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. 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

Lena Damaj  1   2 , Alexis Lupien-Meilleur  3 , Anne Lortie  1   3 , Émilie Riou  4 , Luis H Ospina  5 , Louise Gagnon  1 , Catherine Vanasse  1 , Elsa Rossignol  1   3
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CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

Lena Damaj et al. Eur J Hum Genet. 2015 Nov.

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

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Figures

Figure 1
Figure 1
Family trees. The genealogical tree for each family is illustrated, with color-coding for associated symptoms (cf inset). Asterisks denote patients for which CACNA1A mutations were confirmed.
Figure 2
Figure 2
New and previously reported mutations in CaV2.1. Previously reported mutations in CACNA1A, causing either episodic ataxia type II (EA2; blue circles) or familial hemiplegic migraine type I (FHM1; white circles) affect most domains of the alpha1 subunit of the CaV2.1 calcium channel, as illustrated here (adapted from Mantuano et al, 2010). Red circles illustrate loss-of-function mutations reported in this publication.
See this image and copyright information in PMC

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