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Muscle weakness

MedGen UID:
57735
Concept ID:
C0151786
Finding; Sign or Symptom
Synonyms: Muscular weakness; Weakness
SNOMED CT: Muscle strength reduced (26544005); Decreased muscle strength (26544005); Muscle weakness (26544005)
 
HPO: HP:0001324

Definition

Reduced strength of muscles. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMuscle weakness

Conditions with this feature

beta Thalassemia
MedGen UID:
2611
Concept ID:
C0005283
Disease or Syndrome
Beta-thalassemia (ß-thalassemia) is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis. Individuals with thalassemia major have severe anemia and hepatosplenomegaly; they usually come to medical attention within the first two years of life. Without treatment, affected children have severe failure to thrive and shortened life expectancy. Treatment with a regular transfusion program and chelation therapy, aimed at reducing transfusion iron overload, allows for normal growth and development and may improve the overall prognosis. Individuals with thalassemia intermedia present later and have milder anemia that only rarely requires transfusion. These individuals are at risk for iron overload secondary to increased intestinal absorption of iron as a result of ineffective erythropoiesis.
Glycogen storage disease type III
MedGen UID:
6641
Concept ID:
C0017922
Disease or Syndrome
Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSD IIIa, the most common subtype present in about 85% of affected individuals, manifests with liver and muscle involvement; GSD IIIb, with liver involvement only, comprises about 15% of all GSD III. In infancy and early childhood, liver involvement presents as ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Hypertrophic cardiomyopathy develops in the majority of those with GSD IIIa, usually during childhood. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and rarely sudden death. Skeletal myopathy manifesting as weakness is not usually evident in childhood, but slowly progresses, typically becoming prominent in the third to fourth decade.
Glycogen storage disease, type IV
MedGen UID:
6642
Concept ID:
C0017923
Disease or Syndrome
The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features. Clinical findings vary extensively both within and between families. The fatal perinatal neuromuscular subtype presents in utero with fetal akinesia deformation sequence (FADS) with decreased fetal movements, polyhydramnios, and fetal hydrops. Death usually occurs in the neonatal period. The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy. Death usually occurs in early infancy. Infants with the classic (progressive) hepatic subtype may appear normal at birth, but rapidly develop failure to thrive; hepatomegaly, liver dysfunction, and progressive liver cirrhosis; hypotonia; and cardiomyopathy. Without liver transplantation, death from liver failure usually occurs by age five years. Children with the non-progressive hepatic subtype tend to present with hepatomegaly, liver dysfunction, myopathy, and hypotonia; however, they are likely to survive without progression of the liver disease and may not show cardiac, skeletal muscle, or neurologic involvement. The childhood neuromuscular subtype is rare and the course is variable, ranging from onset in the second decade with a mild disease course to a more severe, progressive course resulting in death in the third decade.
Glycogen storage disease, type V
MedGen UID:
5341
Concept ID:
C0017924
Disease or Syndrome
Glycogen storage disease type V (GSDV, McArdle disease) is a metabolic myopathy characterized by exercise intolerance manifested by rapid fatigue, myalgia, and cramps in exercising muscles. Symptoms usually are precipitated by isometric exercise or sustained aerobic exercise. Most individuals improve their exercise tolerance by exploiting the "second wind" phenomenon with relief of myalgia and fatigue after a few minutes of rest. Age of onset is frequently in the first decade of life but can vary. Fixed muscle weakness occurs in approximately 25% of affected individuals, is more likely to involve proximal muscles, and is more common in individuals of advanced age. Approximately 50% of affected individuals have recurrent episodes of myoglobinuria that could eventually result in acute renal failure, although reported cases are rare.
Glycogen storage disease, type VII
MedGen UID:
5342
Concept ID:
C0017926
Disease or Syndrome
Glycogen storage disease VII is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and partial loss of muscle and red cell PFK activity, respectively. Raben and Sherman (1995) noted that not all patients with GSD VII seek medical care because in some cases it is a relatively mild disorder.
Graves disease
MedGen UID:
6677
Concept ID:
C0018213
Disease or Syndrome
Graves disease is an autoimmune disorder in which antibodies to the thyrotropin receptor (TSHR; 603372) result in constitutive activation of the receptor and increased levels of thyroid hormone. Wilkin (1990) reviewed endocrine disorders of hormone excess and hormone deficiency resulting from receptor autoimmunity.
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)
Menkes kinky-hair syndrome
MedGen UID:
44030
Concept ID:
C0022716
Disease or Syndrome
Menkes disease is an X-linked recessive disorder characterized by generalized copper deficiency. The clinical features result from the dysfunction of several copper-dependent enzymes. De Bie et al. (2007) provided a detailed review of the molecular pathogenesis of Menkes disease.
Marinesco-Sjögren syndrome
MedGen UID:
6222
Concept ID:
C0024814
Disease or Syndrome
Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia with cerebellar atrophy, early-onset (not necessarily congenital) cataracts, mild to severe intellectual disability, hypotonia, and muscle weakness. Additional features are short stature and various skeletal abnormalities including scoliosis. Children with MSS usually present with muscular hypotonia in early infancy; distal and proximal muscular weakness is noticed during the first decade of life. Later, cerebellar findings of truncal ataxia, dysdiadochokinesia, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity. Cataracts can develop rapidly and typically require lens extraction in the first decade of life. Although many adults are severely handicapped, life span in MSS appears to be near normal.
Myxedema
MedGen UID:
6506
Concept ID:
C0027145
Disease or Syndrome
A condition characterized by a dry, waxy type of swelling (EDEMA) with abnormal deposits of MUCOPOLYSACCHARIDES in the SKIN and other tissues. It is caused by a deficiency of THYROID HORMONES. The skin becomes puffy around the eyes and on the cheeks. The face is dull and expressionless with thickened nose and lips.
Rett syndrome
MedGen UID:
48441
Concept ID:
C0035372
Disease or Syndrome
MECP2-related disorders in females include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities. A pathogenic MECP2 variant in a male is presumed to most often be lethal; phenotypes in rare surviving males are primarily severe neonatal encephalopathy and manic-depressive psychosis, pyramidal signs, Parkinsonian, and macro-orchidism (PPM-X syndrome). Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Atypical Rett syndrome is observed increasingly as MECP2 variants are identified in individuals previously diagnosed with: clinically suspected but molecularly unconfirmed Angelman syndrome; intellectual disability with spasticity or tremor; mild learning disability; or (rarely) autism. Severe neonatal encephalopathy resulting in death before age two years is the most common phenotype observed in affected males.
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).
Schwartz Jampel syndrome type 1
MedGen UID:
19892
Concept ID:
C0036391
Congenital Abnormality
Schwartz-Jampel syndrome is a rare condition characterized by permanent muscle stiffness (myotonia) and bone abnormalities known as chondrodysplasia. The signs and symptoms of this condition become apparent sometime after birth, usually in early childhood. Either muscle stiffness or chondrodysplasia can appear first. The muscle and bone abnormalities worsen in childhood, although most affected individuals have a normal lifespan. The specific features of Schwartz-Jampel syndrome vary widely.Myotonia involves continuous tensing (contraction) of muscles used for movement (skeletal muscles) throughout the body. This sustained muscle contraction causes stiffness that interferes with eating, sitting, walking, and other movements. Sustained contraction of muscles in the face leads to a fixed, "mask-like" facial expression with narrow eye openings (blepharophimosis) and pursed lips. This facial appearance is very specific to Schwartz-Jampel syndrome. Affected individuals may also be nearsighted and experience abnormal blinking or spasms of the eyelids (blepharospasm).Chondrodysplasia affects the development of the skeleton, particularly the long bones in the arms and legs and the bones of the hips. These bones are shortened and unusually wide at the ends, so affected individuals have short stature. The long bones may also be abnormally curved (bowed). Other bone abnormalities associated with Schwartz-Jampel syndrome include a protruding chest (pectus carinatum), abnormal curvature of the spine, flattened bones of the spine (platyspondyly), and joint abnormalities called contractures that further restrict movement.Researchers originally described two types of Schwartz-Jampel syndrome. Type 1 has the signs and symptoms described above, while type 2 has more severe bone abnormalities and other health problems and is usually life-threatening in early infancy. Researchers have since discovered that the condition they thought was Schwartz-Jampel syndrome type 2 is actually part of another disorder, Stüve-Wiedemann syndrome, which is caused by mutations in a different gene. They have recommended that the designation Schwartz-Jampel syndrome type 2 no longer be used.
Takayasu arteritis
MedGen UID:
21458
Concept ID:
C0039263
Disease or Syndrome
A large vessel vasculitis affecting the aorta and its branches. It usually affects young females. It causes vascular obstruction, resulting in asymmetric pulses.
Kugelberg-Welander disease
MedGen UID:
101816
Concept ID:
C0152109
Disease or Syndrome
Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. Before the genetic basis of SMA was understood, it was classified into clinical subtypes; however, it is now apparent that the phenotype of SMA associated with disease-causing mutations of SMN1 spans a continuum without clear delineation of subtypes. Nonetheless, classification by age of onset and maximum function achieved is useful for prognosis and management; subtypes include: SMA 0 (proposed), with prenatal onset and severe joint contractures, facial diplegia, and respiratory failure; SMA I, with onset before age six months; SMA II, with onset between age six and 12 months; SMA III, with onset in childhood after age 12 months and ability to walk at least 25 meters achieved; and SMA IV, with adult onset.
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.
Mitochondrial myopathy
MedGen UID:
56484
Concept ID:
C0162670
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.
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
MedGen UID:
56485
Concept ID:
C0162671
Disease or Syndrome
MELAS syndrome, comprising mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with a variable clinical phenotype. The disorder is accompanied by features of central nervous system involvement, including seizures, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting (Pavlakis et al., 1984; Montagna et al., 1988). Other mitochondrial encephalomyopathies include Leigh syndrome (LS; 256000), Kearns-Sayre syndrome (KSS; 530000), MERRF syndrome (545000), and Leber optic atrophy (535000).
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.
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.
Hypothalamic hypothyroidism
MedGen UID:
113137
Concept ID:
C0220998
Disease or Syndrome
A type of hypothyroidism that results from a defect in thyrotropin-releasing hormone activity.
Degos disease
MedGen UID:
113138
Concept ID:
C0221011
Disease or Syndrome
Variously described as a vasculopathy, endovasculitis, or occlusive arteriopathy, this condition occurs in a benign cutaneous form and a lethal multiorgan systemic variant. It is characterized by a narrowing and occlusion of the lumen of small to medium-sized blood vessels, leading to ischemia and infarction in the involved organ systems. The etiology and pathophysiology are unknown.
Pseudoprimary hyperaldosteronism
MedGen UID:
67439
Concept ID:
C0221043
Disease or Syndrome
Liddle syndrome is an autosomal dominant disorder characterized by early-onset salt-sensitive hypertension, hypokalemia, metabolic alkalosis, and suppression of plasma renin activity and aldosterone secretion (summary by Yang et al., 2014). Hanukoglu and Hanukoglu (2016) provided a detailed review of the ENaC gene family, including structure, function, tissue distribution, and associated inherited diseases.
