Familial Hemiplegic Migraine

Abstract

Summary: 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 ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ 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 Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-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 ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) 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 ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (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 strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

“…When this mechanism fails, it leads to elevated extracellular levels of glutamate and potassium, and accordingly, to an increased susceptibility to CSD (Pietrobon 2007, Koenderink et al 2005. All FHM2 mutations studied in heterologous expression systems result in a "loss-of-function" or a kinetically altered Na + , K + pump (Pietrobon 2007, Tavraz et al 2008, Vanmolkot et al 2006, Segall et al 2005). …”

Cerebellar Ataxia by Enhanced CaV2.1 Currents Is Alleviated by Ca2+-Dependent K+-Channel Activators inCacna1aS218LMutant Mice

“…An increase or decrease in Ca V 2.1-mediated Ca 2ϩ influx results in different clinical manifestations: CACNA1A gene mutations that increase Ca V 2.1-mediated Ca 2ϩ influx are linked to familial hemiplegic migraine type 1 (FHM1) (Pietrobon, 2007), whereas episodic ataxia type 2 is linked to mutations in the CACNA1A gene that decrease Ca V 2.1-mediated Ca 2ϩ influx (Ophoff et al, 1996;van den Maagdenberg et al, 2007). Studies of ataxic mouse models, such as tottering and leaner mice (Fletcher et al, 1996;Mori et al, 2000) that carry mutations in the orthologous mouse Cacna1a gene revealed that a decreased Ca V 2.1-mediated Ca 2ϩ influx consistently results in disrupted Purkinje cell firing activity (Hoebeek et al, 2005;Walter et al, 2006).…”

Stabilization of the α2 Isoform of Na,K-ATPase by Mutations in a Phospholipid Binding Pocket

“…Familial hemiplegic migraine is a rare but severe autosomal dominant subtype of migraine with aura (28). About 25% of familial hemiplegic migraine cases (type 2) are attributed to mutations to ␣2 (29,30).…”