubert syndrome (JBTS; see 213300) with congenital hepatic fibrosis. Identification of liver disease in these patients is critical because some may develop complications such as portal hypertension with fatal variceal bleeding (Brancati et al., 2008; Doherty et al., 2010).
Joubert syndrome 5
MedGen UID:
347545
Concept ID:
C1857780
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Huntington disease-like 3
MedGen UID:
347622
Concept ID:
C1858114
Disease or Syndrome
As its name suggests, a Huntington disease-like (HDL) syndrome is a condition that resembles Huntington disease. Researchers have described four HDL syndromes, designated Huntington disease-like 1 (HDL1) through Huntington disease-like 4 (HDL4). These progressive brain disorders are characterized by uncontrolled movements, emotional problems, and loss of thinking ability. HDL syndromes occur in people with the characteristic features of Huntington disease who do not have a mutation in HD, the gene typically associated with that disorder.HDL1, HDL2, and HDL4 usually appear in early to mid-adulthood, although they can begin earlier in life. The first signs and symptoms of these conditions often include irritability, emotional problems, small involuntary movements, poor coordination, and trouble learning new information or making decisions. Many affected people develop involuntary jerking or twitching movements known as chorea. As the disease progresses, these abnormal movements become more pronounced. Affected individuals may develop problems with walking, speaking, and swallowing. People with these disorders also experience changes in personality and a decline in thinking and reasoning abilities. Individuals with an HDL syndrome can live for a few years to more than a decade after signs and symptoms begin.HDL3 begins much earlier in life than most of the other HDL syndromes (usually around age 3 or 4). Affected children experience a decline in thinking ability, difficulties with movement and speech, and seizures. Because HDL3 has a somewhat different pattern of signs and symptoms and a different pattern of inheritance, researchers are unsure whether it belongs in the same category as the other HDL syndromes.
Alpha-methylacyl-CoA racemase deficiency
MedGen UID:
348911
Concept ID:
C1858325
Disease or Syndrome
AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (summary by Smith et al., 2010).
Spastic paraplegia 11, autosomal recessive
MedGen UID:
388073
Concept ID:
C1858479
Disease or Syndrome
Spastic paraplegia 11 (SPG11) is characterized by progressive spasticity and weakness of the lower limbs frequently associated with the following: mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs. Less frequent findings include: cerebellar signs (ataxia, nystagmus, saccadic pursuit); retinal degeneration; pes cavus; scoliosis; and parkinsonism. Onset occurs mainly during infancy or adolescence (range: age 1-31 years). Most affected individuals become wheelchair bound one or two decades after disease onset.
Spastic paraplegia 10
MedGen UID:
349003
Concept ID:
C1858712
Disease or Syndrome
Spastic paraplegia-10 is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or young adulthood. Some patients show distal sensory impairment, which can be part of the 'pure' phenotype. However, some patients also show an axonal sensorimotor peripheral neuropathy with distal sensory impairment and distal muscle atrophy reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A, 118210). Rarely, patients with KIF5A mutations may have additional neurologic features, including parkinsonism or cognitive decline, consistent with a 'complicated' phenotype. Spastic paraplegia and peripheral neuropathy in isolation may represent extreme ends of the phenotypic spectrum of KIF5A mutations (summary by Goizet et al., 2008 and Crimella et al., 2012).
Congenital Cataracts, Facial Dysmorphism, and Neuropathy
MedGen UID:
346973
Concept ID:
C1858726
Congenital Abnormality
Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils); mildly dysmorphic facial features apparent in late childhood; and a hypo/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade. Secondary scoliosis and foot deformities are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild non-progressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Roma/Gypsy population.
Cerebellar ataxia, deafness, and narcolepsy
MedGen UID:
347726
Concept ID:
C1858804
Disease or Syndrome
ADCADN is an autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy/cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression (summary by Winkelmann et al., 2012).
Megalencephalic leukoencephalopathy with subcortical cysts 1
MedGen UID:
347006
Concept ID:
C1858854
Congenital Abnormality
The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to the 98th percentile, usually several centimeters above it. Almost all individuals have epilepsy from an early age. Initial mental and motor development is normal in most cases. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Mental deterioration is late and mild. Severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their forties. An atypical improving phenotype has a similar initial presentation without mental or motor regression, followed by an improving clinical course: motor and cognitive functions improve or normalize; macrocephaly usually persists, but some children become normocephalic; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable with or without autism.
Boucher Neuhauser syndrome
MedGen UID:
347798
Concept ID:
C1859093
Disease or Syndrome
Boucher-Neuhauser syndrome is an autosomal recessive disorder characterized classically by the triad of spinocerebellar ataxia, hypogonadotropic hypogonadism, and visual impairment due to chorioretinal dystrophy. The age at onset is variable, but most patients develop one or more symptoms in the first decade of life. Chorioretinal dystrophy may not always be present. BNHS is part of a spectrum of neurodegenerative diseases associated with mutations in the PNPLA6 gene that also includes spastic paraplegia-39 (SPG39; 612020) (summary by Synofzik et al., 2014). See also Gordon Holmes syndrome (GDHS; 212840), caused by mutation in the RNF216 gene (609948), which is also characterized by the combination of cerebellar ataxia and hypogonadotropic hypogonadism.
Cholestasis with gallstone, ataxia, and visual disturbance
MedGen UID:
347812
Concept ID:
C1859161
Disease or Syndrome
Spinocerebellar ataxia, autosomal recessive 2
MedGen UID:
349134
Concept ID:
C1859298
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-2 is an neurologic disorder characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. Brain imaging shows cerebellar atrophy. Overall, the disorder is non- or slowly progressive, with survival into adulthood (summary by Jobling et al., 2015).
