Dados do Trabalho

Título

CACNA1A variants: a conundrum of epilepsy, dystonia, and autistic-like features

Apresentação do caso

A 3-year-old Brazilian boy presented with global developmental delay, early-onset seizures, and autistic-like behavior. The boy was born to healthy nonconsanguineous parents at 39 weeks with Apgar score 9/10. The first episode of epilepsy was at 6 months of age with generalized status epilepticus. There was no language acquisition, and he started walking at age two years. Examination disclosed dystonia in the upper limbs, axial and perioral hypotonia, marked psychomotor agitation. He did not understand the examiner tasks and produced unrecognizable sounds in his speech attempt, such as screams. Electroencephalography revealed multifocal spikes. Brain MR imaging studies were unremarkable. A large next-generation sequencing (NGS)-based multigene panel for inherited epilepsies and movement disorders disclosed the heterozygous variant c.176T>C (p.Met59Thr) in the CACNA1A gene. This variant is absent in gnomAD (exome/genome) database, and fulfilled PM2, PP2 and PP3 ACMG 2015 criteria for “in silico” prediction of pathogenicity. Several “in silico” tools predicted deleterious effect of the variant (MutationTaster2, Revel, Varity, MetaLR, GenoCanyon, fitCons). Currently, he regularly treats with valproate (50mg/kg/day), lamotrigine (3mg/kg/day), oxcarbazepine (30mg/kg/day) and ketogenic diet with good control of seizures.

Discussão

CACNA1A gene variants have been associated with rare and heterogeneous inherited neurological disorders, including autosomal dominant Episodic Ataxia type 2, Familial Hemiplegic Migraine type 1, Spinocerebellar Ataxia type 6, and Early infantile epileptic encephalopathy type 42. Clinical presentation widely ranges from cases associated with pure epileptic phenotypes to complex presentations with early-onset epileptic-dyskinetic encephalopathy and neurological regression. CACNA1A gene encodes the transmembrane pore-forming subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel, which is involved in a variety of Ca(2+)-dependent processes, including muscle contraction, hormone and neurotransmitter release, and gene expression.

Comentários finais

Our case description emphasizes the importance of performing large NGS-based panels to evaluate patients with complex association of refractory epilepsy, dystonia, and autistic-like features.

Área

GENÉTICA EM EPILEPSIA