Genetic prion disease generally manifests with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Although these phenotypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset typically ranges from 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome.

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.

Spinocerebellar ataxia-4 (SCA4) is an autosomal dominant neurologic disorder characterized by the onset of balance disturbances and gait and limb ataxia usually in the fourth decade, although earlier onset in the teens or twenties has been reported. There is evidence of genetic anticipation within families. The disorder is slowly progressive, and most patients eventually become wheelchair-bound. Additional features include hypometric or slow saccades, sensory or sensorimotor axonal peripheral neuropathy, dysarthria, and autonomic dysfunction, including orthostatic hypotension and problems with bowel or bladder control. More severely affected individuals have dysphagia and significant unintended weight loss, which may contribute to premature death. Brain imaging shows cerebellar atrophy (Wallenius et al., 2024). For a discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

For a general discussion of autosomal dominant spinocerebellar ataxia (SCA), see SCA1 (164400).

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The age of onset ranges from 19 to 73 years; mean age of onset is between 43 and 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved.

Disease with characteristics of early-onset tremor, dyskinesia and slowly progressive cerebellar ataxia. Fewer than 30 cases have been reported to date. This disease is caused by a mutation in the fibroblast growth factor 14 FGF14 gene (13q34). Prognosis is relatively good. Life-threatening status epilepticus and intractable seizure or severe dysphagia is rare.

SCA8 is a slowly progressive ataxia with onset typically in the third to fifth decade but with a range from before age one year to after age 60 years. Common initial manifestations are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Over the disease course other findings can include eye movement abnormalities (nystagmus, abnormal pursuit and abnormal saccades, and, rarely, ophthalmoplegia); upper motor neuron involvement; extrapyramidal signs; brain stem signs (dysphagia and poor cough reflex); sensory neuropathy; and cognitive impairment (e.g., executive dysfunction, psychomotor slowing and other features of cerebellar cognitive-affective disorder in some). Life span is typically not shortened.

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.

Spinocerebellar ataxia type 15 (SCA15) is characterized by slowly progressive gait and limb ataxia, often in combination with ataxic dysarthria, titubation, upper limb postural tremor, mild hyperreflexia, gaze-evoked nystagmus, and impaired vestibuloocular reflex gain. Onset is between ages seven and 72 years, usually with gait ataxia but sometimes with tremor. Affected individuals remain ambulatory for ten to 54 years after symptom onset. Mild dysphagia usually after two or more decades of symptoms has been observed in members of multiple affected families and movement-induced oscillopsia has been described in one member of an affected family.

TSEN54 pontocerebellar hypoplasia (TSEN54-PCH) comprises three PCH phenotypes (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three PCH phenotypes (which differ mainly in life expectancy) were considered to be distinct entities before their molecular basis was known. PCH2. Children usually succumb before age ten years (those with PCH4 and 5 usually succumb as neonates). Children with PCH2 have generalized clonus, uncoordinated sucking and swallowing, impaired cognitive development, lack of voluntary motor development, cortical blindness, and an increased risk for rhabdomyolysis during severe infections. Epilepsy is present in approximately 50%. PCH4. Neonates often have seizures, multiple joint contractures ("arthrogryposis"), generalized clonus, and central respiratory impairment. PCH5 resembles PCH4 and has been described in one family.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is clinically characterized by a progressive cerebellar ataxia, peripheral neuropathy, and spasticity. Disease onset of classic ARSACS is often in early childhood, leading to delayed walking because of gait unsteadiness in very young toddlers, while an increasing number of individuals with disease onset in teenage or early-adult years are now being described. Typically the ataxia is followed by lower-limb spasticity and later by peripheral neuropathy – although pronounced peripheral neuropathy has been observed as a first sign of ARSACS. Oculomotor disturbances, dysarthria, and upper-limb ataxia develop with slower progression than the other findings. Brain imaging demonstrates atrophy of the superior vermis and the cerebellar hemisphere with additional findings on MRI, such as linear hypointensities in the pons and hyperintense rims around the thalami. Many affected individuals (though not all) have yellow streaks of hypermyelinated fibers radiating from the edges of the optic disc noted on ophthalmologic exam, and thickened retinal fibers can be demonstrated by optical coherence tomography. Mild intellectual disability, hearing loss, and urinary urgency and incontinence have been reported in some individuals.

