The clinical and genetic diagnosis, genotype-phenotype correlations, pathophysiology and treatment of primary episodic ataxia syndromes are reviewed by researchers from Departments of Neurology, UCLA School of Medicine, Los Angeles, CA; National Hospital for Neurology, Queen Square, London, UK; Johns Hopkins University School of Medicine, Baltimore, MD; and University of Rochester School of Medicine, NY, USA. Primary episodic ataxias (EA) are autosomal dominant channelopathies that present with attacks of imbalance and incoordination. Six EA are described, but two (EA1 and EA2) affecting multiple families, with mutations in genes KCNA1 and CACNA1A, account for the majority of identified cases. Type 1 (EA1) is characterized by brief episodes of ataxia (seconds to minutes) and myokymia (or “neuromyotonia”), with onset in early childhood. Ataxia is precipitated by physical and emotional stress, startle or sudden movement. Attacks are associated with dysarthria and coarse tremor. Myokymia may be apparent clinically or only by EMG. Phenotypic variants can be associated with partial seizures, tight tendon Achilles, postural abnormalities in infancy, peripheral weakness without ataxia, and atypical cases may last 5 to 12 hours. The EA1 locus is mapped to chromosome 12q, and 19 missense mutations in KCNA1 have been reported.

Type 2 (EA2), the most common EA, is characterized by longer episodes of ataxia (hours) with spontaneous nystagmus (usually vertical and downbeat) and mildly progressive baseline ataxia. A gaze-evoked nystagmus is elicited between attacks. Attacks begin in early childhood, and are.associated with vertigo, nausea, vomiting, and migraine headaches. They are responsive to acetazolamide. EA2 is allelic with familial hemiplegic migraine type 1 (FHM1). The EA2 locus is mapped to chromosome 19p, similar to that of FHM1. EA 3-6 are described in only one or two families, but with distinctive genetic features and mapped to different chromosomes. Two North Carolina kindreds with EA4 had late-onset vestibulocerebellar ataxia, vertigo and interictal nystagmus. Linkage analysis ruled out EA1 and EA2 loci.

Differential dignosis of EA syndromes includes epilepsy, paroxysmal dyskinesias and migraine. Myokymia, an irregular undulation of the surface of muscles, distinguishes cases of EA1, and baseline nystagmus, ataxia and headaches are typical of EA2. Genetic testing is available for EA1 and EA2. In treatment, carbamazepine, valproic acid and acetazolamide are effective for EA1, and acetazolamide, flunarazine and 4-aminopyridine in EA2. [1]

COMMENT. Episodic ataxias are characterized by attacks of incoordination and imbalance, with onset in early childhood, and associated with myokymia, nystagmus and sometimes migraine headache or seizures. Attacks may be controlled by acetazolamide and/or carbamazepine. EAs are inherited as autosomal dominant channelopathies with mutations commonly in two genes.