MedGen

Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 µmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment. [from GeneReviews]

PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three clinical stages: infantile multisystem, late-infantile and childhood ataxia–intellectual disability, and adult stable disability. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. Clinical findings tend to be similar in sibs. In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, faltering growth, and developmental delay are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical courses are observed: (1) a nonfatal neurologic course with faltering growth, strabismus, developmental delay, cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade; and (2) a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages 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, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen, thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed; females may lack secondary sexual development and males may exhibit decreased testicular volume. Hypogonadotropic hypogonadism and coagulopathy may occur. The risk for deep venous thrombosis is increased. [from GeneReviews]

Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews of ALS. Some forms of ALS occur with frontotemporal dementia (FTD); see 105500. Ranganathan et al. (2020) provided a detailed review of the genes involved in different forms of ALS with FTD, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration. Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck, 1980), in which the histology is different and dementia and parkinsonism complicate the clinical picture. Genetic Heterogeneity of Amyotrophic Lateral Sclerosis ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. ALS6 (608030) is caused by mutation in the FUS gene (137070) on chromosome 16p11; ALS8 (608627) is caused by mutation in the VAPB gene (605704) on chromosome 13; ALS9 (611895) is caused by mutation in the ANG gene (105850) on chromosome 14q11; ALS10 (612069) is caused by mutation in the TARDBP gene (605078) on 1p36; ALS11 (612577) is caused by mutation in the FIG4 gene (609390) on chromosome 6q21; ALS12 (613435) is caused by mutation in the OPTN gene (602432) on chromosome 10p13; ALS15 (300857) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11; ALS18 (614808) is caused by mutation in the PFN1 gene (176610) on chromosome 17p13; ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on chromosome 2q34; ALS20 (615426) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13; ALS21 (606070) is caused by mutation in the MATR3 gene (164015) on chromosome 5q31; ALS22 (616208) is caused by mutation in the TUBA4A gene (191110) on chromosome 2q35; ALS23 (617839) is caused by mutation in the ANXA11 gene (602572) on chromosome 10q23; ALS26 (619133) is caused by mutation in the TIA1 gene (603518) on chromosome 2p13; ALS27 (620285) is caused by mutation in the SPTLC1 gene (605712) on chromosome 9q22; and ALS28 (620452) is caused by mutation in the LRP12 gene (618299) on chromosome 8q22. Loci associated with ALS have been found on chromosomes 18q21 (ALS3; 606640) and 20p13 (ALS7; 608031). Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (601517) contribute to susceptibility to ALS (ALS13; 183090). Susceptibility to ALS24 (617892) is conferred by mutation in the NEK1 gene (604588) on chromosome 4q33, and susceptibility to ALS25 (617921) is conferred by mutation in the KIF5A gene (602821) on chromosome 12q13. Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; 162230); deletions in the gene encoding peripherin (PRPH; 170710); and mutations in the dynactin gene (DCTN1; 601143). Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (205100), caused by mutation in the alsin (606352) gene on 2q33; ALS4 (602433), caused by mutation in the senataxin gene (SETX; 608465) on 9q34; ALS5 (602099), caused by mutation in the SPG11 gene (610844) on 15q21; and ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13. [from OMIM]

Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three major clinical subtypes have been suggested: A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1). A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2). A severe form manifested as prenatal loss or early death from progressive central nervous system involvement or infection (type 3). Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease – mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; some individuals may live into the sixth decade. [from GeneReviews]

Leigh syndrome is a clinical diagnosis based primarily on characteristic brain imaging findings associated with progressive and severe neurodegenerative features with onset within the first months or years of life, sometimes resulting in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by Lake et al., 2015). Genetic Heterogeneity of Nuclear Leigh Syndrome Leigh syndrome is a presentation of numerous genetic disorders resulting from defects in the mitochondrial OXPHOS complex. Accordingly, the genes implicated in Leigh syndrome most commonly encode structural subunits of the OXPHOS complex or proteins required for their assembly, stability, and activity. Mutations in both nuclear and mitochondrial genes have been identified. For a discussion of genetic heterogeneity of mitochondrial Leigh syndrome, see MILS (500017). Nuclear Leigh syndrome can be caused by mutations in nuclear-encoded genes involved in any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), and complex V deficiency (see 604273) (summary by Lake et al., 2015). Some forms of combined oxidative phosphorylation deficiency (COXPD) can present as Leigh syndrome (see, e.g., 617664). Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome. [from OMIM]