Spinocerebellar ataxia-34 (SCA34) is an autosomal dominant disorder characterized by slowly progressive cerebellar ataxia. Onset usually occurs during the young adult years, and most patients remain ambulatory until late in life. One family with SCA34 also had onset of erythema and hyperkeratosis in early childhood (Cadieux-Dion et al., 2014), whereas other families have additional neurologic signs, including ocular movement disturbances and pyramidal tract signs (Ozaki et al., 2015). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: Infantile neuroaxonal dystrophy (INAD). Atypical neuroaxonal dystrophy (atypical NAD). PLA2G6-related dystonia-parkinsonism. INAD usually begins between ages six months and three years with psychomotor regression or delay, hypotonia, and progressive spastic tetraparesis. Many affected children never learn to walk or lose the ability shortly after attaining it. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid, resulting in severe spasticity, progressive cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade. Atypical NAD shows more phenotypic variability than INAD. In general, onset is in early childhood but can be as late as the end of the second decade. The presenting signs may be gait instability, ataxia, or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. Strabismus, nystagmus, and optic atrophy are common. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years. PLA2G6-related dystonia-parkinsonism has a variable age of onset, but most individuals present in early adulthood with gait disturbance or neuropsychiatric changes. Affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability.

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.

Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (summary by Gu et al., 1997). Mutation in TULP1 can also cause a form of autosomal recessive retinitis pigmentosa (RP14; 600132). For a general phenotypic description and a discussion of the genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000.

Spinocerebellar ataxia-36 (SCA36) is a slowly progressive neurodegenerative disorder characterized by adult-onset gait ataxia, eye movement abnormalities, tongue fasciculations, and variable upper motor neuron signs. Some affected individuals may develop hearing loss (summary by Garcia-Murias et al., 2012). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood. Some patients with PEX10 mutations have a milder disorder characterized by childhood-onset cerebellar ataxia and neuropathy without mental retardation (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX10 gene have cells of complementation group 7 (CG7, equivalent to CGB). For information on the history of PBD complementation groups, see 214100.

Ataxia-telangiectasia-like disorder-1 is an autosomal recessive disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia. Laboratory studies of patient cells showed increased susceptibility to radiation, consistent with a defect in DNA repair. The disorder shares some phenotypic features of ataxia-telangiectasia (AT; 208900), but telangiectases and immune deficiency are not present in ATLD1 (summary by Hernandez et al., 1993 and Stewart et al., 1999). Genetic Heterogeneity of Ataxia-Telangiectasia-Like Disorder See also ATLD2 (615919), caused by mutation in the PCNA gene (176740) on chromosome 20p12.

In patients with SSMED, short stature and microcephaly are apparent at birth, and there is progressive postnatal growth failure. Endocrine dysfunction, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus, is present in affected adults. Progressive ataxia has been reported in some patients, with onset ranging from the second to fifth decade of life. In addition, a few patients have developed tumors, suggesting that there may be a predisposition to tumorigenesis. In contrast to syndromes involving defects in other components of the nonhomologous end-joining (NHEJ) complex (see, e.g., 606593), no clinically overt immunodeficiency has been observed in SSMED, although laboratory analysis has revealed lymphopenia or borderline leukopenia in some patients (Murray et al., 2015; Bee et al., 2015; de Bruin et al., 2015; Guo et al., 2015).

GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.

A rare hereditary cerebellar ataxia disorder with characteristics of late-onset spinocerebellar ataxia, manifesting with slowly progressive gait disturbances, dysarthria, limb and truncal ataxia and smooth-pursuit eye movement disturbance, associated with a history of psychomotor delay from childhood. Mild atrophy of the cerebellar vermis and hemispheres is observed on brain imaging. There is evidence the disease is caused by homozygous mutation in the SYT14 gene on chromosome 1q32.

Autosomal recessive spinocerebellar ataxia-28 (SCAR28) is a neurologic disorder characterized by onset in early childhood of mildly delayed motor development, gait ataxia, incoordination of fine motor movements, and dysarthria. Affected individuals may have features of spasticity and may show mildly impaired cognitive function. Brain imaging shows cerebellar vermis hypoplasia (summary by Walker et al., 2019).

Myoclonic dystonia-34 (DYT34) is an autosomal dominant neurologic disorder characterized by childhood-onset dystonia primarily involving the hands and neck, with a fast tremor with superimposed myoclonus (Balint et al., 2020).