Episodic ataxia

Episodic ataxia is a rare form of hereditary ataxia in which a central nervous system channelopathy presents with distinct episodes of incoordination and imbalance.

• Ataxic symptoms occur in ‘attacks’ with a clear onset and resolution. There may be a recognisable trigger, such as emotional stress, physical exertion, environmental temperature, caffeine, alcohol or sudden movement.
• The core features during an episode are ataxia, dysarthria and nystagmus. Other features can include sweating, vertigo, headache, muscle stiffness or weakness, rippling muscle movement (myokymia), dystonia, tremor, diplopia, hemiplegia, nausea, vomiting and tinnitus.
• Episodes can vary in length from seconds to days. Frequency and age of onset vary.
• Interictal features such as ataxia, myokymia or gaze-evoked nystagmus may be present and can be progressive.
• Epilepsy or intellectual disability can be present. Joint contractures can develop as a complication.
• Brain imaging may show cerebellar vermis atrophy.

Eight subtypes of episodic ataxia have been described clinically, although there is significant overlap between them and genetic confirmation is advised. Episodic ataxia results from variants in genes involved in neurotransmission and neuronal excitability.

• Episodic ataxia type 1 is caused by variants in the KCNA1 gene, which encodes for part of a neuronal potassium channel.
• Episodic ataxia type 2 is caused by variants in the CACNA1A gene, which encodes for part of a neuronal calcium channel. This condition is allelic to spinocerebellar ataxia type 6 and familial hemiplegic migraine, and there may be significant overlap in features.
• Episodic ataxia type 6 is caused by variants in the SLC1A3 gene, which encodes for part of a glial excitatory amino acid transporter. Fever is a prominent trigger.
• The genetic bases for some clinically identified subtypes of episodic ataxia have not yet been identified, but the genomic testing currently available will identify a causative variant in the majority of those assessed.

There are a number of important points to bear in mind when considering genomic testing.

• Genes involved in a variety of other conditions, including progressive ataxia syndromes, complex movement conditions, metabolic conditions, epilepsy syndromes and mitochondrial conditions can also present with episodic features. The wider differential in those with atypical or complex features should be considered.
• Choice of genomic testing type in patients with features of episodic ataxia is important. Whole genome sequencing may not detect multi-exon deletions or duplications, which will be detected by multiplex ligation-dependent probe amplification (MLPA). The panel R66 Paroxysmal central nervous system disorders includes sequencing and MLPA of the known episodic ataxia genes. Other panels may not include MLPA.
• Because episodic ataxia is primarily a clinical diagnosis, the absence of a causative variant on genomic testing does not exclude the possibility of a diagnosis.

Episodic ataxia types 1, 2 and 6 are inherited in an autosomal dominant pattern, and both inherited and de novo variants have been reported. In patients with no identifiable genetic cause, the inheritance is likely to be autosomal dominant; in those with atypical or complex features, the inheritance may depend on the underlying diagnosis.

Management of individuals with episodic ataxia is complex and should be delivered via a multidisciplinary team. Symptomatic drug management may involve off-license prescription of acetazolamide or anti-epileptic medications.

For clinicians

• GeneReviews: Episodic ataxia type 1
• NHS England: National Genomic Test Directory

References:

• Olszewska DA, Rajalingam R, Shetty A and others. ‘Genotype-phenotype relations for episodic ataxia genes: MDSGene systematic review’. European Journal of Neurology 2023: volume 30, issue 10, pages 3,377–3,393. DOI: 10.1111/ene.15969

For patients

• Ataxia UK
• National Ataxia Foundation