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Eur J Hum Genet. 2015 Nov;23(11):1505-12. doi: 10.1038/ejhg.2015.21. Epub 2015 Mar 4.

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

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Department of Pediatrics, Neurology Service, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Department of Pediatrics, Teaching Hospital of Rennes, Rennes, France.
Department of Neuroscience, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Department of Pediatrics, CHUS, U. de Sherbrooke, Sherbrooke, Quebec, Canada.
Department of Ophtalmology, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.


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 CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

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