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.
Freeman-Sheldon syndrome
MedGen UID:
120516
Concept ID:
C0265224
Congenital Abnormality
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Coffin-Lowry syndrome
MedGen UID:
75556
Concept ID:
C0265252
Disease or Syndrome
Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Intellect ranges from normal to profoundly impaired in heterozygous females. The facial appearance is characteristic in the affected, older male child or adult. The hands are short, soft, and fleshy, often with remarkably hyperextensible fingers that taper from wide (proximally) to narrow with small terminal phalanges and nails. Males are consistently below the third centile in height. Microcephaly is common. Cardiac abnormalities may be present and can contribute to premature death. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Progressive kyphoscoliosis is one of the most difficult aspects of long-term care. Life span may be reduced.
Pyle metaphyseal dysplasia
MedGen UID:
82704
Concept ID:
C0265294
Disease or Syndrome
Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by Simsek Kiper et al., 2016).
Bannayan-Riley-Ruvalcaba syndrome
MedGen UID:
78554
Concept ID:
C0265326
Congenital Abnormality
The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome. CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The risk for endometrial cancer may approach 28%. BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis. PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.
Distichiasis-lymphedema syndrome
MedGen UID:
75566
Concept ID:
C0265345
Congenital Abnormality
Lymphedema-distichiasis syndrome is characterized by lower-limb lymphedema and distichiasis (aberrant eyelashes ranging from a full set of extra eyelashes to a single hair). Lymphedema typically appears in late childhood or puberty, is confined to the lower limbs, and is often asymmetric; severity varies within families. Males develop edema at an earlier age and have more problems with cellulitis than females. Distichiasis, which may be present at birth, is observed in 94% of affected individuals. About 75% of affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia; other common findings include varicose veins, congenital heart disease, and ptosis. About 25% of individuals are asymptomatic.
Atrophia bulborum hereditaria
MedGen UID:
75615
Concept ID:
C0266526
Congenital Abnormality
NDP-related retinopathies are characterized by a spectrum of fibrous and vascular changes of the retina at birth that progress through childhood or adolescence to cause varying degrees of visual impairment. The most severe phenotype is described as Norrie disease (ND), characterized by greyish yellow fibrovascular masses (pseudogliomas) secondary to retinal vascular dysgenesis and detachment. Congenital blindness is almost always present. Approximately 30%-50% of males with ND have developmental delay/intellectual disability, behavioral abnormalities, or psychotic-like features. The majority of males with ND develop sensorineural hearing loss. Less severe phenotypes include: persistent hyperplastic primary vitreous (PHPV), characterized by a fibrotic white stalk from the optic disk to the lens; X-linked familial exudative vitreoretinopathy (XL-FEVR), characterized by peripheral retinal vascular anomalies with or without fibrotic changes and retinal detachment; retinopathy of prematurity (ROP); and Coats disease, an exudative proliferative vasculopathy. Phenotypes can vary within families.
Muscle AMP deaminase deficiency
MedGen UID:
78640
Concept ID:
C0268123
Disease or Syndrome
Myoadenylate deaminase deficiency (MMDD) is an autosomal recessive condition that can manifest as exercise-induced muscle pain, occasionally associated with rhabdomyolysis and/or increased serum creatine kinase, or even infantile hypotonia. However, the finding of homozygous mutations among asymptomatic individuals have suggested to some (e.g., Verzijl et al., 1998) that AMPD1 deficiency may be a harmless entity (summary by Castro-Gago et al., 2011). Genetta et al. (2001) stated that AMPD1 deficiency is the most prevalent genetic disease in humans, the number of people heterozygous approaching 10% of Caucasians and individuals of African descent (Sabina et al., 1989). A small percentage of homozygous-deficient individuals, approximately 1.8% of the population, display symptoms of chronic fatigue and lost productivity as well as a predisposition to stress-related ailments, including heart disease and stroke, according to Genetta et al. (2001).
Sialidosis, type II
MedGen UID:
120621
Concept ID:
C0268226
Disease or Syndrome
Sialidosis is an autosomal recessive disorder characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. Common to the sialidoses is the accumulation and/or excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins (summary by Lowden and O'Brien, 1979). The sialidoses are distinct from the sialurias in which there is storage and excretion of 'free' sialic acid, rather than 'bound' sialic acid; neuraminidase activity in sialuria is normal or elevated. Salla disease (604369) is a form of 'free' sialic acid disease. Classification Lowden and O'Brien (1979) provided a logical nosology of neuraminidase deficiency into sialidosis type I and type II. Type I is the milder form, also known as the 'normosomatic' type or the cherry red spot-myoclonus syndrome. Sialidosis type II is the more severe form with an earlier onset, and is also known as the 'dysmorphic' type. Type II has been subdivided into juvenile and infantile forms. Other terms for sialidosis type II are mucolipidosis I and lipomucopolysaccharidosis.
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.
Niemann-Pick disease, type A
MedGen UID:
78650
Concept ID:
C0268242
Disease or Syndrome
Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic (Niemann-Pick disease type A [NPD-A]), with death in early childhood, or non-neuronopathic (Niemann-Pick disease type B [NPD-B]). While forms intermediate to these two extremes occur, all ASM deficiency that is not NPD-A is designated in this review as NPD-B, despite its wide range of manifestations and severity. The first symptom in NPD-A is hepatosplenomegaly, usually noted by age three months; over time the liver and spleen become massive. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year. NPD type B, later in onset and milder in manifestations than NPD type A, is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, and atherogenic lipid profile. Progressive and/or clinically significant neurologic manifestations occur infrequently. Survival to adulthood can occur.
Sphingolipid activator protein 1 deficiency
MedGen UID:
120624
Concept ID:
C0268262
Disease or Syndrome
Metachromatic leukodystrophy is an inherited disorder characterized by the accumulation of fats called sulfatides in cells. This accumulation especially affects cells in the nervous system that produce myelin, the substance that insulates and protects nerves. Nerve cells covered by myelin make up a tissue called white matter. Sulfatide accumulation in myelin-producing cells causes progressive destruction of white matter (leukodystrophy) throughout the nervous system, including in the brain and spinal cord (the central nervous system) and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system).In people with metachromatic leukodystrophy, white matter damage causes progressive deterioration of intellectual functions and motor skills, such as the ability to walk. Affected individuals also develop loss of sensation in the extremities (peripheral neuropathy), incontinence, seizures, paralysis, an inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive. While neurological problems are the primary feature of metachromatic leukodystrophy, effects of sulfatide accumulation on other organs and tissues have been reported, most often involving the gallbladder.The most common form of metachromatic leukodystrophy, affecting about 50 to 60 percent of all individuals with this disorder, is called the late infantile form. This form of the disorder usually appears in the second year of life. Affected children lose any speech they have developed, become weak, and develop problems with walking (gait disturbance). As the disorder worsens, muscle tone generally first decreases, and then increases to the point of rigidity. Individuals with the late infantile form of metachromatic leukodystrophy typically do not survive past childhood.In 20 to 30 percent of individuals with metachromatic leukodystrophy, onset occurs between the age of 4 and adolescence. In this juvenile form, the first signs of the disorder may be behavioral problems and increasing difficulty with schoolwork. Progression of the disorder is slower than in the late infantile form, and affected individuals may survive for about 20 years after diagnosis.The adult form of metachromatic leukodystrophy affects approximately 15 to 20 percent of individuals with the disorder. In this form, the first symptoms appear during the teenage years or later. Often behavioral problems such as alcoholism, drug abuse, or difficulties at school or work are the first symptoms to appear. The affected individual may experience psychiatric symptoms such as delusions or hallucinations. People with the adult form of metachromatic leukodystrophy may survive for 20 to 30 years after diagnosis. During this time there may be some periods of relative stability and other periods of more rapid decline.Metachromatic leukodystrophy gets its name from the way cells with an accumulation of sulfatides appear when viewed under a microscope. The sulfatides form granules that are described as metachromatic, which means they pick up color differently than surrounding cellular material when stained for examination.
Ehlers-Danlos syndrome, procollagen proteinase deficient
MedGen UID:
78662
Concept ID:
C0268345
Disease or Syndrome
EDS type VII is distinguished from the other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement (Byers et al., 1997; Giunta et al., 2008). Beighton et al. (1998) reported on a revised nosology of the Ehlers-Danlos syndromes, designated the Villefranche classification. Major and minor diagnostic criteria were defined for each type and complemented whenever possible with laboratory findings. Six main descriptive types were substituted for earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of 'unspecified forms.'
Hyperphosphatasemia with bone disease
MedGen UID:
75678
Concept ID:
C0268414
Disease or Syndrome
Paget disease of bone-5 is an autosomal recessive, juvenile-onset form of Paget disease, a disorder of the skeleton resulting from abnormal bone resorption and formation. Clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. There is phenotypic variability, with some patients presenting in infancy, while others present later in childhood (summary by Naot et al., 2014). For discussion of genetic heterogeneity of Paget disease of bone, see 167250.
Thyrotoxic periodic paralysis
MedGen UID:
120639
Concept ID:
C0268446
Disease or Syndrome
Thyrotoxic periodic paralysis is a sporadic muscle disorder characterized by episodic attacks of weakness associated with hypokalemia in individuals with hyperthyroidism. The paralysis resolves upon treatment of hyperthyroidism. The disorder is most common among males of Asian descent, including Chinese, Japanese, Vietnamese, Filipino, and Koreans, although it occurs less commonly in individuals of Caucasian background. Thyrotoxic periodic paralysis is clinically similar to hereditary hypokalemic periodic paralysis (HOKPP; 170400), but the paralysis in TTPP occurs only in the presence of hyperthyroidism. TTPP can also be precipitated by factors that result in hypokalemia, such as carbohydrate ingestion and rest after exercise (review by Kung, 2006). Genetic Heterogeneity of Thyrotoxic Periodic Paralysis See also TTPP2 (613239), conferred by variation in the KCNJ18 gene (613236) on chromosome 17p11, and TTPP3 (614834), mapped to chromosome 17q24.
Hypervalinemia
MedGen UID:
120652
Concept ID:
C0268573
Disease or Syndrome
An increased concentration of valine in the blood.
Glutaric aciduria, type 2
MedGen UID:
75696
Concept ID:
C0268596
Disease or Syndrome
Glutaric aciduria II (GA II) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003). The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by Frerman and Goodman, 2001). Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009).
Lysinuric protein intolerance
MedGen UID:
75704
Concept ID:
C0268647
Disease or Syndrome
Lysinuric protein intolerance (LPI) typically presents after an infant is weaned; variable findings include recurrent vomiting and episodes of diarrhea, episodes of stupor and coma after a protein-rich meal, poor feeding, aversion to protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia. Over time, findings include: poor growth; osteoporosis; involvement of the lungs (progressive interstitial changes; pulmonary alveolar proteinosis) and of kidneys (progressive glomerular and proximal tubular disease); hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis at the bone marrow aspirate) and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Acute pancreatitis can also be seen.
