The Ataxias as an Example of Rare Diseases: Diagnosis, Genetics, and Treatment

BACKGROUND: Ataxias are a group of rare diseases. In the European Union, a disease is defined as rare if its prevalence is less than 5 per 10 000 people. Ataxias are rarer than this threshold, although reliable prevalence estimates are largely lacking. The worldwide mean prevalence of autosomal dominant hereditary ataxias is approximately 2.7 per 100 000 people (95% confidence interval [1.5; 4.0/100 000]), and that of autosomal-recessive ataxias is approximately 3.3 per 100 000 people [1.8; 4.9/100 000]. Ataxias include hereditary (genetic), sporadic degenerative, and acquired types. METHODS: This narrative review is based on the guidelines of the German Society for Neurology (Deutsche Gesellschaft für Neurologie) and on other current reviews, supplemented by the findings of targeted PubMed searches. RESULTS: In the more common types of hereditary ataxia, a presumptive diagnosis (spot diagnosis) can already be made on the basis of the history, neurological examination, and brain MRI findings and can then be confirmed by genetic testing. These include Friedreich ataxia, the RFC1-CANVAS syndrome (cerebellar ataxia, neuropathy, and vestibular areflexia), and spinocerebellar ataxia types 3 and 27B (SCA3 and SCA27B). When a spot diagnosis is not possible, the diagnosis can often be established by genetic testing (preferably genome-based). Multisystem atrophy of the cerebellar type (MSA-C) arises sporadically. Ataxia with a subacute course suggests an acquired type of ataxia-in particular, immune-mediated ataxias and vitamin B1 deficiency (Wernicke) encephalopathy. Omaveloxolone has been approved for the treatment of Friedreich ataxia. In a phase 2 trial with 103 patients, the clinical severity score (mFARS value, maximum 99 points) improved by a mean of 1.55 points after 48 weeks of treatment, compared with worsening by 0.85 points with placebo. Fampridine is used off-label to treat episodic ataxias, downbeat nystagmus, and SCA27B. Randomized trials have documented the benefit of physiotherapy and regular exercise training for patients with ataxia. CONCLUSION: An increasing number of ataxias can be diagnosed with the improved genetic and immunological diagnostic techniques that are now available. Opportunities for treatment remain limited, but many new therapies are under development, including gene therapy.