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

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.

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

New and previously reported mutations in Ca_V2.1. 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 Ca_V2.1 calcium channel, as illustrated here (adapted from Mantuano et al, 2010). Red circles illustrate loss-of-function mutations reported in this publication.