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.
Cronkhite-Canada syndrome
MedGen UID:
129128
Concept ID:
C0282207
Disease or Syndrome
Cronkhite-Canada syndrome is characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, skin hyperpigmentation, and diarrhea. It is associated with high morbidity (summary by Sweetser et al., 2012).
Idiopathic livedo reticularis with systemic involvement
MedGen UID:
76449
Concept ID:
C0282492
Disease or Syndrome
Sneddon syndrome is a noninflammatory arteriopathy characterized by onset of livedo reticularis in the second decade and onset of cerebrovascular disease in early adulthood (summary by Bras et al., 2014). Livedo reticularis occurs also with polyarteritis nodosa, systemic lupus erythematosus, and central thrombocythemia, any one of which may be accompanied by cerebrovascular accidents (Bruyn et al., 1987).
Fanconi renotubular syndrome 1
MedGen UID:
137960
Concept ID:
C0341703
Disease or Syndrome
Fanconi renotubular syndrome is a consequence of decreased solute and water reabsorption in the proximal tubule of the kidney. Patients have polydipsia and polyuria with phosphaturia, glycosuria, and aminoaciduria. They may develop hypophosphatemic rickets or osteomalacia, acidosis, and a tendency toward dehydration. Some will eventually develop renal insufficiency. Common laboratory abnormalities include glucosuria with a normal serum glucose, hyperaminoaciduria, hypophosphatemia, progressive renal insufficiency, renal sodium and potassium wasting, acidosis, uricosuria, and low-molecular-weight proteinuria (summary by Lichter-Konecki et al., 2001). Genetic Heterogeneity of Fanconi Renotubular Syndrome Fanconi renotubular syndrome-1 has been mapped to chromosome 15q15.3. See also FRTS2 (613388), caused by mutation in the SLC34A1 gene (182309) on chromosome 5q35; FRTS3 (615605), caused by mutation in the EHHADH gene (607037) on chromosome 3q27; and FRTS4 (616026), which is associated with maturity-onset diabetes of the young (MODY), caused by mutation in the HNF4A gene (600281) on chromosome 20q13.
Diabetes-deafness syndrome maternally transmitted
MedGen UID:
90979
Concept ID:
C0342289
Congenital Abnormality
Maternally inherited diabetes-deafness syndrome (MIDD) is a mitochondrial disorder characterized by onset of sensorineural hearing loss and diabetes in adulthood. Some patients may have additional features observed in mitochondrial disorders, including pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, renal problems, and neuropsychiatric symptoms (Ballinger et al., 1992; Reardon et al., 1992; Guillausseau et al., 2001). The association of diabetes and deafness is observed with Wolfram syndrome (see 222300), Rogers syndrome (249270), and Herrmann syndrome (172500), but all 3 of these disorders have other clinical manifestations.
Autosomal dominant hypophosphatemic rickets
MedGen UID:
83346
Concept ID:
C0342642
Congenital Abnormality
Autosomal dominant hypophosphatemic rickets is characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses. In contrast to X-linked dominant hypophosphatemic rickets (XLH; 307800), ADHR shows incomplete penetrance, variable age at onset (childhood to adult), and resolution of the phosphate-wasting defect in rare cases (Econs et al., 1997). See also hypophosphatemic bone disease (146350). Genetic Heterogeneity of Hypophosphatemic Rickets Other forms of hypophosphatemic rickets include an autosomal recessive forms, i.e., ARHR1 (241520), caused by mutation in the DMP1 gene (600980) on chromosome 4q21, and ARHR2 (613312), caused by mutation in the ENPP1 gene (173335) on chromosome 6q22-q23. An X-linked dominant form (307800) is caused by mutation in the PHEX gene (300550), and an X-linked recessive form (300554) is caused by mutation in the CLCN5 gene (300008). Clinical Variability of Hypophosphatemic Rickets Hypophosphatemic rickets can be caused by disorders of vitamin D metabolism or action (see VDDR1A, 264700). A form of hypophosphatemic rickets with hypercalciuria (HHRH; 241530) is caused by mutation in the SLC34A3 gene (609826), and there is evidence that a form of hypophosphatemic rickets with hyperparathyroidism (612089) may be caused by a translocation that results in an increase in alpha-klotho levels (KLOTHO; 604824).
Autosomal recessive hypophosphatemic bone disease
MedGen UID:
87448
Concept ID:
C0342645
Disease or Syndrome
Hereditary hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006).
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.
Very long chain acyl-CoA dehydrogenase deficiency
MedGen UID:
87459
Concept ID:
C0342784
Disease or Syndrome
Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial ß-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multi-organ failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.
Renal carnitine transport defect
MedGen UID:
90999
Concept ID:
C0342788
Disease or Syndrome
Systemic primary carnitine deficiency (CDSP) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. It encompasses a broad clinical spectrum including: Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis; Childhood myopathy involving heart and skeletal muscle with onset between age two and four years; Fatigability in adulthood; or Absence of symptoms. The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants.
Carnitine acylcarnitine translocase deficiency
MedGen UID:
91000
Concept ID:
C0342791
Disease or Syndrome
Carnitine-acylcarnitine translocase deficiency is a rare autosomal recessive metabolic disorder of long-chain fatty acid oxidation. Metabolic consequences include hypoketotic hypoglycemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have been reported (summary by Rubio-Gozalbo et al., 2004).
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.
Spinal muscular atrophy, type II
MedGen UID:
95975
Concept ID:
C0393538
Disease or Syndrome
Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. Before the genetic basis of SMA was understood, it was classified into clinical subtypes; however, it is now apparent that the phenotype of SMA associated with disease-causing mutations of SMN1 spans a continuum without clear delineation of subtypes. Nonetheless, classification by age of onset and maximum function achieved is useful for prognosis and management; subtypes include: SMA 0 (proposed), with prenatal onset and severe joint contractures, facial diplegia, and respiratory failure; SMA I, with onset before age six months; SMA II, with onset between age six and 12 months; SMA III, with onset in childhood after age 12 months and ability to walk at least 25 meters achieved; and SMA IV, with adult onset.
X-linked hereditary motor and sensory neuropathy
MedGen UID:
98290
Concept ID:
C0393808
Disease or Syndrome
Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families.
Hereditary liability to pressure palsies
MedGen UID:
98291
Concept ID:
C0393814
Disease or Syndrome
Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop. The first attack usually occurs in the second or third decade. Recovery from acute neuropathy is often complete; when recovery is not complete, the resulting disability is usually mild. Some affected individuals also have signs of a mild to moderate peripheral neuropathy.
McLeod neuroacanthocytosis syndrome
MedGen UID:
140765
Concept ID:
C0398568
Disease or Syndrome
McLeod neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, and hematologic manifestations in males. CNS manifestations are a neurodegenerative basal ganglia disease including (1) movement disorders, (2) cognitive alterations, and (3) psychiatric symptoms. Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees. Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod) that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Allo-antibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers. Females heterozygous for XK pathogenic variants have mosaicism for the Kell and Kx blood group antigens but usually lack CNS and neuromuscular manifestations; however, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline.
Microcephaly, normal intelligence and immunodeficiency
MedGen UID:
140771
Concept ID:
C0398791
Congenital Abnormality
Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, an increased risk for cancer, and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild to moderate intellectual disability. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Approximately 40% of affected individuals have developed malignancies before age 20 years, with the risk being highest for T-cell (55%) and B-cell lymphomas (45%). Other tumors include T-cell lymphoma and solid tumors (e.g., medulloblastoma, glioma, and rhabdomyosarcoma). Note, however, that much of what is reported about NBS is based on individuals who are homozygous for the single most common Eastern European pathogenic variant, 657_661del5.
Fukuyama congenital muscular dystrophy
MedGen UID:
140820
Concept ID:
C0410174
Disease or Syndrome
Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and CNS migration disturbances that result in changes consistent with cobblestone (previously type II) lissencephaly with cerebral and cerebellar cortical dysplasia. Mild, typical, and severe phenotypes are recognized. Onset typically occurs in early infancy, with a poor suck, weak cry, and floppiness. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech retardation, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement in individuals older than age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death.
Scapulohumeral muscular dystrophy
MedGen UID:
98373
Concept ID:
C0410192
Disease or Syndrome
Progressive pseudorheumatoid dysplasia
MedGen UID:
96581
Concept ID:
C0432215
Congenital Abnormality
Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness and enlargement in the absence of inflammation. Onset – typically between ages three and six years – begins with the involvement of the interphalangeal joints. Over time, involvement of large joints and the spine causes significant joint contractures, gait disturbance, and scoliosis and/or kyphosis, resulting in abnormal posture and significant morbidity. Despite the considerable arthropathy, pain is not a major presenting feature of this condition.
Singleton-Merten syndrome
MedGen UID:
98481
Concept ID:
C0432254
Disease or Syndrome
Muscle eye brain disease
MedGen UID:
105341
Concept ID:
C0457133
Congenital Abnormality
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. Affected infants typically appear "floppy" with low muscle tone and poor spontaneous movements. Affected children may present with delay or arrest of gross motor development together with joint and/or spinal rigidity. Muscle weakness may improve, worsen, or stabilize in the short term; however, with time progressive weakness and joint contractures, spinal deformities, and respiratory compromise may affect quality of life and life span. The main CMD subtypes, grouped by involved protein function and gene in which causative allelic variants occur, are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutation of POMT1, POMT2, FKTN, FKRP, LARGE1, POMGNT1, and ISPD), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). Several less known CMD subtypes have been reported in a limited number of individuals. Cognitive impairment ranging from intellectual disability to mild cognitive delay, structural brain and/or eye abnormalities, and seizures are found almost exclusively in the dystroglycanopathies while white matter abnormalities without major cognitive involvement tend to be seen in the laminin alpha-2-deficient subtype.
Amyotrophic lateral sclerosis-parkinsonism/dementia complex 1
MedGen UID:
107775
Concept ID:
C0543859
Disease or Syndrome
Amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam is a neurodengenerative disorder with unusually high incidence among the Chamorro people of Guam. Both ALS and parkinsonism-dementia are chronic, progressive, and uniformly fatal disorders in this population. Both diseases are known to occur in the same kindred, the same sibship, and even the same individual.
Cockayne syndrome 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.
Congenital myotonia, autosomal recessive form
MedGen UID:
155852
Concept ID:
C0751360
Disease or Syndrome
Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the “warm-up” phenomenon). Muscles are usually hypertrophic. The autosomal recessive form of myotonia congenita is often associated with more severe symptoms than the autosomal dominant form. Individuals with the autosomal recessive form may have progressive, minor distal weakness and attacks of transient weakness brought on by movement after rest. The age of onset is variable: in autosomal dominant myotonia congenita, onset of symptoms is usually in infancy or early childhood; in the autosomal recessive form, the average age of onset is slightly older. In both, onset may be as late as the third or fourth decade of life.
Cowchock syndrome
MedGen UID:
162891
Concept ID:
C0795910
Disease or Syndrome
Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy. The affected individual typically has distal muscle weakness and atrophy often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet.
