1. ¹Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
2. ²Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
3. ³Department of Neurology, Dr Lütfi Kirdar State Hospital, Maltepe, Istanbul, Turkey
4. ⁴Department of Pediatric Neurology, Institute of Neurological Sciences, Maltepe, Istanbul, Turkey
5. ⁵Department of Neurology, University Medical Centre St Radboud, Nijmegen, The Netherlands
6. ⁶Department of Pharmacology & Toxicology, Nijmegen, Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
7. ⁷Department of Neurology, The Mayo Clinic, Rochester, MD, USA
8. ⁸Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands
9. ⁹Human Molecular Genetics Unit, Dibit-Dan Raffaele Scientific Institute, Milan, Italy
10. ¹⁰Vita-Salute San Raffaele University, School of Medicine, Milan, Italy

Correspondence: Dr AMJM van den Maagdenberg, Department of Human Genetics, Leiden University Medical Centre, Postbus 9600, 2300 RC, Leiden, the Netherlands. Tel: +31 71 5276062; Fax: +31 71 5276075; E-mail: maagdenberg@lumc.nl

Received 9 September 2005; Revised 19 January 2006; Accepted 8 February 2006; Published online 15 March 2006.

Abstract

Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine, in which hemiparesis occurs during the aura. The majority of the families carry mutations in the CACNA1A gene on chromosome 19p13 (FHM1). About 20% of FHM families is linked to chromosome 1q23 (FHM2), and has mutations in the ATP1A2 gene, encoding the 2-subunit of the Na,K-ATPase. Mutation analysis in a Dutch and a Turkish family with pure FHM revealed two novel de novo missense mutations, R593W and V628M, respectively. Cellular survival assays support the hypothesis that both mutations are disease-causative. The identification of the first de novo mutations underscores beyond any doubt the involvement of the ATP1A2 gene in FHM2.