The genetic spectrum of a population-based sample of familial hemiplegic migraine

Lise Lykke Thomsen*, M. Kirchmann, A. Bjornsson, H. Stefansson, R. M. Jensen, A. C. Fasquel, H. Petursson, M. Stefansson, M. L. Frigge, A. Kong, J. Gulcher, K. Stefansson, J. Olesen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura and transient hemiplegia. FHM mutations are known in three genes, the CACNA1A (FHM1) gene, the ATP1A2 (FHM2) and the SCN1A (FHM3) gene and seem to have an autosomal-dominant mode of inheritance. The aim of this study was to search for FHM mutations in FHM families identified through a screen of the Danish population of 5.2 million people. FHM patients were diagnosed according to the International Classification of Headache Disorders and all FHM patients had a physical and neurological examination by a physician. A total of 147 FHM patients from 44 different families were identified; 43 FHM families participated in this study. Linkage analysis of these families shows clear linkage to the FHM locus (FHM1) on chromosome 19, supportive linkage to the FHM2 locus whereas no linkage was found to the FHM3 locus. Furthermore, we sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes and screened for the Q1489K mutation in the SCN1A gene. CACNA1A gene mutations were identified in three of the FHM families, two known FHM mutations, R583Q and T666M and one novel C1369Y mutation. Three FHM families were identified with novel mutations in the ATP1A2 gene; a family with a V138A mutation, a family with a R202Q mutation and a family with a R763C mutation. None of the Danish FHM families have the Q1489K mutation in the SCN1A gene. Our study shows that only 14% (6/42) of FHM families in the general Danish population have exonic FHM mutations in the CACNA1A or ATP1A2 gene. The families we identified with FHM mutations in the CACNA1A and ATP1A2 genes were extended, multiple affected families whereas the remaining FHM families were smaller. The existence of many small families in the Danish FHM cohort may reflect less bias in FHM family ascertainment and/or more locus heterogeneity than described previously.

Original languageEnglish
Pages (from-to)346-356
Number of pages11
JournalBrain
Volume130
Issue number2
DOIs
Publication statusPublished - Feb 2007

Bibliographical note

Funding Information:
We thank the patients with FHM and their unaffected relatives who agreed to participate. We also thank our colleagues for their excellent collaboration. The work was supported by deCODE genetics and grants from the Cool sorption Foundation of 1988, the Foundation for Research in Neurology, the Danish Headache Society, The A.P. Møller Foundation for advancement of medical science, the Novo Nordisk Foundation, the IMK-Almene Foundation, The Glaxo Wellcome Research Prize and Ms Else Torp Foundation.

Other keywords

  • Familial hemiplegic migraine
  • Genetics
  • Genome scan
  • Loci
  • Mutations

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