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.
Worster Drought syndrome
MedGen UID:
163228
Concept ID:
C0796204
Disease or Syndrome
A syndrome with variable expression characterized by suprabulbar paresis, selective weakness and impairment of movement of the orbicularis oris muscle, tongue, and soft palate, resulting in speech and swallowing difficulty.
Danon disease
MedGen UID:
209235
Concept ID:
C0878677
Disease or Syndrome
Danon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease; 232300) with 'normal acid maltase' or alpha-glucosidase (GAA; 606800) (Danon et al., 1981). However, Nishino et al. (2000) stated that Danon disease is not a glycogen storage disease because glycogen is not always increased. Sugie et al. (2005) classified Danon disease as a form of autophagic vacuolar myopathy, characterized by intracytoplasmic autophagic vacuoles with sarcolemmal features. The characteristic vacuole is believed to be an autolysosome surrounded by secondarily-generated membranes containing sarcolemmal proteins, basal lamina, and acetylcholinesterase activity. X-linked myopathy with excessive autophagy (XMEA; 310440) is a distinct disorder with similar pathologic features.
Becker muscular dystrophy
MedGen UID:
182959
Concept ID:
C0917713
Disease or Syndrome
The dystrophinopathies include a spectrum of muscle disease caused by pathogenic variants in DMD, which encodes the protein dystrophin. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed milestones, including delays in sitting and standing independently. Proximal weakness causes a waddling gait and difficulty climbing. DMD is rapidly progressive, with affected children being wheelchair dependent by age 13 years. Cardiomyopathy occurs in individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness; some individuals remain ambulatory into their 20s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.
Spinal arachnoiditis
MedGen UID:
318191
Concept ID:
C1710146
Disease or Syndrome
A chronic adhesive arachnoiditis in the spinal arachnoid, with root and spinal cord symptoms similar to those caused by pressure from a tumor.
Episodic ataxia type 2
MedGen UID:
314039
Concept ID:
C1720416
Disease or Syndrome
Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia, vertigo, and nausea typically lasting minutes to days in duration. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache. About 50% of individuals with EA2 have migraine headaches. Onset is typically in childhood or early adolescence (age range 2-32 years). Frequency of attacks can range from once or twice a year to three or four times a week. Attacks can be triggered by stress, exertion, caffeine, alcohol, fever, heat, and phenytoin; they can be stopped or decreased in frequency and severity by administration of acetazolamide or 4-aminopyridine. Between attacks, individuals may initially be asymptomatic but commonly develop interictal findings that can include nystagmus, pursuit and saccade alterations, and ataxia.
Permanent neonatal diabetes mellitus
MedGen UID:
371484
Concept ID:
C1833104
Disease or Syndrome
Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include intrauterine growth retardation, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. The course of PNDM varies by genotype.
Carnitine palmitoyltransferase II deficiency, late-onset
MedGen UID:
371584
Concept ID:
C1833508
Disease or Syndrome
Carnitine palmitoyltransferase II (CPT II) deficiency is a disorder of long-chain fatty-acid oxidation. The three clinical presentations are: lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form (which is usually mild and can manifest from infancy to adulthood). While the former two are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death, the latter is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. Males are more likely to be affected than females.
Amyotrophy, hereditary neuralgic
MedGen UID:
320318
Concept ID:
C1834304
Disease or Syndrome
Hereditary neuralgic amyotrophy (HNA) is characterized by sudden onset of severe, non-abating pain in the shoulder girdle and/or the upper limb and amyotrophy (muscle wasting or atrophy) that typically develops within two weeks of the onset of severe pain. Other sites may also be involved in an attack; sensory symptoms, present in the majority of affected individuals, can include hypoesthesia (decreased sensation) and paresthesias. Onset is typically in the second or third decade (median age 28 years). Although attacks appear to become less frequent with age, residual deficits accumulate with subsequent attacks. In some families, non-neurologic findings (characteristic craniofacial features, bifid uvula or cleft palate, short stature, and/or partial syndactyly of the fingers or toes) are present.
Myoglobinuria, autosomal dominant
MedGen UID:
320384
Concept ID:
C1834567
Disease or Syndrome
Muscular hypoplasia, congenital universal, of krabbe
MedGen UID:
320398
Concept ID:
C1834651
Disease or Syndrome
Muscular dystrophy, pseudohypertrophic, with internalized capillaries
MedGen UID:
320399
Concept ID:
C1834652
Disease or Syndrome
Keratoderma palmoplantar spastic paralysis
MedGen UID:
322722
Concept ID:
C1835671
Disease or Syndrome
Aminoacylase 1 deficiency
MedGen UID:
324393
Concept ID:
C1835922
Disease or Syndrome
Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by Ferri et al., 2014).
Rhabdoid tumor predisposition syndrome 1
MedGen UID:
322892
Concept ID:
C1836327
Neoplastic Process
The rhabdoid tumor predisposition syndrome is an autosomal dominant cancer syndrome predisposing to renal or extrarenal malignant rhabdoid tumors and to a variety of tumors of the central nervous system, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumors (Sevenet et al., 1999). Rhabdoid tumors are a highly malignant group of neoplasms that usually occur in children less than 2 years of age. Malignant rhabdoid tumors (MRTs) of the kidney were first described as a sarcomatous variant of Wilms tumors (Beckwith and Palmer, 1978). Later, extrarenal rhabdoid tumor was reported in numerous locations, including the central nervous system (CNS) (Parham et al., 1994). Classification has been difficult because of considerable variation in the histologic and immunologic characteristics within and between rhabdoid tumors of the liver, soft tissues, and CNS. In the CNS, rhabdoid tumors may be pure rhabdoid tumors or a variant that has been designated atypical teratoid tumor (AT/RT).
Schindler disease, type 1
MedGen UID:
373113
Concept ID:
C1836544
Disease or Syndrome
Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy; type II, also known as Kanzaki disease (609242), is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder with mild to moderate neurologic manifestations (Desnick and Schindler, 2001).
Vitamin d hydroxylation-deficient rickets, type 1b
MedGen UID:
374020
Concept ID:
C1838657
Disease or Syndrome
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), NDUFAF1 (606934), and TMEM126B (615533). 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).
Spastic paraplegia 2
MedGen UID:
374177
Concept ID:
C1839264
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.
Fragile X tremor/ataxia syndrome
MedGen UID:
333403
Concept ID:
C1839780
Disease or Syndrome
FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related primary ovarian insufficiency (POI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function mutation and is nearly always characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Because FMR1 mutations are complex alterations involving non-classic gene-disrupting alterations (trinucleotide repeat expansion) and abnormal gene methylation, affected individuals occasionally have an atypical presentation with an IQ above 70, the traditional demarcation denoting intellectual disability (previously referred to as mental retardation). Males with an FMR1 full mutation accompanied by aberrant methylation may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), connective tissue findings (joint laxity), and large testes after puberty. Behavioral abnormalities, sometimes including autism spectrum disorder, are common. FXTAS occurs in males (and some females) who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor. FMR1-related POI (age at cessation of menses <40 years) occurs in approximately 20% of females who have an FMR1 premutation.
Corpus callosum, partial agenesis of, X-linked
MedGen UID:
374339
Concept ID:
C1839909
Disease or Syndrome
L1 syndrome is an inherited disorder that primarily affects the nervous system. L1 syndrome involves a variety of features that were once thought to be distinct disorders, but are now considered to be part of the same syndrome. The most common characteristics of L1 syndrome are muscle stiffness (spasticity) of the lower limbs, intellectual disability, increased fluid in the center of the brain (hydrocephalus), and thumbs bent toward the palm (adducted thumbs). People with L1 syndrome can also have difficulty speaking (aphasia), seizures, and underdeveloped or absent tissue connecting the left and right halves of the brain (agenesis of the corpus callosum). The symptoms of L1 syndrome vary widely among affected individuals, even among members of the same family. Because this disorder involves spasticity of the lower limbs, L1 syndrome is sometimes referred to as spastic paraplegia type 1 (SPG1).
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.
Charcot-Marie-Tooth disease, X-linked recessive, type 3
MedGen UID:
375530
Concept ID:
C1844865
Disease or Syndrome
Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy. The affected individual typically has distal muscle weakness and atrophy often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet.
Charcot-Marie-Tooth disease, X-linked recessive, type 2
MedGen UID:
336803
Concept ID:
C1844873
Disease or Syndrome
Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy. The affected individual typically has distal muscle weakness and atrophy often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet.
Spinocerebellar ataxia X-linked type 3
MedGen UID:
337124
Concept ID:
C1844936
Disease or Syndrome
A progressive disorder of the central nervous system characterized by ataxia, deafness, hypotonia, developmental delay, esotropia, and optic atrophy.
Cataracts, ataxia, short stature, and mental retardation
MedGen UID:
375579
Concept ID:
C1845094
Disease or Syndrome
Glycogen storage disease IXd
MedGen UID:
335112
Concept ID:
C1845151
Disease or Syndrome
Glycogen storage disease type IXd is an X-linked recessive, relatively mild metabolic disorder characterized by variable exercise-induced muscle weakness or stiffness. Most patients have adult-onset of symptoms, and some can remain asymptomatic even in late adulthood. The phenotype is usually only apparent with intense exercise (summary by Preisler et al., 2012).
Mental retardation X-linked syndromic 7
MedGen UID:
337403
Concept ID:
C1846170
Disease or Syndrome
Episodic muscle weakness, X-linked
MedGen UID:
337525
Concept ID:
C1846173
Disease or Syndrome
Infantile-onset ascending hereditary spastic paralysis
MedGen UID:
335467
Concept ID:
C1846588
Disease or Syndrome
ALS2-related disorders involve retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP), to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis [JPLS]), to forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis [JALS]). IAHSP is characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome. JPLS is characterized by onset and loss of ability to walk during the second year of life, progressive signs of upper motor neuron disease, wheelchair dependence by adolescence, and later loss of motor speech production. JALS is characterized by onset during childhood (mean age of onset 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, moderate muscle atrophy (variably present), bladder dysfunction, and sensory disturbances; some individuals are bedridden by age 12 to 50 years.
Episodic ataxia, type 3
MedGen UID:
376220
Concept ID:
C1847839
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.
Ehlers-Danlos-like syndrome due to tenascin-X deficiency
MedGen UID:
336244
Concept ID:
C1848029
Disease or Syndrome
Tenascin-X deficiency leads to a clinically distinct form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, hypermobile joints, and tissue fragility. For further background information on EDS, see 130000.
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.
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.
Myoglobinuria, acute recurrent, autosomal recessive
MedGen UID:
340308
Concept ID:
C1849386
Disease or Syndrome
Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis associated with muscle pain and weakness and followed by excretion of myoglobin in the urine. Renal failure may occasionally occur. Onset is usually in early childhood under the age of 5 years. Unlike the exercise-induced rhabdomyolyses such as McArdle syndrome (232600), carnitine palmitoyltransferase deficiency (see 255110), and the Creteil variety of phosphoglycerate kinase deficiency (311800), the attacks in recurrent myoglobinuria no relation to exercise, but are triggered by intercurrent illnesses, commonly upper respiratory tract infections. (Ramesh and Gardner-Medwin, 1992). See 160010 for discussion of a possible autosomal dominant form of myglobinuria. Severe rhabdomyolysis is a major clinical feature of anesthetic-induced malignant hyperthermia (145600), an autosomal dominant disorder.