CEREBELLOPARENCHYMAL DISORDER II
MedGen UID:
395223
Concept ID:
C1859299
Disease or Syndrome
Cerebellar hypoplasia with endosteal sclerosis
MedGen UID:
347849
Concept ID:
C1859301
Disease or Syndrome
Cerebellar ataxia and neurosensory deafness
MedGen UID:
395224
Concept ID:
C1859304
Disease or Syndrome
Cerebellar ataxia and hypogonadotropic hypogonadism
MedGen UID:
349137
Concept ID:
C1859305
Disease or Syndrome
Gordon Holmes syndrome is an autosomal recessive adult-onset neurodegenerative disorder characterized by progressive cognitive decline, dementia, and variable movement disorders, such as ataxia and chorea. The neurologic phenotype is associated with hypogonadotropic hypogonadism (summary by Santens et al., 2015).
Cerebellar ataxia ectodermal dysplasia
MedGen UID:
347850
Concept ID:
C1859306
Disease or Syndrome
Adult onset ataxia with oculomotor apraxia
MedGen UID:
395301
Concept ID:
C1859598
Disease or Syndrome
Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed.
Ataxia-telangiectasia with generalized skin pigmentation and early death
MedGen UID:
395306
Concept ID:
C1859615
Disease or Syndrome
Ataxia, deafness and cardiomyopathy
MedGen UID:
395312
Concept ID:
C1859645
Disease or Syndrome
Ataxia with myoclonic epilepsy and presenile dementia
MedGen UID:
347924
Concept ID:
C1859646
Disease or Syndrome
Angiomatosis, diffuse corticomeningeal, of Divry and Van Bogaert
MedGen UID:
347234
Concept ID:
C1859783
Disease or Syndrome
Tremor of intention, ataxia, and lipofuscinosis
MedGen UID:
396002
Concept ID:
C1860872
Disease or Syndrome
Spinocerebellar ataxia 29
MedGen UID:
350085
Concept ID:
C1861732
Disease or Syndrome
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Dementia, familial Danish
MedGen UID:
396208
Concept ID:
C1861735
Disease or Syndrome
Hereditary cerebral amyloid angiopathy is a condition that can cause a progressive loss of intellectual function (dementia), stroke, and other neurological problems starting in mid-adulthood. Due to neurological decline, this condition is typically fatal in one's sixties, although there is variation depending on the severity of the signs and symptoms. Most affected individuals die within a decade after signs and symptoms first appear, although some people with the disease have survived longer.There are many different types of hereditary cerebral amyloid angiopathy. The different types are distinguished by their genetic cause and the signs and symptoms that occur. The various types of hereditary cerebral amyloid angiopathy are named after the regions where they were first diagnosed.The Dutch type of hereditary cerebral amyloid angiopathy is the most common form. Stroke is frequently the first sign of the Dutch type and is fatal in about one third of people who have this condition. Survivors often develop dementia and have recurrent strokes. About half of individuals with the Dutch type who have one or more strokes will have recurrent seizures (epilepsy).People with the Flemish and Italian types of hereditary cerebral amyloid angiopathy are prone to recurrent strokes and dementia. Individuals with the Piedmont type may have one or more strokes and typically experience impaired movements, numbness or tingling (paresthesias), confusion, or dementia.The first sign of the Icelandic type of hereditary cerebral amyloid angiopathy is typically a stroke followed by dementia. Strokes associated with the Icelandic type usually occur earlier than the other types, with individuals typically experiencing their first stroke in their twenties or thirties.Strokes are rare in people with the Arctic type of hereditary cerebral amyloid angiopathy, in which the first sign is usually memory loss that then progresses to severe dementia. Strokes are also uncommon in individuals with the Iowa type. This type is characterized by memory loss, problems with vocabulary and the production of speech, personality changes, and involuntary muscle twitches (myoclonus).Two types of hereditary cerebral amyloid angiopathy, known as familial British dementia and familial Danish dementia, are characterized by dementia and movement problems. Strokes are uncommon in these types. People with the Danish type may also have clouding of the lens of the eyes (cataracts) or deafness.
Spinocerebellar ataxia 31
MedGen UID:
348439
Concept ID:
C1861736
Disease or Syndrome
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Brachydactyly-nystagmus-cerebellar ataxia
MedGen UID:
350589
Concept ID:
C1862099
Disease or Syndrome
Ataxia with fasciculations
MedGen UID:
400052
Concept ID:
C1862440
Disease or Syndrome
Familial hypobetalipoproteinemia
MedGen UID:
349549
Concept ID:
C1862596
Disease or Syndrome
Familial hypobetalipoproteinemia (FHBL) is a disorder that impairs the body's ability to absorb and transport fats. This condition is characterized by low levels of a fat-like substance called cholesterol in the blood. The severity of signs and symptoms experienced by people with FHBL vary widely. The most mildly affected individuals have few problems with absorbing fats from the diet and no related signs and symptoms. Many individuals with FHBL develop an abnormal buildup of fats in the liver called hepatic steatosis or fatty liver. In more severely affected individuals, fatty liver may progress to chronic liver disease (cirrhosis). Individuals with severe FHBL have greater difficulty absorbing fats as well as fat-soluble vitamins such as vitamin E and vitamin A. This difficulty in fat absorption leads to excess fat in the feces (steatorrhea). In childhood, these digestive problems can result in an inability to grow or gain weight at the expected rate (failure to thrive).
Hemophagocytic lymphohistiocytosis, familial, 2
MedGen UID:
400366
Concept ID:
C1863727
Disease or Syndrome
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Congenital disorder of glycosylation type 1C
MedGen UID:
400469
Concept ID:
C1864178
Disease or Syndrome
Congenital disorders of N-linked glycosylation (abbreviated here as CDG-N-linked), are a group of disorders of N-linked oligosaccharides caused by deficiency in 42 different enzymes in the N-linked synthetic pathway. Most commonly, the disorders begin in infancy; manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development. However, most types have been described in only a few individuals, and thus understanding of the phenotypes is limited. In PMM2-CDG (CDG-Ia), the most common type reported, the clinical presentation and course are highly variable, ranging from death in infancy to mild involvement in adults.
Ceroid lipofuscinosis neuronal 10
MedGen UID:
350481
Concept ID:
C1864669
Disease or Syndrome
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Combined oxidative phosphorylation deficiency 3
MedGen UID:
355842
Concept ID:
C1864840
Disease or Syndrome
Spondyloepimetaphyseal dysplasia Genevieve type
