Episodic ataxias

Primary episodic ataxias (EAs) are a group of dominantly inherited disorders characterized by transient recurrent incoordination and truncal instability, often triggered by physical exertion and emotional stress, variably associated with progressive baseline ataxia. There are now eight designated subtypes based largely on genetic loci. Mutations have been identified in multiple individuals and families with EA1, EA2, and EA6, mostly with onset before adulthood. EA1 and EA2 are prototypical neurologic channelopathies. EA1 is caused by heterozygous mutations in KCNA1, which encodes the α1 subunit of a neuronal voltage-gated potassium channel, Kv1.1. EA2, the most common and best characterized, is caused by heterozygous mutations in CACNA1A, which encodes the α1A subunit of a neuronal voltage-gated calcium channel, Cav2.1. EA6 is caused by heterozygous mutations in SLC1A3, which encodes a subunit of a glial excitatory amino acid transporter, EAAT1. The other EA subtypes were defined in single families awaiting gene identification and further confirmation. This chapter focuses on the best-characterized EA syndromes, the clinical assessment and genetic diagnosis of EA, and the management of EA, as well as newly recognized allelic disorders that have greatly expanded the clinical spectrum of EA2. Illustrative cases are discussed, with a focus on sporadic patients with congenital features without episodic ataxia who present diagnostic and therapeutic challenges.