Pulmonary hypertension, primary, autosomal recessive
MedGen UID:
340354
Concept ID:
C1849552
Disease or Syndrome
Polyglucosan body disease, adult
MedGen UID:
342338
Concept ID:
C1849722
Disease or Syndrome
Adult polyglucosan body disease (APBD) is characterized by adult-onset progressive neurogenic bladder, gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly in the distal lower extremities, and mild cognitive difficulties (often executive dysfunction).
Glycogen storage disease IXb
MedGen UID:
337918
Concept ID:
C1849812
Disease or Syndrome
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth retardation, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). Symptoms and biochemical abnormalities of liver PhK deficiency are thought to improve with age.
Ophthalmoplegic neuromuscular disorder with abnormal mitochondria
MedGen UID:
340508
Concept ID:
C1850302
Disease or Syndrome
Nakajo syndrome
MedGen UID:
376827
Concept ID:
C1850568
Disease or Syndrome
This autosomal recessive systemic autoinflammatory disorder is characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011). This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions.
Native American myopathy
MedGen UID:
340586
Concept ID:
C1850625
Disease or Syndrome
Native American myopathy (NAM) is an autosomal recessive disorder characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, myopathic facies, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia provoked by anesthesia. It was first reported in the Lumbee Indian tribe in North Carolina (summary by Stamm et al., 2008).
Myopathy with lactic acidosis, hereditary
MedGen UID:
342573
Concept ID:
C1850718
Disease or Syndrome
Myopathy with deficiency of ISCU, a mitochondrial myopathy, is classically characterized by lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles; episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe; and typically full recovery of muscle strength between episodes of rhabdomyolysis. Affected individuals usually have near-normal strength; they can have large calves.
Myopathy, granulovacuolar lobular, with electrical myotonia
MedGen UID:
338114
Concept ID:
C1850745
Disease or Syndrome
Muscular dystrophy, congenital, with rapid progression
MedGen UID:
338135
Concept ID:
C1850840
Disease or Syndrome
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. Affected infants typically appear "floppy" with low muscle tone and poor spontaneous movements. Affected children may present with delay or arrest of gross motor development together with joint and/or spinal rigidity. Muscle weakness may improve, worsen, or stabilize in the short term; however, with time progressive weakness and joint contractures, spinal deformities, and respiratory compromise may affect quality of life and life span. The main CMD subtypes, grouped by involved protein function and gene in which causative allelic variants occur, are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutation of POMT1, POMT2, FKTN, FKRP, LARGE1, POMGNT1, and ISPD), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). Several less known CMD subtypes have been reported in a limited number of individuals. Cognitive impairment ranging from intellectual disability to mild cognitive delay, structural brain and/or eye abnormalities, and seizures are found almost exclusively in the dystroglycanopathies while white matter abnormalities without major cognitive involvement tend to be seen in the laminin alpha-2-deficient subtype.
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.
Nemaline myopathy 7
MedGen UID:
343979
Concept ID:
C1853154
Disease or Syndrome
Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. The clinical classification defines six forms of NM, which are classified by onset and severity of motor and respiratory involvement: Severe congenital (neonatal) (16% of all individuals with NM). Amish NM. Intermediate congenital (20%). Typical congenital (46%). Childhood-onset (13%). Adult-onset (late-onset) (4%). Considerable overlap occurs among the forms. There are significant differences in survival between individuals classified as having severe, intermediate, and typical congenital NM. Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life. Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk.
Juvenile primary lateral sclerosis
MedGen UID:
342870
Concept ID:
C1853396
Disease or Syndrome
ALS2-related disorders involve retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprise a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP), to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis [JPLS]), to forms with lower motor neuron involvement (autosomal recessive juvenile amyotrophic lateral sclerosis [JALS]). IAHSP is characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome. JPLS is characterized by onset and loss of ability to walk during the second year of life, progressive signs of upper motor neuron disease, wheelchair dependence by adolescence, and later loss of motor speech production. JALS is characterized by onset during childhood (mean age of onset 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, moderate muscle atrophy (variably present), bladder dysfunction, and sensory disturbances; some individuals are bedridden by age 12 to 50 years.
Spondyloocular syndrome, autosomal recessive
MedGen UID:
343011
Concept ID:
C1853925
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome 1
MedGen UID:
343044
Concept ID:
C1854052
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (summary by Seyda et al., 2001). Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome See also MMDS2 (614299), caused by mutation in the BOLA3 gene (613183) on chromosome 2p13; MMDS3 (615330), caused by mutation in the IBA57 gene (615316) on chromosome 1q42; and MMDS4 (616370), caused by mutation in the ISCA2 gene (615317) on chromosome 14q24.
Muscular dystrophy, adult-onset, with leukoencephalopathy
MedGen UID:
340269
Concept ID:
C1854646
Disease or Syndrome
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).
Mitochondrial myopathy with a defect in mitochondrial-protein transport
MedGen UID:
381541
Concept ID:
C1855034
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.
Kaufman oculocerebrofacial syndrome
MedGen UID:
343403
Concept ID:
C1855663
Disease or Syndrome
Homocysteinemia due to MTHFR deficiency
MedGen UID:
383829
Concept ID:
C1856058
Disease or Syndrome
Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. In the classic form, both thermostable and thermolabile enzyme variants have been identified (Rosenblatt et al., 1992).
3-methylglutaconic aciduria type V
MedGen UID:
347542
Concept ID:
C1857776
Disease or Syndrome
3-Methylglutaconic aciduria type V is an autosomal recessive disorder characterized by the onset of dilated or noncompaction cardiomyopathy in infancy or early childhood. Many patients die of cardiac failure. Other features include microcytic anemia, growth retardation, mild ataxia, mild muscle weakness, genital anomalies in males, and increased urinary excretion of 3-methylglutaconic acid. Some patients may have optic atrophy or delayed psychomotor development (summary by Davey et al., 2006 and Ojala et al., 2012). For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).
Cataract and cardiomyopathy
MedGen UID:
395228
Concept ID:
C1859317
Disease or Syndrome
Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).
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.
Stiff skin syndrome
MedGen UID:
348877
Concept ID:
C1861456
Disease or Syndrome
Stiff skin syndrome is characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness (Loeys et al., 2010). Patients with similar phenotypes involving stiff skin have been described; see, e.g., familial progressive scleroderma (181750), symmetric lipomatosis (151800), and congenital fascial dystrophy (228020).
Frontotemporal dementia and/or amyotrophic lateral sclerosis
MedGen UID:
350795
Concept ID:
C1862937
Disease or Syndrome
Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) is an autosomal dominant neurodegenerative disorder characterized by adult onset of one or both of these features in an affected individual, with significant intrafamilial variation. The disorder is genetically and pathologically heterogeneous (summary by Vance et al., 2006). Patients with C9ORF72 repeat expansions tend to show a lower age of onset, shorter survival, bulbar symptom onset, increased incidence of neurodegenerative disease in relatives, and a propensity toward psychosis or hallucinations compared to patients with other forms of ALS and/or FTD (summary by Harms et al., 2013). Patients with C9ORF72 repeat expansions also show psychiatric disturbances that may predate the onset of dementia (Meisler et al., 2013; Gomez-Tortosa et al., 2013). For a general phenotypic description of frontotemporal dementia, also known as frontotemporal lobar degeneration (FTLD), see 600274. For a general discussion of motor neuron disease (MND), see amyotrophic lateral sclerosis-1 (ALS1; 105400). Genetic Heterogeneity of Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis See also FTDALS2 (615911), caused by mutation in the CHCHD10 gene (615903) on chromosome 22q11; FTDALS3 (616437), caused by mutation in the SQSTM1 gene (601530) on chromosome 5q35; and FTDALS4 (616439), caused by mutation in the TBK1 gene (604834) on chromosome 12q14.
Amyotrophic lateral sclerosis type 1
MedGen UID:
400169
Concept ID:
C1862939
Disease or Syndrome
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Initial presentation varies. Affected individuals typically present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and labile affect, but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. The mean age of onset is 56 years in individuals with no known family history and 46 years in individuals with more than one affected family member (familial ALS or FALS). Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles.
Myoadenylate Deaminase Deficiency, Myopathy due to
MedGen UID:
354933
Concept ID:
C1863229
Disease or Syndrome
MADA DEFICIENCY
MedGen UID:
350116
Concept ID:
C1863231
Disease or Syndrome
Combined oxidative phosphorylation deficiency 3
MedGen UID:
355842
Concept ID:
C1864840
Disease or Syndrome
Neuropathy, hereditary thermosensitive
MedGen UID:
355568
Concept ID:
C1865856
Disease or Syndrome
Paramyotonia congenita of von Eulenburg
MedGen UID:
358367
Concept ID:
C1868617
Disease or Syndrome
Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements.Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling.
Multiple sclerosis susceptibility 1
MedGen UID:
358269
Concept ID:
C1868685
Finding
Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) of unknown etiology. The peak onset is between age 20 and 40 years; it may develop in children and has also been identified in persons older than age 60 years. Women are affected approximately twice as often as men. The most common clinical signs and symptoms, occurring in isolation or in combination, include sensory disturbance of the limbs (~30%), partial or complete visual loss (~15%), acute and subacute motor dysfunction of the limbs (~13%), diplopia (7%), and gait dysfunction (5%). The course may be relapsing-remitting or progressive, severe or mild, and may involve the entire neuroaxis in a widespread fashion or predominantly affect the spinal cord and optic nerves. The four clinical phenotypes of MS are: relapsing-remitting MS (RR-MS) (initially occurring in more than 80% of individuals with MS); primary progressive MS (PP-MS) (occurring in 10%-20% of individuals with MS); progressive relapsing MS (PR-MS) (a rare form); and secondary progressive MS (SP-MS), to which approximately half of all persons diagnosed with RR-MS convert within a decade after the initial diagnosis.
Temporal arteritis
MedGen UID:
365495
Concept ID:
C1956391
Disease or Syndrome
An autoimmune, systemic, giant cell granulomatous arteritis predominantly involving the arteries that supply blood to the central nervous system, head and eyes. Superficial arteries of the scalp that are involved tend to be enlarged and tender. Signs and symptoms include headaches, myalgias, visual disturbances, and skin necrosis.
Acyl-CoA dehydrogenase family, member 9, deficiency of
MedGen UID:
370195
Concept ID:
C1970173
Disease or Syndrome
ACAD9 deficiency is an autosomal recessive multisystemic disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010). For a general description and a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
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.
Spastic paraplegia 42, autosomal dominant
MedGen UID:
393407
Concept ID:
C2675528
Disease or Syndrome
Episodic ataxia, type 7
MedGen UID:
383209
Concept ID:
C2677843
Disease or Syndrome
