CACNA1A – Episodic Ataxia Type 2

Episodic ataxia type 2 (EA2) is an autosomal dominant paroxysmal cerebellar channelopathy characterized by recurrent attacks of vertigo, ataxia, nystagmus, nausea, and fatigue, often responsive to acetazolamide. EA2 is caused by heterozygous mutations in CACNA1A, encoding the P/Q-type voltage‐gated calcium channel α1A subunit Gene Symbol associated with EA2.

Multiple case series and linkage studies support a definitive gene–disease relationship. A de novo C>T substitution at c.4410 in exon 23 resulting in p.Ter1470Ter was identified in a sporadic EA2 patient responsive to acetazolamide (PMID:9600739). In familial EA2, a novel splice-site mutation IVS36-2A>G segregated in 13 affected individuals across three generations with a maximum LOD score of 4.48 (PMID:14530926). Conversely, a kindred with typical EA2 lacked CACNA1A mutations, highlighting locus heterogeneity (PMID:12525875).

The variant spectrum in EA2 exceeds 50 alleles, including nonsense, frameshift, splice-site, missense, and large‐scale deletions. Representative variants include c.1913G>A (p.Gly638Asp) identified in late-onset EA2 with interictal dystonia (PMID:19232643), IVS36-2A>G splice-site, and multiexon deletions detected by MLPA (PMID:19633872).

Functional assays demonstrate that truncating and missense EA2 mutations yield loss-of-function via reduced Ca2+ currents, impaired membrane trafficking, or accelerated inactivation. Six new truncations in familial and sporadic cases abolished channel function (PMID:10371528); two novel truncating mutations were linked to interictal dystonia (PMID:15710862). The H1736L missense variant near the pore reduced current density and shifted activation to more positive voltages (PMID:15293273). Premature stop codons in an EF-hand exon abolished facilitation (PMID:18606230).

Confounding evidence in EA2-like pedigrees without CACNA1A mutations suggests additional loci may underlie EA2 phenotypes (PMID:12525875). However, comprehensive genetic and functional concordance across numerous unrelated families supports a definitive classification for CACNA1A–EA2.

Key take-home: Heterozygous CACNA1A mutations cause EA2 via P/Q channel loss-of-function; genetic testing and functional annotation guide diagnosis and acetazolamide therapy.

References

• American Journal of Medical Genetics • 1998 • De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia. PMID:9600739
• Neurogenetics • 2004 • Novel splice site CACNA1A mutation causing episodic ataxia type 2. PMID:14530926
• International Journal of Molecular Medicine • 2003 • A family of episodic ataxia type 2: no evidence of genetic linkage to the CACNA1A gene. PMID:12525875
• Journal of the Neurological Sciences • 2009 • Late-onset episodic ataxia type 2 associated with a novel loss-of-function mutation in the CACNA1A gene. PMID:19232643
• Neurology • 1999 • High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. PMID:10371528
• Archives of Neurology • 2005 • Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia. PMID:15710862
• Annals of Neurology • 2004 • Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. PMID:15293273
• Neurobiology of Disease • 2008 • Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2. PMID:18606230

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