MedGen

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. [from GeneReviews]

Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years, and the median survival time is 15 to 18 years after onset. [from GeneReviews]

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by progressive cerebellar ataxia and variable findings including pyramidal signs, a dystonic-rigid extrapyramidal syndrome, significant peripheral amyotrophy and generalized areflexia, progressive external ophthalmoplegia, action-induced facial and lingual fasciculations, and bulging eyes. Neurologic findings tend to evolve as the disorder progresses. [from GeneReviews]

Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration. [from GeneReviews]

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal-lethal disorder to an asymptomatic type. The characterization of three major clinical types (1, 2, and 3) and two clinical forms (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. Cardiopulmonary complications have been described with all the clinical phenotypes, although varying in frequency and severity. Type 1 GD is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia, thrombocytopenia, lung disease, and the absence of primary central nervous system disease. Type 2 GD is characterized by primary central nervous system disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years. Type 3 GD is characterized by primary central nervous system disease with childhood onset, a more slowly progressive course, and survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. [from GeneReviews]

Pantothenate kinase-associated neurodegeneration (PKAN) is a type of neurodegeneration with brain iron accumulation (NBIA). The phenotypic spectrum of PKAN includes classic PKAN and atypical PKAN. Classic PKAN is characterized by early-childhood onset of progressive dystonia, dysarthria, rigidity, and choreoathetosis. Pigmentary retinal degeneration is common. Atypical PKAN is characterized by later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease. [from GeneReviews]

GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur. [from GeneReviews]

Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; see 234200) (summary by Bruggemann et al., 2010). For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600. Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia-78 (SPG78; 617225), an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by Estrada-Cuzcano et al., 2017). [from OMIM]

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined before the molecular basis was known. POLG-related disorders can therefore be considered an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the clinical phenotype. In individuals with early-onset disease (prior to age 12 years), liver involvement, feeding difficulties, seizures, hypotonia, and muscle weakness are the most common clinical features. This group has the worst prognosis. In the juvenile/adult-onset form (age 12-40 years), disease is typically characterized by peripheral neuropathy, ataxia, seizures, stroke-like episodes, and, in individuals with longer survival, progressive external ophthalmoplegia (PEO). This group generally has a better prognosis than the early-onset group. Late-onset disease (after age 40 years) is characterized by ptosis and PEO, with additional features such as peripheral neuropathy, ataxia, and muscle weakness. This group overall has the best prognosis. [from GeneReviews]

LRRK2 Parkinson disease (PD) is characterized by features consistent with idiopathic PD: initial motor features of slowly progressive asymmetric tremor at rest and/or bradykinesia, cogwheel muscle rigidity, postural instability, and gait abnormalities that may include festination and freezing. Certain nonmotor symptoms in LRRK2-PD, especially REM sleep behavior disorder and cognitive decline, may occur at similar or slightly reduced frequency compared to typical idiopathic* PD. Onset is generally after age 50, although early-onset (in the 20s) and late-onset (in the 90s) disease has been described. * Idiopathic PD refers to the presence of signs and symptoms of PD for which the etiology is currently unknown and in which there is no known family history of PD. [from GeneReviews]

Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene. Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed. [from OMIM]

Parkin type of early-onset Parkinson disease (PARK-Parkin) is characterized by the cardinal signs of Parkinson disease (PD): bradykinesia, resting tremor, and rigidity. The median age at onset is 31 years (range: 3-81 years). The disease is slowly progressive: disease duration of more than 50 years has been reported. Clinical findings vary; hyperreflexia is common. Lower-limb dystonia may be a presenting sign and cognitive decline appears to be no more frequent than in the general population. Dyskinesia as a result of treatment with levodopa frequently occurs. [from GeneReviews]

Neuroferritinopathy is an adult-onset progressive movement disorder characterized by chorea or dystonia and speech and swallowing deficits. The movement disorder typically affects one or two limbs and progresses to become more generalized within 20 years of disease onset. When present, asymmetry in the movement abnormalities remains throughout the course of the disorder. Most individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity and orolingual dyskinesia are common. Cognitive deficits and behavioral issues become major problems with time. [from GeneReviews]

PINK1 type of young-onset Parkinson disease is characterized by early onset (median age at onset 32 years) of tremor, bradykinesia, and rigidity that are often indistinguishable from other causes of Parkinson disease. Lower-limb dystonia may be a presenting sign. Postural instability, hyperreflexia, abnormal behavior, and psychiatric manifestations have been described. The disease is usually slowly progressive. Individuals have a marked and sustained response to oral administration of levodopa (L-dopa), frequently associated with L-dopa-induced fluctuations and dyskinesias. [from GeneReviews]

Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. Ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs. Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course. [from GeneReviews]

Beta-propeller protein-associated neurodegeneration (BPAN) is typically characterized by early-onset seizures, infantile-onset developmental delay, intellectual disability, absent-to-limited expressive language, motor dysfunction (ataxia), and abnormal behaviors often similar to autism spectrum disorder. Seizure types including generalized (absence, tonic, atonic, tonic-clonic and myoclonic), focal with impaired consciousness, and epileptic spasms, as well as epileptic syndromes (West syndrome and Lennox-Gastaut syndrome) can be seen. With age seizures tend to resolve or become less prominent, whereas cognitive decline and movement disorders (progressive parkinsonism and dystonia) emerge as characteristic findings. [from GeneReviews]

ATP1A3-related disorder consists of heterogenous overlapping clinical findings that pertain to the four most common historically defined phenotypes: alternating hemiplegia of childhood (AHC); cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndrome; relapsing encephalopathy with cerebellar ataxia (RECA) / fever-induced paroxysmal weakness and encephalopathy (FIPWE); and rapid-onset dystonia-parkinsonism (RDP). These phenotypes exist on a spectrum and should be regarded as classifications of convenience. AHC is characterized by onset prior to age 18 months of paroxysmal hemiplegic episodes, predominately involving the limbs and/or the whole body, lasting from minutes to hours to days (and sometimes weeks) with remission only during sleep, only to resume after awakening. Although paroxysmal episodic neurologic dysfunction predominates early in the disease course, with age increasingly persistent neurologic dysfunction predominates, including oculomotor apraxia and strabismus, dysarthria, speech and language delay, developmental delay, and impairment in social skills. Other system involvement may include cardiovascular (cardiac conduction abnormalities) and gastrointestinal (constipation, vomiting, anorexia, diarrhea, nausea, and abdominal pain) manifestations. CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever. The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma. Usually, considerable recovery occurs within days to weeks; however, persistence of some degree of ataxia and other manifestations is typical. RECA/FIPWE primarily presents with fever-induced episodes (infancy to age 5 years); however, first episodes can occur occasionally in young adults during illnesses such as mononucleosis. Recurrent fever-induced episodes may be ataxia-dominated RECA-like motor manifestations or FIPWE-like non-motor manifestations (encephalopathy) and can vary among affected individuals. Notably, RECA-like and FIPWE-like manifestations can occur in the same individual in different episodes. In some individuals episodes seem to decrease in frequency and severity over time, whereas others might experience worsening of manifestations. RDP presents in individuals ages 18 months to 60 years and older with dystonia that is typically of abrupt onset over hours to several weeks, though some individuals report gradual onset over the course of months. A stress-related trigger is identifiable in up to 75% of individuals. Dystonia rarely improves significantly after onset; some individuals report mild improvement over time, whereas others can experience subsequent episodes of abrupt worsening months to years after onset. Limbs are usually the first to be affected, although by the time of diagnosis – typically many years after onset – individuals most commonly display a bulbar-predominant generalized dystonia. Exceptions are common and a rostrocaudal gradient is rare rather than typical. Migraines and seizures are also observed. [from GeneReviews]

Spinocerebellar ataxia type 10 (SCA10) is characterized by slowly progressive cerebellar ataxia that usually starts as poor balance and unsteady gait, followed by upper-limb ataxia, scanning dysarthria, and dysphagia. Abnormal tracking eye movements are common. Recurrent seizures after the onset of gait ataxia have been reported with variable frequencies among different families. Some individuals have cognitive dysfunction, behavioral disturbances, mood disorders, mild pyramidal signs, and peripheral neuropathy. Age of onset ranges from 12 to 48 years. [from GeneReviews]

The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: 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. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years. [from GeneReviews]

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined before the molecular basis was known. POLG-related disorders can therefore be considered an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the clinical phenotype. In individuals with early-onset disease (prior to age 12 years), liver involvement, feeding difficulties, seizures, hypotonia, and muscle weakness are the most common clinical features. This group has the worst prognosis. In the juvenile/adult-onset form (age 12-40 years), disease is typically characterized by peripheral neuropathy, ataxia, seizures, stroke-like episodes, and, in individuals with longer survival, progressive external ophthalmoplegia (PEO). This group generally has a better prognosis than the early-onset group. Late-onset disease (after age 40 years) is characterized by ptosis and PEO, with additional features such as peripheral neuropathy, ataxia, and muscle weakness. This group overall has the best prognosis. [from GeneReviews]