Episodic ataxia is a group of related conditions that affect the nervous system and cause problems with movement. People with episodic ataxia have recurrent episodes of poor coordination and balance (ataxia). During these episodes, many people also experience dizziness (vertigo), nausea and vomiting, migraine headaches, blurred or double vision, slurred speech, and ringing in the ears (tinnitus). Seizures, muscle weakness, and paralysis affecting one side of the body (hemiplegia) may also occur during attacks. Additionally, some affected individuals have a muscle abnormality called myokymia during or between episodes. This abnormality can cause muscle cramping, stiffness, and continuous, fine muscle twitching that appears as rippling under the skin.Episodes of ataxia and other symptoms can begin anytime from early childhood to adulthood. They can be triggered by environmental factors such as emotional stress, caffeine, alcohol, certain medications, physical activity, and illness. The frequency of attacks ranges from several per day to one or two per year. Between episodes, some affected individuals continue to experience ataxia, which may worsen over time, as well as involuntary eye movements called nystagmus.Researchers have identified at least seven types of episodic ataxia, designated type 1 through type 7. The types are distinguished by their pattern of signs and symptoms, age of onset, length of attacks, and, when known, genetic cause.
Mental retardation and microcephaly with pontine and cerebellar hypoplasia
MedGen UID:
437070
Concept ID:
C2677903
Disease or Syndrome
Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder affecting females and characterized by severe intellectual disability, microcephaly, and variable degrees of pontocerebellar hypoplasia. Affected individuals have very poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss or eye anomalies. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (summary by Moog et al., 2011).
Congenital muscular dystrophy, LMNA-related
MedGen UID:
413043
Concept ID:
C2750785
Disease or Syndrome
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. Affected infants typically appear "floppy" with low muscle tone and poor spontaneous movements. Affected children may present with delay or arrest of gross motor development together with joint and/or spinal rigidity. Muscle weakness may improve, worsen, or stabilize in the short term; however, with time progressive weakness and joint contractures, spinal deformities, and respiratory compromise may affect quality of life and life span. The main CMD subtypes, grouped by involved protein function and gene in which causative allelic variants occur, are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutation of POMT1, POMT2, FKTN, FKRP, LARGE1, POMGNT1, and ISPD), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). Several less known CMD subtypes have been reported in a limited number of individuals. Cognitive impairment ranging from intellectual disability to mild cognitive delay, structural brain and/or eye abnormalities, and seizures are found almost exclusively in the dystroglycanopathies while white matter abnormalities without major cognitive involvement tend to be seen in the laminin alpha-2-deficient subtype.
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.
Congenital disorder of glycosylation type 1O
MedGen UID:
414534
Concept ID:
C2752007
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.
Congenital disorder of glycosylation type 1t
MedGen UID:
414536
Concept ID:
C2752015
Disease or Syndrome
Congenital disorder of glycosylation type It (CDG1T) is an autosomal recessive disorder characterized by a wide range of clinical manifestations and severity. The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism (summary by Tegtmeyer et al., 2014). For a discussion of the classification of CDGs, see CDG1A (212065).
Neurofibromatosis-Noonan syndrome
MedGen UID:
419089
Concept ID:
C2931482
Disease or Syndrome
Deficiency of AMP deaminase
MedGen UID:
444140
Concept ID:
C2931781
Disease or Syndrome
Fanconi renotubular syndrome 2
MedGen UID:
462002
Concept ID:
C3150652
Disease or Syndrome
Amyotrophic lateral sclerosis type 12
MedGen UID:
462042
Concept ID:
C3150692
Disease or Syndrome
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Initial presentation varies. Affected individuals typically present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and labile affect, but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. The mean age of onset is 56 years in individuals with no known family history and 46 years in individuals with more than one affected family member (familial ALS or FALS). Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles.
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).
Glycogen storage disease XV
MedGen UID:
462104
Concept ID:
C3150754
Disease or Syndrome
Limb-girdle muscular dystrophy, type 1H
MedGen UID:
462136
Concept ID:
C3150786
Disease or Syndrome
Limb-girdle muscular dystrophy type 1H (LGMD1H) is an autosomal dominant disorder characterized by adult onset of progressive proximal muscle weakness affecting both the upper and lower limbs (Bisceglia et al., 2010). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMD1A (159000).
Striatal necrosis, bilateral, and progressive polyneuropathy
MedGen UID:
462323
Concept ID:
C3150973
Disease or Syndrome
Thiamine metabolism dysfunction syndrome-4 is an autosomal recessive metabolic disorder characterized by childhood onset of episodic encephalopathy, often associated with a febrile illness, and causing transient neurologic dysfunction. Most patients recover fully, but some may have mild residual weakness. Affected individuals also develop a slowly progressive axonal polyneuropathy beginning in childhood. Brain imaging during the acute episodes shows lesions consistent with bilateral striatal degeneration or necrosis (summary by Spiegel et al., 2009). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Hypomagnesemia 6, renal
MedGen UID:
462645
Concept ID:
C3151295
Disease or Syndrome
Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia
MedGen UID:
462753
Concept ID:
C3151403
Disease or Syndrome
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Initial presentation varies. Affected individuals typically present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and labile affect, but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. The mean age of onset is 56 years in individuals with no known family history and 46 years in individuals with more than one affected family member (familial ALS or FALS). Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles.
D-2-hydroxyglutaric aciduria 1
MedGen UID:
463405
Concept ID:
C3152055
Disease or Syndrome
D-2-hydroxyglutaric aciduria is a neurometabolic disorder first described by Chalmers et al. (1980). Clinical symptoms include developmental delay, epilepsy, hypotonia, and dysmorphic features. Mild and severe phenotypes were characterized (van der Knaap et al., 1999). The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and, often, cardiomyopathy. The mild phenotype has a more variable clinical presentation. Genetic Heterogeneity of D-2-Hydroxyglutaric Aciduria D-2-hydroxyglutaric aciduria-2 (D2HGA2; 613657) is caused by heterozygous mutation in the mitochondrial isocitrate dehydrogenase-2 gene (IDH2; 147650) on chromosome 15q26.
Myopathy, distal, 4
MedGen UID:
481352
Concept ID:
C3279722
Disease or Syndrome
Williams distal myopathy is an autosomal dominant slowly progressive muscular disorder characterized by distal muscle weakness and atrophy affecting the upper and lower limbs. Onset occurs around the third to fourth decades of life, and patients remain ambulatory even after long disease duration. Muscle biopsy shows nonspecific changes with no evidence of rods, necrosis, or inflammation (summary by Duff et al., 2011). Mutation in the FLNC gene can also cause myofibrillar myopathy-5 (MFM5; 609524), which shows a different pattern of muscle involvement and different histologic changes.
Multiple mitochondrial dysfunctions syndrome 2
MedGen UID:
482008
Concept ID:
C3280378
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).
Peripheral neuropathy, myopathy, hoarseness, and hearing loss
MedGen UID:
482186
Concept ID:
C3280556
Disease or Syndrome
Myopathy, centronuclear, 3
MedGen UID:
482333
Concept ID:
C3280703
Disease or Syndrome
Spastic ataxia 5, autosomal recessive
MedGen UID:
482607
Concept ID:
C3280977
Disease or Syndrome
Spastic ataxia-5 (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (summary by Pierson et al., 2011). For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600).
Congenital disorder of glycosylation type 2k
MedGen UID:
766485
Concept ID:
C3553571
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.
Amyotrophic lateral sclerosis 18
MedGen UID:
766633
Concept ID:
C3553719
Disease or Syndrome
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Initial presentation varies. Affected individuals typically present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and labile affect, but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. The mean age of onset is 56 years in individuals with no known family history and 46 years in individuals with more than one affected family member (familial ALS or FALS). Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles.
Peroxisome biogenesis disorder 11B
MedGen UID:
766915
Concept ID:
C3554001
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 PEX13 gene have cells of complementation group 13 (CG13, equivalent to CGH). For information on the history of PBD complementation groups, see 214100.
Mitochondrial complex III deficiency, nuclear type 2
MedGen UID:
767519
Concept ID:
C3554605
Disease or Syndrome
Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life (summary by Ghezzi et al., 2011). The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances (Morino et al., 2014; Atwal, 2014; Nogueira et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
MYOPATHY DUE TO MYOADENYLATE DEAMINASE DEFICIENCY
MedGen UID:
811508
Concept ID:
C3714933
Disease or Syndrome
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 14
MedGen UID:
815546
Concept ID:
C3809216
Disease or Syndrome
Mitochondrial DNA depletion syndrome 12 (cardiomyopathic type)
MedGen UID:
815773
Concept ID:
C3809443
Disease or Syndrome
Mitochondrial DNA depletion syndrome-12 is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and accumulation of abnormal mitochondria (summary by Echaniz-Laguna et al., 2012). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).
Charcot-Marie-Tooth disease, axonal, type 2R
MedGen UID:
815985
Concept ID:
C3809655
Disease or Syndrome
Nemaline myopathy 9
MedGen UID:
816714
Concept ID:
C3810384
Disease or Syndrome
Nemaline myopathy-9 is an autosomal recessive muscle disorder characterized by onset of muscle weakness in early infancy. The phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. Muscle biopsy shows typical rod-like structure in myofibers (summary by Gupta et al., 2013). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.
MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 1
MedGen UID:
854774
Concept ID:
C3888106
Finding
Carnitine palmitoyltransferase I deficiency
MedGen UID:
87461
Concept ID:
C0342789
Disease or Syndrome
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation. Clinical manifestations usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased; onset of symptoms is usually rapid. The recognized phenotypes are: acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in CPT1A that causes CPT1A deficiency; and hepatic encephalopathy, in which individuals (typically children) present with hypoketotic hypoglycemia and sudden onset of liver failure. Individuals with hepatic encephalopathy typically present with hypoglycemia, absent or low levels of ketones, and elevated serum concentrations of liver transaminases, ammonia, and total carnitine. Between episodes of hepatic encephalopathy, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage.
Potassium aggravated myotonia
MedGen UID:
156269
Concept ID:
C0752355
Disease or Syndrome
In a report on the 37th ENMC Workshop, Rudel and Lehmann-Horn (1997) stated that the sodium channelopathies can be divided into 3 different forms: paramyotonia, potassium-aggravated myotonia, and periodic paralysis. Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia.
Congenital myotonia, autosomal dominant form
MedGen UID:
422446
Concept ID:
C2936781
Disease or Syndrome
Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the “warm-up” phenomenon). Muscles are usually hypertrophic. The autosomal recessive form of myotonia congenita is often associated with more severe symptoms than the autosomal dominant form. Individuals with the autosomal recessive form may have progressive, minor distal weakness and attacks of transient weakness brought on by movement after rest. The age of onset is variable: in autosomal dominant myotonia congenita, onset of symptoms is usually in infancy or early childhood; in the autosomal recessive form, the average age of onset is slightly older. In both, onset may be as late as the third or fourth decade of life.

