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Título

CACNA1A GENE ASSOCIATED WITH EPILEPTIC AND DEVELOPMENTAL ENCEPHALOPATHY: A CASE REPORT

Apresentação do caso único

The CACNA1A gene encodes the transmembrane pore-forming subunit of voltage-dependent calcium channels. These are widely expressed throughout the CNS and mediate the influx of calcium ions into excitable cells involved in different processes, including muscle contraction and neurotransmitter release, among others. Heterozygous pathogenic variants in this gene are associated with a wide phenotypic spectrum.
Case Description: Male patient, 6 years old, son of non-consanguineous parents with intellectual disabilities. Global hypotonia was noted from the age of four months. All developmental milestones were delayed. Acquired independent walking at the age of 2. At the age of 3, frequent intermittent falls were noted. At the age of 4, he began to suffer from difficult-to-control epilepsy. Currently, he continues to have global developmental delay, significant behavioral changes, neurological examination without hypotonia or spasticity of limbs or other pathological findings. Etiological investigation with karyotype and PCR for Fragile X within the normal range, awaiting skull MRI. A genetic panel for movement disorders was requested, which detected a heterozygous copy of the CACNA1A gene.

Discussão

The CACNA1A gene in heterozygosity has been associated with a variety of clinical conditions, including: Episodic Ataxia Type 2, Hemiplegic Migraine and Epileptic and Developmental Encephalopathy (DEE). The variant found, chr19:13.275.893 C>T (or alternatively c.3946G>A - ENST00000360228), promotes the replacement of the amino acid aspartate at codon 1316 with asparagine. The aspartate at position 1316 is highly conserved in different biological species and studies suggest that its substitution by asparagine is potentially deleterious. This variant has been described 4 times in databases, 1 as potentially pathogenic and 3 as a variant of uncertain significance.

Comentários finais

New variant studies show a wide phenotypic spectrum, from mild epilepsy and developmental delay to patients with ASD. According to the patient's clinical picture and the characteristics of the region where the variant is found, there is a high probability that it is associated with the clinical picture; however, according to the recommendations of the American College of Medical Genetics and Genomics (ACMG), it remains classified as a variant of uncertain significance (VUS). This case is important because it demonstrates symptoms related to this genetic variation, adding data for confirmation as a Pathogenic Variant.

Referências

Li XL, Li ZJ, Liang XY, Liu DT, Jiang M, Gao LD, Li H, Tang XQ, Shi YW, Li BM, He N, Li B, Bian WJ, Yi YH, Cheng CF, Wang J. CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications. Front Mol Neurosci. 2022 May 4;15:860662. doi: 10.3389/fnmol.2022.860662. PMID: 35600082; PMCID: PMC9116572.

Palavras Chave

Genetic; CACNA1A; VUS