CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.
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.
Department of Pediatrics, Neurology Service, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.|Department of Pediatrics, Teaching Hospital of Rennes, Rennes, France.
Lena
L
Damaj
Department of Neuroscience, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Alexis
A
Lupien-Meilleur
Department of Pediatrics, Neurology Service, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.|Department of Neuroscience, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Anne
A
Lortie
Department of Pediatrics, CHUS, U. de Sherbrooke, Sherbrooke, Quebec, Canada.
Émilie
É
Riou
Department of Ophtalmology, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Luis H
LH
Ospina
Department of Pediatrics, Neurology Service, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Louise
L
Gagnon
Department of Pediatrics, Neurology Service, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Catherine
C
Vanasse
Department of Pediatrics, Neurology Service, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.|Department of Neuroscience, CHU Ste-Justine, U. de Montréal, Montreal, Quebec, Canada.
Elsa
E
Rossignol
D000328:Adult; D001259:Ataxia / Q000235:genetics / Q000503:physiopathology; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology; D001927:Brain Diseases / Q000235:genetics* / Q000503:physiopathology; D015220:Calcium Channels / Q000235:genetics*; D002526:Cerebellar Diseases / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D009759:Nystagmus, Pathologic / Q000235:genetics / Q000503:physiopathology; D017354:Point Mutation; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type