Recent clinical studies

Etiology

Lalani SR, Liu P, Rosenfeld JA, Watkin LB, Chiang T, Leduc MS, Zhu W, Ding Y, Pan S, Vetrini F, Miyake CY, Shinawi M, Gambin T, Eldomery MK, Akdemir ZH, Emrick L, Wilnai Y, Schelley S, Koenig MK, Memon N, Farach LS, Coe BP, Azamian M, Hernandez P, Zapata G, Jhangiani SN, Muzny DM, Lotze T, Clark G, Wilfong A, Northrup H, Adesina A, Bacino CA, Scaglia F, Bonnen PE, Crosson J, Duis J, Maegawa GH, Coman D, Inwood A, McGill J, Boerwinkle E, Graham B, Beaudet A, Eng CM, Hanchard NA, Xia F, Orange JS, Gibbs RA, Lupski JR, Yang Y
Am J Hum Genet 2016 Feb 4;98(2):347-57. Epub 2016 Jan 21 doi: 10.1016/j.ajhg.2015.12.008. [Epub ahead of print] PMID: 26805781Free PMC Article
Kharbanda S, Ramakrishna A, Krishnan S
Int J Chron Obstruct Pulmon Dis 2015;10:1727-35. Epub 2015 Sep 1 doi: 10.2147/COPD.S87791. PMID: 26366065Free PMC Article
Lightfoot AP, McArdle A, Jackson MJ, Cooper RG
Ann Rheum Dis 2015 Jul;74(7):1340-6. Epub 2015 Apr 28 doi: 10.1136/annrheumdis-2014-207172. [Epub ahead of print] PMID: 26063809
Cornett KM, North KN, Rose KJ, Burns J
Dev Med Child Neurol 2015 Aug;57(8):733-6. Epub 2015 Apr 23 doi: 10.1111/dmcn.12777. [Epub ahead of print] PMID: 25913846
Øiestad BE, Juhl CB, Eitzen I, Thorlund JB
Osteoarthritis Cartilage 2015 Feb;23(2):171-7. Epub 2014 Nov 1 doi: 10.1016/j.joca.2014.10.008. [Epub ahead of print] PMID: 25450853

