CAMTA1 – Cerebellar dysfunction with variable cognitive and behavioral abnormalities

CAMTA1 encodes a calmodulin-binding transcriptional activator highly expressed in cerebellar neurons, implicated in cell cycle regulation, neuronal differentiation, and long-term memory formation. Pathogenic variants in CAMTA1 underlie cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), manifesting as congenital ataxia with cognitive and behavioral deficits.

In the largest multicenter cohort to date, 26 new individuals and literature review totaling 53 affected cases demonstrate autosomal recessive CECBA due to biallelic CAMTA1 variants. Twenty-three novel variants were identified: frameshift (n=7), nonsense (n=6), splicing (n=1), initiation codon (n=1), missense (n=5), and intragenic deletions (n=3) (PMID:38044714).

Inheritance is autosomal recessive with evidence of segregation in multiple families; clinical data reveal reduced penetrance and variable expressivity, as over one-third of alleles were inherited from asymptomatic or mildly affected parents (PMID:38044714).

Affected individuals uniformly exhibit developmental delay/intellectual disability, unsteady gait, hypotonia, behavioral abnormalities, and eye findings. Dysarthria, dysgraphia, microcephaly, gastrointestinal issues, sleep disturbances, and nonspecific MRI abnormalities are also frequent features of CECBA.

Functional studies in patients with CAMTA1 intragenic deletions reveal a neuropsychological profile of slowed processing, memory consolidation deficits, and phonological and working memory impairments. MRI and FDG-PET imaging demonstrate parietal and temporal hypometabolism concordant with cerebellar and cognitive dysfunction (PMID:24145135).

No studies have refuted the CAMTA1-CECBA association; experimental and clinical data are concordant, supporting a loss-of-function mechanism with impaired transcriptional regulation in cerebellar neurons.

Taken together, the genetic and functional evidence firmly supports a strong clinical validity for CAMTA1 in CECBA. Genetic testing for CAMTA1 variants informs diagnosis, prognosis, and management recommendations for affected individuals.

References

• Clinical Genetics • 2024 • CAMTA1-related disorder: Phenotypic and molecular characterization of 26 new individuals and literature review. PMID:38044714
• Brain & development • 2014 • Neuropsychological and neuroimaging phenotype induced by a CAMTA1 mutation. PMID:24145135

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