CACNA1G – spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits

Autosomal-dominant, early-onset spinocerebellar ataxia 42 with neurodevelopmental deficits (SCA42ND) is caused by heterozygous de novo missense variants in CACNA1G, encoding the Cav3.1 T-type calcium channel. Patients present in infancy with cerebellar ataxia and global developmental delay, often without clear cerebellar atrophy on neuroimaging.

A recent cohort of 19 unrelated pediatric cases carrying congenital CACNA1G variants—including 6 new heterozygotes for the recurrent p.(Ala961Thr) and p.(Met1531Val) and 8 novel missense changes—supports a strong genetic association (19 probands) (PMID:39674904). All variants arose de novo without evidence of familial segregation.

The variant spectrum in SCA42ND is dominated by missense changes clustered in the intracellular gate of Cav3.1. A representative recurrent allele is c.2881G>A (p.Ala961Thr) (PMID:32736238). No loss-of-function alleles or deep-intronic variants have been described to date.

Patch-clamp recordings in HEK293T cells demonstrate that intracellular-gate variants slow channel inactivation and deactivation kinetics and increase window current, consistent with a gain-of-function mechanism. By contrast, a variant in the IS4–S5 linker (p.Met197Arg) shows loss of channel activity (PMID:39674904).

Mechanistically, gain-of-function Cav3.1 activity is expected to disrupt cerebellar Purkinje cell firing and early neurodevelopment, correlating with severe ataxia and cognitive impairment. The recurrent p.(Ala961Thr) and p.(Met1531Val) alleles show concordant electrophysiological defects across independent studies.

Key take-home: De novo gain-of-function missense variants in CACNA1G are strongly associated with autosomal-dominant SCA42ND and should be included in genetic testing panels for early-onset cerebellar ataxia with neurodevelopmental deficits.

References

• Genetics in medicine • 2025 • The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND. PMID:39674904
• Journal of the neurological sciences • 2020 • De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies. PMID:32736238

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