Novel Mutation Confirms Seizure Locus SCN1A is Also Familial Hemiplegic Migraine Locus FHM3

Abstract

While the gene encoding the neuronal voltage-gated sodium channel, type 1A is a well-recognized target of mutations underlying a spectrum of epilepsy syndromes, and lies within an extended 12 megabase disease-associated haplotype at the Familial Hemiplegic Migraine, type 3 locus, it remains to be confirmed that mutations within this gene itself cause syndromes that include migraine phenotypes. This report presents a family segregating the novel T1174S missense mutation of this gene detected in a heterozygous female child who presented with myoclonus and an abnormal EEG, and in her mother who has an ataxic migraine syndrome similar to that of her own mother. This threegeneration family exhibits the broad phenotypic spectrum of the dominant neuronal hyperexcitability syndromes produced by even a given allele of this sodium channel gene. It also exhibits the second allele of this sodium channel gene associated with a migraine syndrome similar to those caused at the two other Familial Hemiplegic Migraine loci, confirming that this gene itself, not some linked gene, is the Familial Hemiplegic Migraine, type 3 locus.

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

“…Loss-of-function mutations in Na v 1.1 produce epilepsy syndromes, likely reflecting the critical importance of this Na v channel subtype in controlling the excitability of inhibitory interneurons in the brain (2)(3)(4). In contrast, gain-offunction mutations that diminish Na v 1.1 fast inactivation are linked to familial hemiplegic migraine type 3 (5)(6)(7)(8)(9). Therefore, Na v 1.1 has emerged as an important therapeutic target for brain disorders and, more recently, mechanical pain (10).…”

Sodium channelopathies and pain

“…The aura is followed by uni-or bilateral headache, which can be accompanied by nausea and photophobia. Probably due to the wider tissue distribution of Nav1.1 in the CNS, some FHM3 patients also suffer from accompanying symptoms such as epilepsy [12,36,50,115] or elicited repetitive transient daily blindness (ERDB) [115]. All three investigated FHM3 mutations display a significant shift of steady-state fast inactivation to more negative potentials as compared to wild-type Nav1.1, and in two cases, this shift is accompanied by slower current decay and faster recovery from fast inactivation (Table 4 [16,68,116]).…”

Self-Limited Hyperexcitability: Functional Effect of a Familial Hemiplegic Migraine Mutation of the Nav1.1 (SCN1A) Na+Channel

“…More recently, FHM (type 3) mutations have been identified in SCN1A, the gene encoding neuronal voltage-gated Na v 1.1 Na ϩ channel ␣ subunit (Dichgans et al, 2005;Gargus and Tournay, 2007;Vanmolkot et al, 2007), but the functional studies have been done using the cardiac Na v 1.5 Na ϩ channel. However, Na v 1.1 is the major target of epileptogenic mutations, and the functional effects that have been observed for some of them are similar to those reported for migraine mutations studied with Na v 1.5 (Spampanato et al, 2001;Meisler and Kearney, 2005;Avanzini et al, 2007), complicating our understanding of the differential pathophysiological mechanism of the two diseases.…”