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Genetics of Migraine

A main research line of the Neurogenetics lab is on the genetics of migraine, one of the most common neurological disorders. Twin and family history studies suggest there is a strong genetic component in migraine. Common forms of migraine (migraine with aura [MA] and migraine without aura [MO]) are genetically complex, multifactorial disorders and we are currently - in collaboration with other groups - aiming for a genome-wide association study to unravel genes implicated in common forms of migraine. The group has identified a third gene for familial hemiplegic migraine (FHM), a severe monogenic variant of MA with an autosomal-dominant pattern of inheritance. Current projects include the search for additional genes for FHM, a study on the role of FHM genes in sporadic hemiplegic migraine (SHM) and the generation of a SCN1A knock-in mouse model.

Familial hemiplegic migraine

Phenotype

According to the International Headache Society ,  FHM is defined by the following criteria:

  • autosomal-dominant inheritance (at least one more affected among first- or second-degree relatives)
  • presence of some degree of hemiparesis during the aura
  • presence of at least one further aura symptom (i.e. visual, sensory or aphasic disturbance)

Age at onset is typically in childhood or early adulthood. Attacks may be triggered by minor head trauma or exposure to contrast material. The frequency and severity of attacks is highly variable. Complications include prolonged duration of the aura phase as well as fever, confusion, coma and epileptic seizures. About 20% of families develop permanent cerebellar signs such as nystagmus, ataxia, or dysarthria (FHM plus)  and may show cerebellar atrophy on imaging.

Molecular genetics and pathophysiology

FHM is genetically heterogeneous. So far, three causative genes have been identified:

  • Families with FHM1 (OMIM 141500 ) have missense mutations in the CACNA1A gene (chromosome 19p13) which encodes the pore-forming alpha1a subunit of a neuronal voltage-gated calcium channel. Of note, different types of mutations in this gene are associated with episodic ataxia type 2 (EA-2) or spinocerebellar ataxia type 6 (SCA-6) (Ophoff et al. 1996 ; Zhuchenko et al. 1999).
  • FHM2 (OMIM 602481 ) is caused by missense mutations in ATP1A2 (chromosome 1q21-23) which encodes an astrocytic Na+/K+-transporter (De Fusco et al. 2003).

According to functional studies, mutations in the FHM1-3 genes seem to cause an increased neuronal excitability which may facilitate the initiation and propagation of cortical spreading depression, the likely correlate of migraine aura.

Projects

Our group has established a database of about 30 mostly German FHM families. Apart from active recruitment of further families ongoing projects include:

  • mutational analysis of the FHM1 - 3 genes (direct sequencing)
  • mutational analysis of the FHM1 - 3 genes in a sample of patients with sporadic hemiplegic migraine
  • functional characterization of ATP1A2 mutations associated with FHM by cell survival assays
  • generation of a knock-in mouse model for FHM3

Diagnostics

We offer molecular genetic testing for FHM on an individual basis. Before sending samples to our institute, pleae contact us for further details.

Sporadic migraine

Common forms of Migraine (MA and MO), though not monogenic conditions like FHM, also have a significant genetic component, as indicated by twin, family and population-based studies. Our group aims at identifying genes implicated in MA and MO . To this end we are currently recruiting a large sample of migraineurs (MA and MO) preferentially with a positive family history. To date, the database includes DNA samples from approximately 1000 index cases.

Team

Collaborators

  • Leiden University Medical Centre, Departments of Neurology and Human Genetics (Prof. M. Ferrari, A. van den Maagdenberg), Leiden, The Netherlands
  • Institute of Human Genetics (Prof. Th. Meitinger), GSF Research Center, Neuherberg, Germany
  • Institue of Developmental Genetics (Prof. W. Wurst), GSF Research Center, Neuherberg, Germany
  • Istituto di Biofisica (M. Pusch), Genua, Italy
  • Max-Volmer-Laboratorium für Biophysikalische Chemie, Technische Universität Berlin, (Th. Friedrich), Berlin, Germany
  • Department of Pharmacology / Toxicology, Radboud University Nijmegen Medical Centre (J. Koenderink), Nijmegen, The Netherlands
  • Migräneklinik Königstein (Drs. Brand), Königstein, Germany
  • Praxis Dr. Pfaffenrath und Reiter (Dr. Pfaffenrath), Munich, Germany

References

Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM. Lancet 2005; 366(9483):371-7 Pubmed
 
Freilinger T, Dichgans M. Genetik der Migräne. Nervenarzt 2006;77(10):1186-1195 Pubmed

Vanmolkot KRJ, Babini E, de Vries B, Stam AH, Freilinger T, Terwindt GM, Norris L, Haan J, Frants R, Ramadan NM, Ferrari MD, Pusch M, van den Maagdenberg AMJM, Dichgans M. The novel p.L1649Q mutation in the SCN1A epilepsy gene is associated with Familial Hemiplegic Migraine: genetic and functional studies. Hum Mut  (in press)

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