Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Ataxia, episodic type 2 (EA2) [G11.9]

OMIM numbers: 601011 (CACNA1A), 108500 (EA2), 141500 (familial hemiplegic migraine)

Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh, M.Sc. Anna Munzig

Scientific Background

The clinically and genetically heterogeneous group of autosomal dominant episodic ataxia disorders is divided into 7 subtypes, although the genetic cause of all subtypes is not yet known. The main symptom in all subtypes is a paroxysmal, continuous ataxia lasting from seconds to days, often associated with nystagmus and dysarthria.

The most common type, episodic ataxia type 2 (EA2), has a prevalence of approximately 1:100,000. It is characterized by recurrent phases of stance and gait ataxia, vertigo and nausea triggered by, among other things, physical exertion or emotional stress. Accompanying symptoms include dysarthria, oscillopsia, tinnitus, dystonia, migraine-like headaches (in about 50% of cases) and light myasthenia symptoms. Between attacks, patients are initially asymptomatic, however, 90% develop ocular-motor disturbances and nystagmus. Although symptoms usually being in childhood or early adulthood (2-32 years), people with late onset disease, after 63 years of age, have also been described.  There is variable clinical expression, even within a family.

EA2 is caused by mutations in the CACNA1A gene. This gene codes for the alpha-1A subunit of voltage-controlled calcium channel CaV2.1, which is expressed predominantly in the brain stem and in cerebellar Purkinje cells. Mutations in this gene have also been described as a cause of familial hemiplegic migraine. In addition, the expansion of a CAG triplet in the coding region of this gene is the cause of spinocerebellar ataxia type 6 (SCA6).