Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A.
Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.
Division of Molecular Pediatrics, Lausanne University Hospital, Lausanne, Switzerland. Electronic address: nuria.garcia-segarra@chuv.ch.
Nuria
N
García Segarra
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Ivan
I
Gautschi
Division of Molecular Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
Laureane
L
Mittaz-Crettol
Neuropediatric Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
Christine
C
Kallay Zetchi
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Lama
L
Al-Qusairi
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Miguel Xavier
MX
Van Bemmelen
Department of Radiology, Lausanne University Hospital, Lausanne, Switzerland.
Philippe
P
Maeder
Division of Molecular Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
Luisa
L
Bonafé
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Laurent
L
Schild
Neuropediatric Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
Eliane
E
Roulet-Perez
D000086:Acetazolamide / Q000627:therapeutic use; D000293:Adolescent; D000818:Animals; D001259:Ataxia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D001929:Brain Edema / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics* / Q000502:physiology; D002524:Cerebellar Ataxia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008564:Membrane Potentials; D008881:Migraine Disorders / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D059906:Neuroimaging; D009865:Oocytes; D014982:Xenopus laevis; D020864:Calcium Channels, N-Type
D000086:Acetazolamide; D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type
Acetazolamide response; Congenital ataxia; Developmental delay; Gain of function; Novel CACNA1A mutation; Severe SHM1