MedGen UID:
355314
Concept ID:
C1864872
Disease or Syndrome
Ethylmalonic encephalopathy
MedGen UID:
355966
Concept ID:
C1865349
Disease or Syndrome
Ethylmalonic encephalopathy is an autosomal recessive severe metabolic disorder of infancy affecting the brain, gastrointestinal tract, and peripheral vessels. The disorder is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Brain MRI shows necrotic lesions in deep gray matter structures. Death usually occurs in the first decade of life (summary by Drousiotou et al., 2011).
Friedreich ataxia 2
MedGen UID:
356134
Concept ID:
C1865981
Disease or Syndrome
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty (summary by Delatycki et al., 2000). For a general phenotypic description of Friedreich ataxia (FRDA), see FRDA1 (229300), which is caused by mutation in the FXN gene (606829) on chromosome 9q13.
Spinocerebellar ataxia with rigidity and peripheral neuropathy
MedGen UID:
401079
Concept ID:
C1866770
Disease or Syndrome
Posterior column ataxia
MedGen UID:
357379
Concept ID:
C1867923
Disease or Syndrome
Telfer Sugar Jaeger syndrome
MedGen UID:
358177
Concept ID:
C1868311
Disease or Syndrome
Leukodystrophy, adult-onset, autosomal dominant
MedGen UID:
356995
Concept ID:
C1868512
Disease or Syndrome
Autosomal dominant adult-onset demyelinating leukodystrophy is a slowly progressive and fatal disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. ADLD differs from multiple sclerosis and other demyelinating disorders in that neuropathology shows preservation of oligodendroglia in the presence of subtotal demyelination and lack of astrogliosis (summary by Padiath et al., 2006). Characteristic MRI findings include T2-weighted hyperintense changes in the upper corticospinal tract and cerebellar peduncles, with later development of confluent white matter changes in the frontoparietal area with relative sparing of the periventricular white matter (summary by Schuster et al., 2011).
Ceroid lipofuscinosis, neuronal, 2
MedGen UID:
406281
Concept ID:
C1876161
Disease or Syndrome
The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure. The lipopigment pattern seen most often in CLN2 consists of 'curvilinear' profiles (Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
Mental retardation, X-linked, syndromic 13
MedGen UID:
368466
Concept ID:
C1968550
Disease or Syndrome
The MECP2 gene is mutated in Rett syndrome (RTT; 312750), a severe neurodevelopmental disorder that almost always occurs in females. Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes, including X-linked mental retardation with spasticity and other variable features, described here, and Lubs X-linked mental retardation syndrome (MRXSL; 300260). Males with RTT-associated MECP2 mutations have neonatal severe encephalopathy that is usually lethal (300673) (Moog et al., 2003; Villard, 2007).
Lissencephaly 3
MedGen UID:
369910
Concept ID:
C1969029
Disease or Syndrome
Joubert syndrome 7
MedGen UID:
369401
Concept ID:
C1969053
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Mental retardation, autosomal dominant 1
MedGen UID:
409857
Concept ID:
C1969562
Disease or Syndrome
Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation
MedGen UID:
370845
Concept ID:
C1970180
Disease or Syndrome
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction (decreased position and vibration sense) in most patients. The neurologic dysfunction involves the legs more than the arms. The tendon reflexes are retained. Deterioration of motor skills usually starts in childhood or adolescence, but occasionally not until adulthood. Dysarthria develops over time. Occasional findings include: epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. Many affected individuals become wheelchair dependent in their teens or twenties. Neonatal or early-infantile onset patients have a severe disease course and may die, whereas late-infantile and early-childhood onset is associated with early wheelchair dependency.
Choreoathetosis, hypothyroidism, and neonatal respiratory distress
MedGen UID:
369694
Concept ID:
C1970269
Disease or Syndrome
Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) is an autosomal dominant disorder characterized by onset of this triad of features in infancy. Movement abnormalities begin with muscular hypotonia followed by the development of chorea, athetosis, dystonia, ataxia, and dysarthria. Some patients show neonatal respiratory distress and developmental delay. The phenotype is variable both between and within families (summary by Thorwarth et al., 2014).
Xeroderma pigmentosum, complementation group b
MedGen UID:
373493
Concept ID:
C1970808
Disease or Syndrome
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, and marked freckle-like pigmentation of the face before age 2 years in most affected individuals); Ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Phosphoribosylpyrophosphate synthetase superactivity
MedGen UID:
370358
Concept ID:
C1970827
Disease or Syndrome
Phosphoribosylpyrophosphate synthetase (PRS) superactivity is characterized by hyperuricemia and hyperuricosuria and is divided into a severe phenotype with infantile or early-childhood onset and a milder phenotype with late-juvenile or early-adult onset. Variable combinations of sensorineural hearing loss, hypotonia, and ataxia observed in the severe type are not usually present in the mild type. In the mild type, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled.
Phosphoglycerate kinase 1 deficiency
MedGen UID:
410166
Concept ID:
C1970848
Disease or Syndrome
Phosphoglycerate kinase-1 deficiency is an X-linked recessive condition with a highly variable clinical phenotype that includes hemolytic anemia, myopathy, and neurologic involvement. Patients can express 1, 2, or all 3 of these manifestations (Shirakawa et al., 2006).
Leukodystrophy, hypomyelinating, 6
MedGen UID:
436642
Concept ID:
C2676244
Disease or Syndrome
Hypomyelinating leukodystrophy-6, also known as hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum, is a neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen. The disorder usually shows sporadic occurrence, but sibs may be affected if a parent is somatic mosaic for the mutation (summary by Simons et al., 2013). Hypomyelinating leukodystrophies (HLD) comprise a genetically heterogeneous entity in which there is a substantial permanent deficit in myelin deposition within the brain, resulting in neurologic deficits (van der Knaap et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.
Cerebroretinal microangiopathy with calcifications and cysts
MedGen UID:
383079
Concept ID:
C2677299
Disease or Syndrome
Cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anemia and thrombocytopenia (summary by Anderson et al., 2012 and Polvi et al., 2012). Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome (614561), has similar central nervous system features as CRMCC in the absence of extraneurologic or systemic manifestations. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic (Anderson et al., 2012; Polvi et al., 2012). Some features of CRMCC resemble those observed in dyskeratosis congenita (see, e.g., 127550), which is a clinically and genetically heterogeneous telomere-related genetic disorder.
Spastic paraplegia 39
MedGen UID:
383142
Concept ID:
C2677586
Disease or Syndrome
The form of motor neuron disease designated spastic paraplegia-39 (SPG39) by Rainier et al. (2008) is an autosomal recessive progressive spastic paraplegia associated with distal upper and lower extremity wasting. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Coenzyme Q10 deficiency, primary, 4
MedGen UID:
436985
Concept ID:
C2677589
Disease or Syndrome
Primary coenzyme Q10 deficiency-4 is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. Oral coenzyme Q10 supplementation does not result in significant improvement of neurologic symptoms (summary by Mollet et al., 2008 and Lagier-Tourenne et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (607426).
Congenital disorder of glycosylation type 1N
MedGen UID:
383145
Concept ID:
C2677590
Disease or Syndrome
Congenital disorders of N-linked glycosylation (abbreviated here as CDG-N-linked), are a group of disorders of N-linked oligosaccharides caused by deficiency in 42 different enzymes in the N-linked synthetic pathway. Most commonly, the disorders begin in infancy; manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development. However, most types have been described in only a few individuals, and thus understanding of the phenotypes is limited. In PMM2-CDG (CDG-Ia), the most common type reported, the clinical presentation and course are highly variable, ranging from death in infancy to mild involvement in adults.
Riddle syndrome
MedGen UID:
394368
Concept ID:
C2677792
Disease or Syndrome
Spinocerebellar ataxia, X-linked 5
MedGen UID:
394718
Concept ID:
C2678048
Disease or Syndrome
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 1
MedGen UID:
398105
Concept ID:
C2700431
Disease or Syndrome
A distinct group of inborn defects of complex V (ATP synthase) is represented by the enzyme deficiency due to nuclear genome mutations characterized by a selective inhibition of ATP synthase biogenesis. Biochemically, the patients show a generalized decrease in the content of ATP synthase complex which is less than 30% of normal. Most cases present with neonatal-onset hypotonia, lactic acidosis, hyperammonemia, hypertrophic cardiomyopathy, and 3-methylglutaconic aciduria. Many patients die within a few months or years (summary by Mayr et al., 2010). Genetic Heterogeneity of Mitochondrial Complex V Deficiency Other nuclear types of mitochondrial complex V deficiency include MC5DN2 (614052), caused by mutation in the TMEM70 gene (612418) on chromosome 8q21; MC5DN3 (614053), caused by mutation in the ATP5E gene (606153) on chromosome 20q13; and MC5DN4 (615228), caused by mutation in the ATP5A1 gene (164360) on chromosome 18q. Mutations in the mitochondrial-encoded MTATP6 (516060) and MTATP8 (516070) genes can also cause mitochondrial complex V deficiency (see, e.g., 551500 and 500003).
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3
MedGen UID:
442496
Concept ID:
C2750509
Disease or Syndrome
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by Gulsuner et al., 2011). For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).
Nijmegen breakage syndrome-like disorder
MedGen UID:
442700
Concept ID:
C2751318
Disease or Syndrome
Amyloidogenic transthyretin amyloidosis
MedGen UID:
414031
Concept ID:
C2751492
Disease or Syndrome
Familial transthyretin (TTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor neuropathy and autonomic neuropathy as well as non-neuropathic changes of cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis. The disease usually begins in the third to fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. Typically, sensory neuropathy starts in the lower extremities with paresthesias and hypesthesias of the feet, followed within a few years by motor neuropathy. In some persons, particularly those with early onset disease, autonomic neuropathy is the first manifestation of the condition; findings can include: orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis is mainly characterized by progressive cardiomyopathy. Individuals with leptomeningeal amyloidosis may have the following CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage.
Leukoencephalopathy, cystic, without megalencephaly
MedGen UID:
416646
Concept ID:
C2751843
Disease or Syndrome
Spinocerebellar ataxia 30
MedGen UID:
424821
Concept ID:
C2936793
Disease or Syndrome
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Early infantile epileptic encephalopathy 10
MedGen UID:
462017
Concept ID:
C3150667
Disease or Syndrome
Microcephaly, seizures, and developmental delay is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients have a disease course consistent with early infantile epileptic encephalopathy (EIEE), whereas others have more well-controlled seizures and a protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Hemolytic anemia, nonspherocytic, due to glucose phosphate isomerase deficiency
MedGen UID:
462080
Concept ID:
C3150730
Disease or Syndrome
Glucose phosphate isomerase (GPI) deficiency is an inherited disorder that affects red blood cells, which carry oxygen to the body's tissues. People with this disorder have a condition known as chronic hemolytic anemia, in which red blood cells are broken down (undergo hemolysis) prematurely, resulting in a shortage of red blood cells (anemia). Chronic hemolytic anemia can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), extreme tiredness (fatigue), shortness of breath (dyspnea), and a rapid heart rate (tachycardia). An enlarged spleen (splenomegaly), an excess of iron in the blood, and small pebble-like deposits in the gallbladder or bile ducts (gallstones) may also occur in this disorder.Hemolytic anemia in GPI deficiency can range from mild to severe. In the most severe cases, affected individuals do not survive to birth. Individuals with milder disease can survive into adulthood. People with any level of severity of the disorder can have episodes of more severe hemolysis, called hemolytic crises, which can be triggered by bacterial or viral infections.A small percentage of individuals with GPI deficiency also have neurological problems, including intellectual disability and difficulty with coordinating movements (ataxia).
Congenital disorder of glycosylation type 2J
MedGen UID:
462086
Concept ID:
C3150736
Disease or Syndrome
