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NEUROLOGY 2007;69:2170-2176
© 2007 American Academy of Neurology

Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine

B. de Vries, MSc, T. Freilinger, MD, K.R.J. Vanmolkot, MSc, J. B. Koenderink, PhD, A. H. Stam, MD, G. M. Terwindt, MD, PhD, E. Babini, PhD, E. H. van den Boogerd, BSc, J. J.M.W. van den Heuvel, BSc, R. R. Frants, PhD, J. Haan, MD, PhD, M. Pusch, PhD, A. M.J.M. van den Maagdenberg, PhD, M. D. Ferrari, MD, PhD and M. Dichgans, MD, PhD

From the Departments of Human Genetics (B.d.V., K.R.J.V., E.H.v.d.B., R.R.F., A.M.J.M.v.d.M.) and Neurology (A.H.S., G.M.T., J.H., A.M.J.M.v.d.M., M.D.F.), Leiden University Medical Centre, Leiden, The Netherlands; Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität, München, Germany (T.F., M.D.); Department of Pharmacology and Toxicology, Centre for Molecular Life Sciences, University Medical Centre St. Radboud, Nijmegen, The Netherlands (J.B.K., J.J.M.W.v.d.H.); Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genoa, Italy (E.B., M.P.); and Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands (J.H.).

Address correspondence and reprint requests to Dr. Michel D. Ferrari, Department of Neurology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands

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.

Conclusion: 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.

Abbreviations: ATPase = adenosine triphosphatase; BAM = basilar artery migraine; Ctrl = control; cDNA = complementary DNA; Fam = family; FHM = familial hemiplegic migraine; HM = hemiplegic migraine; IHS = International Headache Society; MA = migraine with aura; MO = migraine without aura; SHM = sporadic hemiplegic migraine; WT = wild type.

m.d.ferrari{at}lumc.nl

Supplemental data at www.neurology.org

*These authors contributed equally.

Supported by grants from The Netherlands Organization for Scientific Research (903-52-291, M.D.F., R.R.F., and Vici 918.56.602, M.D.F.), The Migraine Trust, (R.R.F., M.D.F.), the EU "EUROHEAD" grant (LSHM-CT-2004-504837, M.D.F., R.R.F., A.M.J.M.v.d.M), Hersenstichting (J.B.K., A.M.J.M.v.d.M.), and the Center of Medical System Biology established by The Netherlands Genomics Initiative/Netherlands Organization for Scientific Research. Further supported by the Deutsche Forschungsgemeinschaft (DFG D1 722/8-1 and DI 722/8-2) and Telethon Italy (grant GGP04018).

Disclosure: The authors report no conflicts of interest.

Received March 30, 2007. Accepted in final form May 31, 2007.




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