Ataxias (without repeat expansion analysis)

The hereditary cerebellar ataxias primarily affect the cerebellum but often involve multisystem neurodegeneration. Typical presentations include wide-based staggering gait, truncal instability, dysmetria, dysarthria, and abnormal eye movements such as nystagmus, saccadic intrusions, or impaired smooth pursuit. Cerebellar atrophy is present on neuroimaging. Certain genetic subtypes are
associated with a pure cerebellar phenotype, whereas others include additional neurological and systemic features, including pyramidal tract signs, peripheral neuropathy, movement disorders/parkinsonism, cognitive impairment and seizures. Onset is highly variable with overlaps across the spectrum: early-onset forms manifest before age 25 years (e.g., ataxia with oculomotor apraxia) or before age 5 years (e.g., ataxia-telangiectasia), while the most common adult-onset forms manifest between ages 30 and 50 years and late-onset forms after age 50 years. Progression typically leads to the use of assistive devices 5–10 years after onset and ultimately to wheelchair dependence; common causes of morbidity include falls resulting in head injury or hip fracture, choking episodes, and intercurrent infections such as aspiration pneumonia and urinary tract infection.

The prevalence of autosomal dominant cerebellar ataxias has been reported with an estimated global average of 2.7/100,000 and 3.3/100,000 for autosomal recessive cerebellar ataxias. However, the reported prevalence may vary between studies due to different inclusion criteria, as well as variability in prevalence in different geographic regions or ethnic groups.

A large number of genes have been associated with hereditary ataxia. Among the autosomal dominant ataxias, the most common are the spinocerebellar ataxias (SCAs), particularly: SCA3 and SCA2. Both are caused by heterozygous CAG trinucleotide repeat expansions, leading to elongated polyglutamine (polyQ) tracts in the respective proteins. Among the autosomal recessive ataxias, Friedreich ataxia is the most common, especially in Caucasian populations. It is caused by a GAA trinucleotide repeat expansion in the FXN gene. Importantly, there are significant geographic variations in the prevalence of different hereditary ataxias.

The genetic conditions underlying hereditary ataxias exhibit heterogeneous inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked forms.

• Where ataxia is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity can guide further clinical management; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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