CA8 – Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium Syndrome 3

Biallelic pathogenic variants in CA8 cause Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3, an autosomal recessive disorder characterized by progressive cerebellar ataxia, variable intellectual disability, and dysequilibrium.

Two singleton reports describe novel homozygous variants in CA8: a truncating variant c.232C>T (p.Arg78Ter) in a 9-year-old boy with normal intellect and progressive cerebellar atrophy (PMID:31693170), and a missense c.251A>G (p.Asn84Ser) in an 11-year-old girl with ataxia and focal seizures despite normal MRI (PMID:32808436). Both parents and an unaffected sibling were heterozygous carriers, supporting autosomal recessive segregation.

A recent cohort study of 27 affected individuals from 14 unrelated families confirmed the association of biallelic CA8 variants with the clinical spectrum of CAMRQ3, including neurodevelopmental delay, progressive cerebellar atrophy—particularly superior vermis—and pyramidal signs, bradykinesia, dystonia, and sensory impairment (PMID:38581205). Zebrafish ca8 knockout models mirrored early neurodevelopmental defects and motor impairment concordant with human phenotypes.

The variant spectrum includes truncating alleles (e.g., c.232C>T (p.Arg78Ter)), missense changes (p.Tyr218Cys, p.Gln171His, p.Gly162Arg), and splice-site mutations (c.738+1G>A, c.100+1G>A). All reported variants are inherited in homozygous or compound heterozygous states under an autosomal recessive model.

Functional evidence further supports a loss-of-function mechanism: a spontaneous mouse model with homozygous intragenic deletion exhibited nonsense-mediated decay and recapitulated cerebellar ataxia and motor delay (PMID:31693170), while zebrafish knockout demonstrated impaired neurodevelopment and motor behavior (PMID:38581205). Disruption of CA8-mediated regulation of IP3R1 calcium signaling provides mechanistic concordance.

Collectively, the genetic and experimental data support a Strong ClinGen gene–disease association. Biallelic CA8 variant detection confirms diagnosis, informs prognosis, and enables genetic counseling. Key take-home: testing for CA8 variants is clinically actionable for individuals presenting with early onset ataxia and dysequilibrium.

References

• Clinical genetics • 2020 • Cerebellar ataxia with normal intellect associated with a homozygous truncating variant in CA8. PMID:31693170
• American journal of medical genetics. Part A • 2020 • Novel homozygous variant of carbonic anhydrase 8 gene expanding the phenotype of cerebellar ataxia, mental retardation, and disequilibrium syndrome subtype 3. PMID:32808436
• Movement Disorders • 2024 • Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia. PMID:38581205

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