Diagnosis

Lalani SR, Liu P, Rosenfeld JA, Watkin LB, Chiang T, Leduc MS, Zhu W, Ding Y, Pan S, Vetrini F, Miyake CY, Shinawi M, Gambin T, Eldomery MK, Akdemir ZH, Emrick L, Wilnai Y, Schelley S, Koenig MK, Memon N, Farach LS, Coe BP, Azamian M, Hernandez P, Zapata G, Jhangiani SN, Muzny DM, Lotze T, Clark G, Wilfong A, Northrup H, Adesina A, Bacino CA, Scaglia F, Bonnen PE, Crosson J, Duis J, Maegawa GH, Coman D, Inwood A, McGill J, Boerwinkle E, Graham B, Beaudet A, Eng CM, Hanchard NA, Xia F, Orange JS, Gibbs RA, Lupski JR, Yang Y
Am J Hum Genet 2016 Feb 4;98(2):347-57. Epub 2016 Jan 21 doi: 10.1016/j.ajhg.2015.12.008. [Epub ahead of print] PMID: 26805781Free PMC Article
Farhan H, Moreno-Duarte I, Latronico N, Zafonte R, Eikermann M
Anesthesiology 2016 Jan;124(1):207-34. doi: 10.1097/ALN.0000000000000874. PMID: 26445385
Kharbanda S, Ramakrishna A, Krishnan S
Int J Chron Obstruct Pulmon Dis 2015;10:1727-35. Epub 2015 Sep 1 doi: 10.2147/COPD.S87791. PMID: 26366065Free PMC Article
Dobbels L, Van Damme P, Mahler M, Bossuyt X
Clin Chem 2015 Sep;61(9):1133-5. doi: 10.1373/clinchem.2014.227819. PMID: 26319449
Maeda MH, Ohta H, Izutsu K, Shimizu J, Uesaka Y
Muscle Nerve 2015 May;51(5):772-4. Epub 2015 Jan 16 doi: 10.1002/mus.24509. [Epub ahead of print] PMID: 25381859

Therapy

Pulham NJ, Cho M, Chan F
Gastroenterology 2016 Apr;150(4):e12-3. Epub 2016 Feb 28 doi: 10.1053/j.gastro.2015.11.012. [Epub ahead of print] PMID: 26930009
Dobbels L, Van Damme P, Mahler M, Bossuyt X
Clin Chem 2015 Sep;61(9):1133-5. doi: 10.1373/clinchem.2014.227819. PMID: 26319449
Srisuma S, Lavonas EJ, Wananukul W
Clin Toxicol (Phila) 2015 Jul;53(6):586-7. Epub 2015 May 15 doi: 10.3109/15563650.2015.1046182. [Epub ahead of print] PMID: 25979106
Øiestad BE, Juhl CB, Eitzen I, Thorlund JB
Osteoarthritis Cartilage 2015 Feb;23(2):171-7. Epub 2014 Nov 1 doi: 10.1016/j.joca.2014.10.008. [Epub ahead of print] PMID: 25450853
Hoang PD, Gandevia SC, Herbert RD
Disabil Rehabil 2014;36(19):1588-93. Epub 2013 Nov 18 doi: 10.3109/09638288.2013.854841. [Epub ahead of print] PMID: 24236496

Prognosis

Jung S, Yabushita N, Kim M, Seino S, Nemoto M, Osuka Y, Okubo Y, Figueroa R, Tanaka K
J Nutr Health Aging 2016 Jan;20(1):28-34. doi: 10.1007/s12603-015-0552-6. PMID: 26728930
Farhan H, Moreno-Duarte I, Latronico N, Zafonte R, Eikermann M
Anesthesiology 2016 Jan;124(1):207-34. doi: 10.1097/ALN.0000000000000874. PMID: 26445385
Kharbanda S, Ramakrishna A, Krishnan S
Int J Chron Obstruct Pulmon Dis 2015;10:1727-35. Epub 2015 Sep 1 doi: 10.2147/COPD.S87791. PMID: 26366065Free PMC Article
Verissimo P, Casalaspo TJ, Gonçalves LH, Yang AS, Eid RC, Timenetsky KT
PLoS One 2015;10(2):e0118218. Epub 2015 Feb 11 doi: 10.1371/journal.pone.0118218. PMID: 25671566Free PMC Article
Mirzakhani H, Williams JN, Mello J, Joseph S, Meyer MJ, Waak K, Schmidt U, Kelly E, Eikermann M
Anesthesiology 2013 Aug;119(2):389-97. doi: 10.1097/ALN.0b013e31829373fe. PMID: 23584384

Clinical prediction guides

Lalani SR, Liu P, Rosenfeld JA, Watkin LB, Chiang T, Leduc MS, Zhu W, Ding Y, Pan S, Vetrini F, Miyake CY, Shinawi M, Gambin T, Eldomery MK, Akdemir ZH, Emrick L, Wilnai Y, Schelley S, Koenig MK, Memon N, Farach LS, Coe BP, Azamian M, Hernandez P, Zapata G, Jhangiani SN, Muzny DM, Lotze T, Clark G, Wilfong A, Northrup H, Adesina A, Bacino CA, Scaglia F, Bonnen PE, Crosson J, Duis J, Maegawa GH, Coman D, Inwood A, McGill J, Boerwinkle E, Graham B, Beaudet A, Eng CM, Hanchard NA, Xia F, Orange JS, Gibbs RA, Lupski JR, Yang Y
Am J Hum Genet 2016 Feb 4;98(2):347-57. Epub 2016 Jan 21 doi: 10.1016/j.ajhg.2015.12.008. [Epub ahead of print] PMID: 26805781Free PMC Article
Farhan H, Moreno-Duarte I, Latronico N, Zafonte R, Eikermann M
Anesthesiology 2016 Jan;124(1):207-34. doi: 10.1097/ALN.0000000000000874. PMID: 26445385
Kharbanda S, Ramakrishna A, Krishnan S
Int J Chron Obstruct Pulmon Dis 2015;10:1727-35. Epub 2015 Sep 1 doi: 10.2147/COPD.S87791. PMID: 26366065Free PMC Article
Verissimo P, Casalaspo TJ, Gonçalves LH, Yang AS, Eid RC, Timenetsky KT
PLoS One 2015;10(2):e0118218. Epub 2015 Feb 11 doi: 10.1371/journal.pone.0118218. PMID: 25671566Free PMC Article
Nicole S, Chaouch A, Torbergsen T, Bauché S, de Bruyckere E, Fontenille MJ, Horn MA, van Ghelue M, Løseth S, Issop Y, Cox D, Müller JS, Evangelista T, Stålberg E, Ioos C, Barois A, Brochier G, Sternberg D, Fournier E, Hantaï D, Abicht A, Dusl M, Laval SH, Griffin H, Eymard B, Lochmüller H
Brain 2014 Sep;137(Pt 9):2429-43. Epub 2014 Jun 20 doi: 10.1093/brain/awu160. [Epub ahead of print] PMID: 24951643

Recent systematic reviews

Casaer MP
Curr Opin Clin Nutr Metab Care 2015 Mar;18(2):162-8. doi: 10.1097/MCO.0000000000000150. PMID: 25603227
Øiestad BE, Juhl CB, Eitzen I, Thorlund JB
Osteoarthritis Cartilage 2015 Feb;23(2):171-7. Epub 2014 Nov 1 doi: 10.1016/j.joca.2014.10.008. [Epub ahead of print] PMID: 25450853
Montemezzo D, Fregonezi GA, Pereira DA, Britto RR, Reid WD
Arch Phys Med Rehabil 2014 Jul;95(7):1398-407. Epub 2014 Mar 13 doi: 10.1016/j.apmr.2014.02.022. [Epub ahead of print] PMID: 24631801
Maffiuletti NA, Roig M, Karatzanos E, Nanas S
BMC Med 2013 May 23;11:137. doi: 10.1186/1741-7015-11-137. [Epub ahead of print] PMID: 23701811Free PMC Article
Maddocks M, Gao W, Higginson IJ, Wilcock A
Cochrane Database Syst Rev 2013 Jan 31;(1):CD009419. doi: 10.1002/14651858.CD009419.pub2. PMID: 23440837

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