Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Familial Hemiplegic Migraine (FHM) [G43.1]

OMIM numbers: 141500, 601001 (CACNA1A), 602481 182340 (ATP1A2), 609634 (FHM3), 182389 (SCN1A)

Dr. med. Imma Rost, Dr. rer. nat. Karin Mayer

Scientific Background

Familial hemiplegic migraine (FHM) is a rare (prevalence approx. 1:10,000) monogenic form of migraine. According to the criteria of the International Headache Society of 2004, it belongs to the group of migraines with aura. Just like in other forms of migraine, aura may consist of visual, sensory and speech disorders; FHM, however, is also characterized by a motor disorder in the form of long-lasting, reversible hemiparesis. Additional cerebellar signs and symptoms such as progressive, mild ataxia and/or nystagmus are seen in 20–40% of all families. By definition, at least one other first-degree relative is affected in the familial form.

The aura is most likely caused by CSD (cortical spreading depression), which was proved from animal models: a depression slowly moving across the cortex and temporarily inhibiting other neuronal activities. The actual headache is thought to be caused by inactivation of what is known as the trigeminovascular system (TGVS). The same therapeutic and prophylactic medication as for migraine may be given; triptans and other vasoconstrictor substances should be avoided.

The three causative genes known so far are CACNA1A (FHM1), ATP1A2 (FHM2) and SCN1A (FHM3) and encode either components of ion channels (CACNA1A and SCN1A) or a Na+-K+ ATPase (ATP1A2). Therefore, FHM belongs to the ion channel diseases. Since mutations in these genes were not detected in every family, it is assumed that there are other, rarer forms (FHM4-6). The sporadic form (SHM) is thought to be caused by a dominant new mutation or a reduced penetrance. Depending on the population that was examined, SHM patients did not, or very rarely, have mutations in the genes known so far to cause FHM. Since the different forms of FHM are dificult to distinguish clinically all three genes can be analyzed simultaneously by next generation sequencing

FHM overlaps clinically, genetically and pathophysiologically with epilepsy and other neurological disorders. Mutations in the three causative genes are also described to cause epilepsy; SCN1A for example is thought to cause the Dravet syndrome or the generalized epilepsy with febrile seizure plus (GEFS+).

Due to the autosomal dominant inheritance, there is a recurrence risk of 50% for children of mutation carriers.