, Volume 4, Issue 2, pp 274–284 | Cite as

Familial hemiplegic migraine

  • Daniela Pietrobon


Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming α1 subunits of the neuronal voltage-gated Ca2+ channels Cav2.1 and Na+ channels Nav1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the α2 subunit of the Na+, K+ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Cav2.1 channel and, as a consequence, increased Cav2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the α2 Na+,K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Nav1.5 (and presumably Nav1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategics that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

Key Words

Migraine cortical spreading depression Ca2+ channel Na+ K+ ATPase Na+ channel epilepsy 


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© Springer New York 2007

Authors and Affiliations

  1. 1.Dept. Biomedical ScicncesUniversity of PadovaPadovaItaly

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