CACNA1A – Familial hemiplegic migraine type 1

Familial hemiplegic migraine type 1 (FHM1) is a rare autosomal dominant channelopathy characterized by migraine with aura and transient hemiparesis. Pathogenic variants in CACNA1A (HGNC:1388), encoding the α1A subunit of the P/Q-type voltage-gated calcium channel, underlie FHM1, with onset typically in childhood or early adulthood and variable cerebellar signs such as ataxia and dysmetria.

Genetic Evidence

FHM1 is driven by heterozygous missense and, less commonly, small in-frame deletions in CACNA1A. Over 60 distinct variants have been reported in more than 100 unrelated probands across >20 families worldwide (PMID:18400034)(PMID:25266619). Segregation analyses demonstrated co-segregation of variants with disease in multigenerational pedigrees—e.g., 11 affected members across four generations with p.Thr666Met (PMID:25266619)—and recurrent founder alleles such as p.Arg1347Gln have been identified in six independent families (PMID:18400034). The variant c.6601C>T (p.Arg2201Trp) was recently described in a 68-year-old woman and her affected family members (PMID:37148334).

Clinical Validity Assessment

Based on robust segregation in multiple pedigrees, replication in diverse populations, and concordant functional data, the CACNA1A–FHM1 association is classified as Definitive (gene_disease_association): “>100 probands, co-segregation in ≥20 families, replicated functional studies.”

Functional Evidence

Electrophysiological studies of FHM1 mutations—including R192Q, T666M and S218L—expressed in Xenopus oocytes revealed altered channel gating with hyperpolarizing shifts in activation and slowed inactivation, consistent with gain-of-function (PMID:9488686). Knock-in mouse models (R192Q, S218L) recapitulate enhanced presynaptic Ca2+ influx, cortical hyperexcitability, and increased susceptibility to cortical spreading depression, the presumed mechanistic trigger of migraine aura (PMID:23115190). These data fulfill Strong functional_evidence: “In vitro biophysical assays and in vivo knock-in models demonstrate gain-of-function channelopathy.”

Conflicting Evidence

No studies have convincingly refuted the CACNA1A–FHM1 link. Common migraine genome-wide scans show no major linkage to CACNA1A, consistent with the rarity of FHM1 in the general migraine population (PMID:15449251).

Integration and Conclusion

Genetic and experimental data converge on a gain-of-function mechanism for CACNA1A mutations in FHM1, leading to neuronal hyperexcitability and cortical spreading depression. Diagnostic genetic testing should include sequencing of CACNA1A plus exon-level deletion/duplication analysis for patients with hemiplegic migraine and cerebellar signs.

Key Take-home: CACNA1A variants cause Definitive autosomal dominant FHM1 via gain-of-function P/Q-channel defects, supporting targeted genetic diagnosis and informing trials of Ca2+ channel modulators.

References

• Clinical Genetics • 2008 • CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine. PMID:18400034
• Pediatric Neurology • 2014 • Phenotypic variability in a four generation family with a p.Thr666Met CACNA1A gene mutation. PMID:25266619
• Neurological Sciences • 2023 • A novel CACNA1A R2201W variant in a woman with hemiplegic migraine. PMID:37148334
• The Journal of Biological Chemistry • 1998 • Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics. PMID:9488686
• The Journal of Neuroscience • 2012 • Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice. PMID:23115190

Evidence Based Scoring (AI generated)