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]

HPRT1 disorders, caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), are typically associated with clinical evidence for overproduction of uric acid (hyperuricemia, nephrolithiasis, and/or gouty arthritis) and varying degrees of neurologic and/or behavioral problems. Historically, three phenotypes were identified in the spectrum of HPRT1 disorders: Lesch-Nyhan disease (LND) at the most severe end with motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior; HPRT1-related neurologic dysfunction (HND) in the intermediate range with similar but fewer severe neurologic findings than LND and no self-injurious behavior; and HPRT1-related hyperuricemia (HRH) at the mild end without overt neurologic deficits. It is now recognized that these neurobehavioral phenotypes cluster along a continuum from severe to mild. [from GeneReviews]

Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage is similar to earlier-onset forms. [from GeneReviews]

Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation. [from GeneReviews]

Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late-adult onset have been reported. Those with onset after age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy. [from GeneReviews]

Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death. Anticipation in this nucleotide repeat disorder may be so dramatic that within a family a child with infantile or early-childhood onset may be diagnosed with what is thought to be an unrelated neurodegenerative disorder years before a parent or grandparent with a CAG repeat expansion becomes symptomatic. In adolescent-onset SCA7, the initial manifestation is typically impaired vision, followed by cerebellar ataxia. In those with adult onset, progressive cerebellar ataxia usually precedes the onset of visual manifestations. While the rate of progression varies in these two age groups, the eventual result for almost all affected individuals is loss of vision, severe dysarthria and dysphagia, and a bedridden state with loss of motor control. [from GeneReviews]

Hereditary transthyretin (ATTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor and/or 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. [from GeneReviews]

Mucolipidosis IV (MLIV) is an ultra-rare lysosomal storage disorder characterized by severe psychomotor delay, progressive visual impairment, and achlorhydria. Individuals with MLIV typically present by the end of the first year of life with delayed developmental milestones (due to a developmental brain abnormality) and impaired vision (resulting from a combination of corneal clouding and retinal degeneration). By adolescence, all individuals with MLIV have severe visual impairment. A neurodegenerative component of MLIV has become more widely appreciated, with the majority of individuals demonstrating progressive spastic quadriparesis and loss of psychomotor skills starting in the second decade of life. About 5% of individuals have atypical MLIV, manifesting with less severe psychomotor impairment, but still exhibiting progressive retinal degeneration and achlorhydria. [from GeneReviews]

Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. [from GeneReviews]

Amyotrophic lateral sclerosis-24 (ALS24) is a fatal neurodegenerative disease characterized by adult-onset loss of motor neurons (Brenner et al., 2016). [from OMIM]

DYT1 early-onset isolated dystonia typically presents in childhood or adolescence and only on occasion in adulthood. Dystonic muscle contractions causing posturing or irregular tremor of a leg or arm are the most common presenting findings. Dystonia is usually first apparent with specific actions such as writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign. [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]

Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. [from GeneReviews]

Sotos syndrome is characterized by a distinctive facial appearance (broad and prominent forehead with a dolichocephalic head shape, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, long chin); learning disability (early developmental delay, mild-to-severe intellectual impairment); and overgrowth (height and/or head circumference =2 SD above the mean). These three clinical features are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral problems (most notably autistic spectrum disorder), advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity with or without pes planus, maternal preeclampsia, neonatal complications, renal anomalies, scoliosis, and seizures. [from GeneReviews]

Sandhoff disease comprises a phenotypic continuum encompassing acute infantile, subacute juvenile, and late-onset disease. Although classification into these phenotypes is somewhat arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, presenting manifestations, rate of progression, and life span. Acute infantile Sandhoff disease (onset age <6 months). Infants are generally normal at birth followed by progressive weakness and slowing of developmental progress, then developmental regression and severe neurologic impairment. Seizures are common. Death usually occurs between ages two and three years. Subacute juvenile Sandhoff disease (onset age 2-5 years). After attaining normal developmental milestones, developmental progress slows, followed by developmental regression and neurologic impairment (abnormal gait, dysarthria, and cognitive decline). Death (usually from aspiration) typically occurs in the early to late teens. Late-onset Sandhoff disease (onset older teen years or young adulthood). Nearly normal psychomotor development is followed by a range of neurologic findings (e.g., weakness, spasticity, dysarthria, and deficits in cerebellar function) and psychiatric findings (e.g., deficits in executive function and memory). Life expectancy is not necessarily decreased. [from GeneReviews]