Clinical characteristics: Spinocerebellar ataxia type 4 (SCA4) is a progressive neurologic disease characterized by cerebellar involvement (gait ataxia, balance disturbances, eye movement abnormalities), brain stem involvement (dysarthria, dysphagia), sensory neuropathy, motor neuron involvement (muscle wasting and spasticity), autonomic dysfunction (especially orthostatic hypotension), and cognition and/or behavior manifestations. Age of onset ranges from 12 to 65 years. In the approximately 10% of individuals whose onset is before age 25 years disease manifestations are more severe and often different from those with later-onset disease. As the disease progresses, particularly in those with early-onset disease, eye movement abnormalities, dysarthria, dysphagia, sensory neuropathy, upper and lower motor neuron involvement, and orthostatic hypotension can further aggravate balance and gait problems. Most individuals eventually require a walker or wheelchair. Reduced life expectancy in individuals with earlier-onset severe SCA4 is associated with weight loss, infections, and cardiac arrhythmia. Life expectancy is normal or near normal in individuals with later-onset SCA4.

Diagnosis/testing: The diagnosis of SCA4 is established in a proband with suggestive findings by the identification of a heterozygous abnormal trinucleotide GGC repeat expansion in the terminal exon of ZFHX3 by molecular genetic testing.

Management: Treatment of manifestations: Multidisciplinary care by neurologists (possible pharmacologic treatment of ataxia); physical therapists (maintain mobility and function); occupational therapists (optimize activities of daily living); speech-language therapists (optimize communication, including augmentative and alternative communication as needed); neuro-ophthalmologists (counsel to minimize impact of eye movement abnormalities); nutritionists and occupational therapists (manage dietary needs and consider need for gastrostomy tube placement); neurologists and neurorehabilitation specialist (manage autonomic dysfunction); and mental health specialists (manage mood disorders and changes in cognition and/or behavior).

Surveillance: Monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations via routine evaluations as recommended by the treating clinicians.

Agents/circumstances to avoid: Medications that (1) further reduce cerebellar function, including drinking alcohol and use of sedating drugs; and (2) exacerbate orthostatic hypotension such as large carbohydrate-rich meals and dehydration.

Genetic counseling: SCA4 is inherited in an autosomal dominant manner. Most individuals diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring. Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in ZFHX3. Once a pathogenic ZFHX3 GGC repeat expansion has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.