Two novel SCN1A mutations identified in families with familial hemiplegic migraine.
BACKGROUND
Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by motor auras. The majority of FHM families have mutations in the CACNA1A and ATP1A2 genes; less than 5% of FHM families are explained by mutations in the SCN1A gene. Here we screened two Spanish FHM families for mutations in the FHM genes.


METHODS
We assessed the clinical features of both FHM families and performed direct sequencing of all coding exons (and adjacent sequences) of the CACNA1A, ATP1A2, PRRT2 and SCN1A genes.


RESULTS
FHM patients in both families had pure hemiplegic migraine with highly variable severity and frequency of attacks. We identified a novel SCN1A missense mutation p.Ile1498Met in all three tested hemiplegic migraine patients of one family. In the other family, novel SCN1A missense mutation p.Phe1661Leu was identified in six out of eight tested hemiplegic migraine patients. Both mutations affect amino acid residues that either reside in an important functional domain (in the case of Ile(1498)) or are known to be important for kinetic properties of the NaV1.1 channel (in the case of Phe(1661)).


CONCLUSIONS
We identified two mutations in families with FHM. SCN1A mutations are an infrequent but important cause of FHM. Genetic testing is indicated in families when no mutations are found in other FHM genes.
Department of Human Genetics, Leiden University Medical Center, the Netherlands a.m.j.m.van_den_maagdenberg@lumc.nl.
Claudia M
CM
Weller
Department of Neurology, Leiden University Medical Center, the Netherlands.
Nadine
N
Pelzer
Department of Human Genetics, Leiden University Medical Center, the Netherlands.
Boukje
B
de Vries
Department of Medical Genetics, Complejo Hospitalario de Navarra, Spain.
Mercè Artigas
MA
López
Department of Neurology, University Hospital Vall d'Hebron, Spain.
Oriol
O
De Fàbregues
Department of Neurology, University Hospital Central de Asturias and INEUROPA, Spain.
Julio
J
Pascual
Department of Medical Genetics, Complejo Hospitalario de Navarra, Spain.
María A Ramos
MA
Arroyo
Department of Human Genetics, Leiden University Medical Center, the Netherlands.
Stephany C
SC
Koelewijn
Department of Neurology, Leiden University Medical Center, the Netherlands.
Anine H
AH
Stam
Department of Neurology, Leiden University Medical Center, the Netherlands Department of Neurology, Rijnland Hospital, the Netherlands.
Joost
J
Haan
Department of Neurology, Leiden University Medical Center, the Netherlands.
Michel D
MD
Ferrari
Department of Neurology, Leiden University Medical Center, the Netherlands.
Gisela M
GM
Terwindt
Department of Human Genetics, Leiden University Medical Center, the Netherlands Department of Neurology, Leiden University Medical Center, the Netherlands.
Arn M J M
AM
van den Maagdenberg
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020325:Migraine with Aura / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human
   SCN1A gene; Migraine; familial hemiplegic migraine; ion channel defects