Congenital disorders of N-linked glycosylation (abbreviated here as CDG-N-linked), are a group of disorders of N-linked oligosaccharides caused by deficiency in 42 different enzymes in the N-linked synthetic pathway. Most commonly, the disorders begin in infancy; manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development. However, most types have been described in only a few individuals, and thus understanding of the phenotypes is limited. In PMM2-CDG (CDG-Ia), the most common type reported, the clinical presentation and course are highly variable, ranging from death in infancy to mild involvement in adults.
Combined oxidative phosphorylation deficiency 7
MedGen UID:
462151
Concept ID:
C3150801
Disease or Syndrome
Mitochondrial DNA depletion syndrome 4B, MNGIE type
MedGen UID:
462264
Concept ID:
C3150914
Disease or Syndrome
Mitochondrial DNA depletion syndrome-4B is an autosomal recessive progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility and pseudoobstruction, cachexia, progressive external ophthalmoplegia (PEO), axonal sensory ataxic neuropathy, and muscle weakness (van Goethem et al., 2003). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Megaloblastic anemia due to dihydrofolate reductase deficiency
MedGen UID:
462555
Concept ID:
C3151205
Disease or Syndrome
Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (Banka et al., 2011) to childhood absence epilepsy with learning difficulties to lack of symptoms (Cario et al., 2011). Treatment with folinic acid can ameliorate some of the symptoms.
Megalencephalic leukoencephalopathy with subcortical cysts 2a
MedGen UID:
462705
Concept ID:
C3151355
Disease or Syndrome
The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to the 98th percentile, usually several centimeters above it. Almost all individuals have epilepsy from an early age. Initial mental and motor development is normal in most cases. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Mental deterioration is late and mild. Severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their forties. An atypical improving phenotype has a similar initial presentation without mental or motor regression, followed by an improving clinical course: motor and cognitive functions improve or normalize; macrocephaly usually persists, but some children become normocephalic; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable with or without autism.
Dyskeratosis congenita, autosomal dominant, 3
MedGen UID:
462795
Concept ID:
C3151445
Disease or Syndrome
Dyskeratosis congenita is an inherited bone marrow failure syndrome classically characterized by the triad of mucosal leukoplakia, nail dysplasia, and abnormal skin pigmentation. Affected individuals have an increased risk of aplastic anemia and malignancy. Less common features include epiphora, premature gray hair, microcephaly, developmental delay, and pulmonary fibrosis, among others. The phenotype is highly variable. All affected individuals have shortened telomeres due to a defect in telomere maintenance (summary by Savage et al., 2008). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DCKA1 (127550).
Mitochondrial DNA depletion syndrome 9 (encephalomyopathic with methylmalonic aciduria)
MedGen UID:
462826
Concept ID:
C3151476
Disease or Syndrome
Mitochondrial DNA depletion syndrome-9 is a severe autosomal recessive disorder characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. Some patients die in early infancy (summary by Rouzier et al., 2010). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).
Proximal tubulopathy, diabetes mellitus and cerebellar ataxia
MedGen UID:
463309
Concept ID:
C3151959
Disease or Syndrome
Niemann-Pick disease type C1
MedGen UID:
465922
Concept ID:
C3179455
Disease or Syndrome
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Mental retardation, X-linked, syndromic, chudley-schwartz type
MedGen UID:
477102
Concept ID:
C3275471
Disease or Syndrome
Epilepsy, progressive myoclonic 6
MedGen UID:
481257
Concept ID:
C3279627
Disease or Syndrome
Progressive myoclonic epilepsy-6 is an autosomal recessive neurologic disorder characterized by onset of ataxia in the first years of life, followed by action myoclonus and seizures later in childhood, and loss of independent ambulation in the second decade. Cognition is not usually affected, although mild memory difficulties may occur in the third decade (summary by Corbett et al., 2011). For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 2
MedGen UID:
481329
Concept ID:
C3279699
Disease or Syndrome
Neurodegeneration with brain iron accumulation 4
MedGen UID:
482001
Concept ID:
C3280371
Disease or Syndrome
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (e.g., emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.
Joubert syndrome 14
MedGen UID:
482396
Concept ID:
C3280766
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE)
MedGen UID:
482496
Concept ID:
C3280866
Disease or Syndrome
Episodic encephalopathy due to thiamine pyrophosphokinase deficiency is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (summary by Mayr et al., 2011). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Joubert syndrome 15
MedGen UID:
482527
Concept ID:
C3280897
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Infantile cerebellar-retinal degeneration
MedGen UID:
482822
Concept ID:
C3281192
Disease or Syndrome
Infantile cerebellar-retinal degeneration is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (summary by Spiegel et al., 2012).
Leukoencephalopathy, brain calcifications, and cysts
MedGen UID:
482830
Concept ID:
C3281200
Disease or Syndrome
Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome, is characterized by a constellation of features restricted to the central nervous system, including leukoencephalopathy, brain calcifications, and cysts, resulting in spasticity, dystonia, seizures, and cognitive decline (summary by Labrune et al., 1996). See also cerebroretinal microangiopathy with calcifications and cysts (CRMCC; 612199), an autosomal recessive disorder caused by mutation in the CTC1 gene (613129) that shows phenotypic similarities to Labrune syndrome. CRMCC includes the neurologic findings of intracranial calcifications, leukodystrophy, and brain cysts, but also includes retinal vascular abnormalities and other systemic manifestations, such as osteopenia with poor bone healing, a high risk of gastrointestinal bleeding, hair, skin, and nail changes, and anemia and thrombocytopenia. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic (Anderson et al., 2012; Polvi et al., 2012).
Ceroid lipofuscinosis, neuronal, 11
MedGen UID:
761331
Concept ID:
C3539123
Disease or Syndrome
Neuronal ceroid lipofuscinosis-11 is an autosomal recessive neurologic disorder characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur (summary by Smith et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
Joubert syndrome 17
MedGen UID:
766178
Concept ID:
