title: De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine.
abstract: OBJECTIVE
  Hemiplegic migraine (HM) is a rare subtype of migraine with aura that may occur as a familial (FHM) or sporadic condition (SHM). Screening of FHM genes in previous series of patients with SHM detected a very low proportion of mutated patients. In this study, we investigated the FHM genes in patients with an early onset sporadic form of HM (onset before 16 years).
  
  
  METHODS
  Twenty-five patients were included. Each one and his or her 2 parents were blood sampled. Mean age at diagnosis was 14.7 ± 8.2 years and mean age at clinical onset was 7.7 ± 3.4 years. Sequencing of ATP1A2 and CACNA1A was conducted in each proband and all identified variants were looked for in both parents. SCN1A was screened in all patients without CACNA1A or ATP1A2 de novo mutation.
  
  
  RESULTS
  Twenty-three different amino acid variants were identified in 23 of the 25 patients. The variants occurred de novo in 19 patients (76%), strongly in favor of their causal role. SCN1A analysis did not show any mutation. Among the 19 patients with a de novo mutation, 5 had a pure HM and 14 had associated neurologic signs such as ataxia, epilepsy, or intellectual disabilities.
  
  
  CONCLUSIONS
  FHM genes are involved in early-onset SHM, in particular when associated with neurologic signs. Molecular analysis can be helpful in those cases. Our study identified 14 novel de novo mutations that will help to interpret genetic tests in molecular diagnosis practice.
authors.affiliation: Laboratoire de Génétique Moléculaire, APHP-Hôpital Lariboisière, Paris, France. florence.riant@lrb.aphp.fr
authors.forename: F
authors.initials: F
authors.lastname: Riant
authors.forename: A
authors.initials: A
authors.lastname: Ducros
authors.forename: C
authors.initials: C
authors.lastname: Ploton
authors.forename: C
authors.initials: C
authors.lastname: Barbance
authors.forename: C
authors.initials: C
authors.lastname: Depienne
authors.forename: E
authors.initials: E
authors.lastname: Tournier-Lasserve
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D019295:Computational Biology; D004247:DNA / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006429:Hemiplegia / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D015222:Sodium Channels / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D055815:Young Adult; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D004247:DNA; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D000254:Sodium-Potassium-Exchanging ATPase; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C568242:SCN1A protein, human; C498531:ATP1A2 protein, human