Submission Details

KCNA1 was first reported in relation to autosomal dominant episodic ataxia type 1 in 1994 (Browne et al., PMID: 7842011). Episodic ataxia type 1 is characterized by continuous muscle fiber activation or rippling (myokymia) and periodic ataxia, although the phenotype is highly variable. Of note, type 1 episodic ataxia is generally associated with brief periods of ataxia, lasting seconds, whereas other types of episodic ataxia present with longer episodes, usually hours (PMID:17575281). Episodic ataxia 1 may also include hypomagnesemia and renal magnesium wasting, features which may be underdiagnosed in patients with this condition due to lack of testing (PMID:32316562). About 20% of individuals with KCNA1-related episodic ataxia have seizures, and we did not identify any cases with isolated epilepsy (PMID: 32316562, 34566847). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no consistent differences in molecular mechanism, inheritance pattern, or variant location on phenotypic variability, so we are unable to “split” out the patients with seizures. Therefore, we are choosing to curate these cases under episodic ataxia type 1 (MONDO:0008047).

Eighteen variants (missense and nonsense) that have been reported in 20 probands in 8 publications (PMIDs: 7842011, 8541859, 11026449, 23349320, 28666963, 28676720, 20660867, 32705822) are included in this curation. Multiple variants have been shown to segregate with disease in families. Of note, we did not identify any cases with isolated epilepsy. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is unclear, as pathogenic variants have been found to have various effects in vitro (loss of function, gain of function, and dominant negative in PMIDs: 34778950, 9526001, and 11773313). This gene-disease relationship is also supported by experimental evidence: hippocampal brain slices lacking KCNA1 showed hyperexcitability and a mouse model expressing p.V408A showed impaired coordination under stress (PMIDs: 9581771, 12612586). In summary, there is a definitive relationship between KCNA1 and autosomal dominant episodic ataxia type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date March 7th, 2023 (SOP Version 9). In July 2024, this record underwent administrative changes to reflect additional review by the Tubulopathy GCEP and inclusion of information about hypomagnesemia. The classification remains the same.