The Aetiologic Spectrum of Cerebellar Ataxia: Inherited Causes of Ataxia

Abstract

Cerebellar ataxia is a frequent finding among patients seen in neurological practice and may result in a wide variety of aetiologies, both acquired and genetic. Inherited ataxia is a large and important subgroup of the ataxic disorders, and includes metabolic ataxias, autosomal recessive degenerative ataxias, autosomal dominant spinocerebellar ataxias (SCAs), X-linked and maternally inherited ataxias. Hereditary ataxia is reviewed in this article and acquired ataxias are covered in the accompanying article.

Hereditary conditions account for the majority of ataxic syndromes in children and one-third to one-half of patients with adult-onset ataxic syndromes. Classification by mode of inheritance is a useful way of organizing the hereditary ataxias for both clinical and research purposes, and this approach will be used in this article.

Key Concepts

• Understand that there are a wide variety of different inherited causes of ataxia.

• Some patients without a family history of ataxia still have the disorder on the basis of a genetic mutation.

• Nucleotide expansion disorders are a common cause of dominantly inherited cerebellar ataxia. The majority of these diseases result from a toxic gain-of-function mechanism and they demonstrate genetic anticipation, wherein intergenerational expansion leads to disease with earlier onset and often more severe symptom.

• Friedreich ataxia is the most common inherited cause of ataxia. It results from decreased expression of the Frataxin protein due to a nucleotide repeat expansion in a noncoding region.

• A variety of mitochondrial disorders are associated with ataxia as one of the number of neurologic and systemic symptoms. These diseases result from mutations in either nuclear DNA in genes involved in mitochondrial function or in mitochondrial DNA itself.

• Wilson disease is a disorder of copper metabolism that can present with dystonia, ataxia or neuropsychiatric symptoms and is also associated with liver failure. Early treatment can be curative.

• Defects in DNA repair underlie many childhood onset forms of inherited ataxia.