Early-onset progressive ataxia associated with the first CACNA1A mutation identified within the I-II loop

Area of Science:

• Neurogenetics
• Molecular Neurology
• Calcium Channelopathies

Background:

• Familial hemiplegic migraine type 1 (FHM1), spinocerebellar ataxia type 6 (SCA6), and episodic ataxia type 2 (EA2) are allelic disorders caused by mutations in the CACNA1A gene.
• The CACNA1A gene encodes the alpha1 subunit of the P/Q-type calcium channel (CaV2.1), crucial for neuronal excitability and neurotransmitter release.
• SCA6 and EA2 exhibit overlapping clinical features, including cerebellar dysfunction and responsiveness to acetazolamide, but differ in onset and progression (late-onset progressive ataxia vs. early-onset episodic ataxia).

Observation:

• Two sisters presented with heterogeneous phenotypes related to CACNA1A mutations.
• The first sister developed progressive cerebellar ataxia after age 30, unresponsive to acetazolamide.
• The second sister experienced childhood-onset episodic vertigo, headache, and gait imbalance with good acetazolamide response, later developing chronic cerebellar ataxia.
• Both patients displayed cerebellar atrophy, particularly in the vermis, on brain MRI.

Findings:

• Direct sequencing of CACNA1A revealed a heterozygous 1360G>A mutation in exon 11, resulting in an alanine to threonine substitution at residue 454 (p.Ala454Thr).
• This mutation is located in the cytoplasmic I-II loop of the CaV2.1 channel.
• This represents the first reported CACNA1A mutation in this specific region associated with a clinical phenotype.

Implications:

• The identified p.Ala454Thr mutation expands the spectrum of CACNA1A mutations linked to neurological disorders.
• The heterogeneous clinical presentation in the sisters highlights the variable expressivity of CACNA1A-related channelopathies.
• This finding underscores the importance of the cytoplasmic I-II loop in CACNA1A channel function and its contribution to disease pathogenesis.