1. CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.
- Author
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Damaj, Lena, Lupien-Meilleur, Alexis, Lortie, Anne, Riou, Émilie, Ospina, Luis H, Gagnon, Louise, Vanasse, Catherine, and Rossignol, Elsa
- Subjects
COGNITION disorder risk factors ,AUTISM risk factors ,EPILEPSY risk factors ,CEREBELLUM diseases ,GENETIC mutation ,SPINOCEREBELLAR ataxia ,FEBRILE seizures - Abstract
CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of Ca
V 2.1 channels function, presumably affecting cerebellar, cortical and limbic networks. [ABSTRACT FROM AUTHOR]- Published
- 2015
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