C3553264
Disease or Syndrome
Classic Joubert syndrome is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Brown-Vialetto-Van Laere syndrome 2
MedGen UID:
766452
Concept ID:
C3553538
Disease or Syndrome
Brown-Vialetto-Van Laere syndrome-2 is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency. Some patients may lose independent ambulation. Because it results from a defect in riboflavin metabolism, some patients may benefit from high-dose riboflavin supplementation (summary by Johnson et al., 2012; Foley et al., 2014). For discussion of genetic heterogeneity of Brown-Vialetto-Van Laere syndrome, see BVVLS1 (211530).
Alternating hemiplegia of childhood 2
MedGen UID:
766702
Concept ID:
C3553788
Disease or Syndrome
Alternating hemiplegia of childhood is a rare syndrome characterized by infantile onset of episodic hemi-or quadriplegia. Most cases are accompanied by dystonic posturing, choreoathetoid movements, abnormal ocular movements, developmental delay, and progressive cognitive impairment (summary by Heinzen et al., 2012). For discussion of genetic heterogeneity of alternating hemiplegia of childhood, see AHC1 (104290).
Peroxisome biogenesis disorder 4B
MedGen UID:
766851
Concept ID:
C3553937
Disease or Syndrome
Peroxisome biogenesis disorder-4B (PDB4B) includes the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX6 gene have cells of complementation group 4 (CG4, equivalent to CG6 and CGC). For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 6B
MedGen UID:
766862
Concept ID:
C3553948
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood. Some patients with PEX10 mutations have a milder disorder characterized by childhood-onset cerebellar ataxia and neuropathy without mental retardation (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX10 gene have cells of complementation group 7 (CG7, equivalent to CGB). For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 8B
MedGen UID:
766874
Concept ID:
C3553960
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX16 gene have cells of complementation group 9 (CG9, equivalent to CGD). For information on the history of PBD complementation groups, see 214100.
Combined oxidative phosphorylation deficiency 15
MedGen UID:
767096
Concept ID:
C3554182
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 4
MedGen UID:
767521
Concept ID:
C3554607
Disease or Syndrome
Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.The severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. Most people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood sugar levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.Mitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.
Ceroid lipofuscinosis, neuronal, 13
MedGen UID:
811566
Concept ID:
C3715049
Disease or Syndrome
Neuronal ceroid lipofuscinosis-13 is an autosomal recessive neurodegenerative disorder characterized by adult onset of progressive cognitive decline and motor dysfunction leading to dementia and often early death. Some patients develop seizures. Neurons show abnormal accumulation of autofluorescent material (summary by Smith et al., 2013). Adult-onset neuronal ceroid lipofuscinosis is sometimes referred to as Kufs disease. For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis (CLN), see CLN1 (256730).
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A14
MedGen UID:
815546
Concept ID:
C3809216
Disease or Syndrome
Limb-girdle muscular dystrophy, type 2S
MedGen UID:
815566
Concept ID:
C3809236
Disease or Syndrome
LGMD2S is an autosomal recessive disorder characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). For discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy (LGMD), see LGMD2A (253600).
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
MedGen UID:
815922
Concept ID:
C3809592
Disease or Syndrome
Mitochondrial DNA depletion syndrome-13 is an autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Cells derived from patient tissues show defects in mitochondrial oxidative phosphorylation and decreased mtDNA content (summary by Bonnen et al., 2013 and Gai et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Joubert syndrome 21
MedGen UID:
816542
Concept ID:
C3810212
Disease or Syndrome
Joubert syndrome is an autosomal recessive congenital condition characterized by a unique brainstem and cerebellar malformation comprising cerebellar vermis hypoplasia and/or dysplasia, elongated superior cerebellar peduncles, and deepened interpeduncular fossa, which together are recognized as the 'molar tooth sign' on brain MRI. The most common clinical features include delayed psychomotor development, hypotonia, abnormal respiratory patterns in the neonatal period, oculomotor apraxia, and cerebellar ataxia. Additional features may include retinal degeneration, cystic kidney, liver fibrosis, and polydactyly. It is caused by ciliary defects and is part of a spectrum of disorders known as 'ciliopathies' (summary by Akizu et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Chromosome 15q11.2 deletion syndrome
MedGen UID:
816588
Concept ID:
C3810258
Disease or Syndrome
A heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011). See also chromosome 15q11.2 duplication syndrome (608636).
Spinocerebellar ataxia, autosomal recessive 15
MedGen UID:
816656
Concept ID:
C3810326
Disease or Syndrome
SPINOCEREBELLAR ATAXIA 37
MedGen UID:
855217
Concept ID:
C3889636
Disease or Syndrome
CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6
MedGen UID:
862720
Concept ID:
C4014283
Disease or Syndrome
IMMUNODEFICIENCY 23
MedGen UID:
862808
Concept ID:
C4014371
Disease or Syndrome
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 24
MedGen UID:
862968
Concept ID:
C4014531
Disease or Syndrome
LEUKOENCEPHALOPATHY, PROGRESSIVE, WITH OVARIAN FAILURE
MedGen UID:
863025
Concept ID:
C4014588
Disease or Syndrome
FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 2
MedGen UID:
863085
Concept ID:
C4014648
Disease or Syndrome
COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 20
MedGen UID:
863097
Concept ID:
C4014660
Disease or Syndrome
ATAXIA-TELANGIECTASIA-LIKE DISORDER 2
MedGen UID:
863113
Concept ID:
C4014676
Disease or Syndrome
ENCEPHALOPATHY, PROGRESSIVE, WITH OR WITHOUT LIPODYSTROPHY
MedGen UID:
863137
Concept ID:
C4014700
Disease or Syndrome
SIDEROBLASTIC ANEMIA WITH B-CELL IMMUNODEFICIENCY, PERIODIC FEVERS, AND DEVELOPMENTAL DELAY
MedGen UID:
863609
Concept ID:
C4015172
Disease or Syndrome
POLYENDOCRINE-POLYNEUROPATHY SYNDROME
MedGen UID:
863698
Concept ID:
C4015261
Disease or Syndrome
PERRAULT SYNDROME 5
MedGen UID:
863744
Concept ID:
C4015307
Disease or Syndrome
EPILEPSY, PROGRESSIVE MYOCLONIC 7
MedGen UID:
863857
Concept ID:
C4015420
Disease or Syndrome
NEUROLOGIC, ENDOCRINE, AND PANCREATIC DISEASE, MULTISYSTEM, INFANTILE-ONSET
MedGen UID:
864165
Concept ID:
C4015728
Disease or Syndrome

