Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine.
BACKGROUND
Familial (FHM) and sporadic (SHM) hemiplegic migraine are severe subtypes of migraine associated with transient hemiparesis. For FHM, three genes have been identified encoding subunits of a calcium channel (CACNA1A), a sodium-potassium pump (ATP1A2), and a sodium channel (SCN1A). Their role in SHM is unknown. Establishing a genetic basis for SHM may further the understanding of its pathophysiology and relationship with common types of migraine. It will also facilitate the often difficult differential diagnosis from other causes of transient hemiparesis.


METHODS
We systematically scanned 39 well-characterized patients with SHM without associated neurologic features for mutations in the three FHM genes. Functional assays were performed for all new sequence variants.


RESULTS
Sequence variants were identified in seven SHM patients: one CACNA1A mutation, five ATP1A2 mutations, and one SCN1A polymorphism. All six mutations caused functional changes in cellular assays. One SHM patient later changed to FHM because another family member developed FHM attacks.


CONCLUSIONS
We show that FHM genes are involved in at least a proportion of SHM patients without associated neurologic symptoms. Screening of ATP1A2 offers the highest likelihood of success. Because FHM gene mutations were also found in family members with "nonhemiplegic" typical migraine with and without aura, our findings reinforce the hypothesis that FHM, SHM, and "normal" migraine are part of a disease spectrum with shared pathogenetic mechanisms.
Departments of Human Genetics, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands.
B
B
de Vries
T
T
Freilinger
K R J
KR
Vanmolkot
J B
JB
Koenderink
A H
AH
Stam
G M
GM
Terwindt
E
E
Babini
E H
EH
van den Boogerd
J J M W
JJ
van den Heuvel
R R
RR
Frants
J
J
Haan
M
M
Pusch
A M J M
AM
van den Maagdenberg
M D
MD
Ferrari
M
M
Dichgans
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015220:Calcium Channels / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005820:Genetic Testing; D005858:Germany; D006801:Humans; D008881:Migraine Disorders / Q000235:genetics*; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000032:analysis*; D009426:Netherlands; D015222:Sodium Channels / Q000032:analysis*; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis*; D014481:United States; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D018389:Codon, Nonsense; 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