Brain Advance Access originally published online on December 2, 2006
Brain 2007 130(2):346-356; doi:10.1093/brain/awl334
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The genetic spectrum of a population-based sample of familial hemiplegic migraine
1 Danish Headache Center, University of Copenhagen, Department of Neurology Glostrup Hospital, Copenhagen, Denmark 2 deCODE Genetics, Reykjavik Iceland
Correspondence to: Lise Lykke Thomsen, MD, PhD, Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital, Nordre Ringvej 57, DK-2600 Glostrup, Denmark E-mail: llt{at}dadlnet.dk
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.
Key Words: familial hemiplegic migraine; mutations; genome scan; genetics; loci
Abbreviations: FHM, familial hemiplegic migraine; HM, hemiplegic migraine; MA, migraine with aura; MO, migraine without aura; SHM, sporadic hemiplegic migraine; TTH, tension type headache; ICHD-1, International Classification of Headache Disorders 1st Edition
Received August 7, 2006. Revised October 20, 2006. Accepted October 26, 2006.
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