Recent clinical studies

Etiology

Pinto WB, Pedroso JL, Souza PV, Albuquerque MV, Barsottini OG
Arq Neuropsiquiatr 2015 Oct;73(10):823-7. Epub 2015 Aug 18 doi: 10.1590/0004-282X20150119. [Epub ahead of print] PMID: 26291991
Ramirez-Zamora A, Zeigler W, Desai N, Biller J
Mov Disord 2015 Apr 15;30(5):614-23. Epub 2015 Mar 11 doi: 10.1002/mds.26158. [Epub ahead of print] PMID: 25757427
Schneider T, Thomalla G, Goebell E, Piotrowski A, Yousem DM
Neuroradiology 2015 Jun;57(6):551-9. Epub 2015 Feb 17 doi: 10.1007/s00234-015-1496-6. [Epub ahead of print] PMID: 25686577
Winser SJ, Smith C, Hale LA, Claydon LS, Whitney SL
Disabil Rehabil 2015;37(2):165-70. Epub 2014 Apr 29 doi: 10.3109/09638288.2014.913709. [Epub ahead of print] PMID: 24773120
Sonni A, Kurdziel LB, Baran B, Spencer RM
J Clin Sleep Med 2014 May 15;10(5):535-43. doi: 10.5664/jcsm.3706. PMID: 24812539Free PMC Article

Diagnosis

Teixeira MJ, Cury RG, Galhardoni R, Barboza VR, Brunoni AR, Alho E, Lepski G, Ciampi de Andrade D
Neurology 2015 Dec 8;85(23):2075-6. doi: 10.1212/WNL.0000000000002204. PMID: 26644050
Pinto WB, Pedroso JL, Souza PV, Albuquerque MV, Barsottini OG
Arq Neuropsiquiatr 2015 Oct;73(10):823-7. Epub 2015 Aug 18 doi: 10.1590/0004-282X20150119. [Epub ahead of print] PMID: 26291991
Ramirez-Zamora A, Zeigler W, Desai N, Biller J
Mov Disord 2015 Apr 15;30(5):614-23. Epub 2015 Mar 11 doi: 10.1002/mds.26158. [Epub ahead of print] PMID: 25757427
Winser SJ, Smith CM, Hale LA, Claydon LS, Whitney SL, Mehta P
Clin Rehabil 2015 Jan;29(1):69-79. Epub 2014 Jun 10 doi: 10.1177/0269215514536412. [Epub ahead of print] PMID: 24917589
Planche V, Marques A, Ulla M, Ruivard M, Durif F
Cerebellum 2014 Jun;13(3):318-22. doi: 10.1007/s12311-013-0534-3. PMID: 24218114

Therapy

Dar MS
Cerebellum 2015 Aug;14(4):447-65. doi: 10.1007/s12311-014-0638-4. PMID: 25578036
Sağlam M, Lehnen N
J Vestib Res 2014;24(5-6):425-31. doi: 10.3233/VES-140538. PMID: 25564085
Marquer A, Barbieri G, Pérennou D
Ann Phys Rehabil Med 2014 Mar;57(2):67-78. Epub 2014 Feb 6 doi: 10.1016/j.rehab.2014.01.002. [Epub ahead of print] PMID: 24582474
Planche V, Marques A, Ulla M, Ruivard M, Durif F
Cerebellum 2014 Jun;13(3):318-22. doi: 10.1007/s12311-013-0534-3. PMID: 24218114
Rigamonti A, Lauria G, Stanzani L, Mantero V, Andreetta F, Salmaggi A
J Neurol Sci 2014 Jan 15;336(1-2):169-70. Epub 2013 Oct 29 doi: 10.1016/j.jns.2013.10.031. [Epub ahead of print] PMID: 24215945

Prognosis

Jones AL, Flanagan EP, Pittock SJ, Mandrekar JN, Eggers SD, Ahlskog JE, McKeon A
JAMA Neurol 2015 Nov;72(11):1304-12. doi: 10.1001/jamaneurol.2015.2378. PMID: 26414229
Sonni A, Kurdziel LB, Baran B, Spencer RM
J Clin Sleep Med 2014 May 15;10(5):535-43. doi: 10.5664/jcsm.3706. PMID: 24812539Free PMC Article
Chen WH, Chen CH, Chui C, Lui CC, Chen CJ, Yin HL
Neuroimmunomodulation 2014;21(6):283-90. Epub 2014 Apr 1 doi: 10.1159/000354614. [Epub ahead of print] PMID: 24714067
Planche V, Marques A, Ulla M, Ruivard M, Durif F
Cerebellum 2014 Jun;13(3):318-22. doi: 10.1007/s12311-013-0534-3. PMID: 24218114
Stowe RC, Karkare S, Puri V
J Child Neurol 2013 Dec;28(12):1653-60. Epub 2012 Oct 3 doi: 10.1177/0883073812460583. [Epub ahead of print] PMID: 23034974

Clinical prediction guides

Calì T, Lopreiato R, Shimony J, Vineyard M, Frizzarin M, Zanni G, Zanotti G, Brini M, Shinawi M, Carafoli E
J Biol Chem 2015 Jun 26;290(26):16132-41. Epub 2015 May 7 doi: 10.1074/jbc.M115.656496. [Epub ahead of print] PMID: 25953895Free PMC Article
Fujisawa Y, Okajima Y
Phys Ther 2015 Nov;95(11):1547-58. Epub 2015 May 7 doi: 10.2522/ptj.20140118. [Epub ahead of print] PMID: 25953596
Coutelier M, Burglen L, Mundwiller E, Abada-Bendib M, Rodriguez D, Chantot-Bastaraud S, Rougeot C, Cournelle MA, Milh M, Toutain A, Bacq D, Meyer V, Afenjar A, Deleuze JF, Brice A, Héron D, Stevanin G, Durr A
Neurology 2015 Apr 28;84(17):1751-9. Epub 2015 Apr 3 doi: 10.1212/WNL.0000000000001524. [Epub ahead of print] PMID: 25841024
Dar MS
Cerebellum 2015 Aug;14(4):447-65. doi: 10.1007/s12311-014-0638-4. PMID: 25578036
Sonni A, Kurdziel LB, Baran B, Spencer RM
J Clin Sleep Med 2014 May 15;10(5):535-43. doi: 10.5664/jcsm.3706. PMID: 24812539Free PMC Article

Recent systematic reviews

Winser SJ, Smith CM, Hale LA, Claydon LS, Whitney SL, Mehta P
Clin Rehabil 2015 Jan;29(1):69-79. Epub 2014 Jun 10 doi: 10.1177/0269215514536412. [Epub ahead of print] PMID: 24917589
van Gaalen J, Kerstens FG, Maas RP, Härmark L, van de Warrenburg BP
CNS Drugs 2014 Dec;28(12):1139-53. doi: 10.1007/s40263-014-0200-4. PMID: 25391707
Marquer A, Barbieri G, Pérennou D
Ann Phys Rehabil Med 2014 Mar;57(2):67-78. Epub 2014 Feb 6 doi: 10.1016/j.rehab.2014.01.002. [Epub ahead of print] PMID: 24582474
Ilg W, Bastian AJ, Boesch S, Burciu RG, Celnik P, Claaßen J, Feil K, Kalla R, Miyai I, Nachbauer W, Schöls L, Strupp M, Synofzik M, Teufel J, Timmann D
Cerebellum 2014 Apr;13(2):248-68. doi: 10.1007/s12311-013-0531-6. PMID: 24222635Free PMC Article
Fonteyn EM, Keus SH, Verstappen CC, Schöls L, de Groot IJ, van de Warrenburg BP
J Neurol 2014 Feb;261(2):251-8. Epub 2013 Apr 16 doi: 10.1007/s00415-013-6910-6. [Epub ahead of print] PMID: 23589192

Supplemental Content

Table of contents

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...