Familial hemiplegic migraine.

Hemiplegic migraine consists of attacks of migraine with aura that includes reversible motor weakness. It is classified as familial or sporadic depending on the involvement or not of a first or second degree relative. The most described subtypes of familial hemiplegic migraine include FHM1, FHM2, and FHM3. These have been demonstrated to have a mutation in either CACNA1A, ATP1A2 or SCN1A, which encode different subunits of channels, involving P/Q-type calcium channel, Na/K pump and Na channel, respectively, located in neurons and glial cells. Mutations localized in different genes are defined as "other loci." Patients with a known mutation can have different genetic penetrance, and may present a more complex and disabling phenotype that develops earlier in life. The clinical manifestations can be similar in the three mutations, including neurologic comorbidities other than muscular weakness, such as episodes of loss of consciousness, epilepsy, gait or limb ataxia or movement disorders, among others. Treatment includes antiepileptics such as lamotrigine, valproate or topiramate, calcium blockers such as flunarizine or verapamil and acetazolamide.

Pathophysiology of migraine aura.

Migraine aura occurs in about a third of patients with migraine and consists of a group of transient focal neurological symptoms that appear from 5 to 60min and then resolve prior to or in the early phase of a migraine headache attack. Migraine auras may consist of visual, language, unilateral sensory, or motor symptoms. There has been considerable debate as to the origins of the migrainous aura. Investigations during physiologically induced visual auras suggest that the phenomenon of cortical spreading depression or its human equivalent underpins the migraine aura. Single gene defects have been linked to relatively rare forms of the motor subtypes of aura known as familial hemiplegic migraine (FHM). These include CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3). In the familial hemiplegic forms of migraine, the more typical forms of aura are almost always also present. Despite ample epidemiological evidence of increased heritability of migraine with aura compared to migraine without aura, identification of the specific variants driving susceptibility to the more common forms of aura has been problematic thus far. In the first genome-wide association study (GWAS) that focused migraine with aura, a single SNP rs835740 reached genome-wide significance. Unfortunately, the SNP did show statistical significance in a later meta-analysis which included GWAS data from subsequent studies. Here, we review the clinical features, pathophysiological theories, and currently available potential evidence for the genetic basis of migraine aura.

Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders.

The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system. The encoded proteins Nav1.1, Nav1.2, Nav1.3, and Nav1.6, respectively, are important players in the initiation and propagation of action potentials and in turn of the neural network activity. In the context of neurological diseases, mutations in the genes encoding Nav1.1, 1.2, 1.3 and 1.6 are responsible for many forms of genetic epilepsy and for Nav1.1 also of hemiplegic migraine. Several pharmacological therapeutic approaches targeting these channels are used or are under study. Mutations of genes encoding VGSCs are also involved in autism and in different types of even severe intellectual disability (ID). It is conceivable that in these conditions their dysfunction could indirectly cause a certain level of neurodegenerative processes; however, so far, these mechanisms have not been deeply investigated. Conversely, VGSCs seem to have a modulatory role in the most common neurodegenerative diseases such as Alzheimer's, where SCN8A expression has been shown to be negatively correlated with disease severity.

Deciphering in silico the Role of Mutated Na V 1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3.

Familial hemiplegic migraine type 3 (FHM3) is caused by gain-of-function mutations in the SCN1A gene that encodes the α1 subunit of voltage-gated NaV1.1 sodium channels. The high level of expression of NaV1.1 channels in peripheral trigeminal neurons may lead to abnormal nociceptive signaling thus contributing to migraine pain. NaV1.1 dysfunction is relevant also for other neurological disorders, foremost epilepsy and stroke that are comorbid with migraine. Here we used computer modeling to test the functional role of FHM3-mutated NaV1.1 channels in mechanisms of trigeminal pain. The activation of Aδ-fibers was studied for two algogens, ATP and 5-HT, operating through P2X3 and 5-HT3 receptors, respectively, at trigeminal nerve terminals. In WT Aδ-fibers of meningeal afferents, NaV1.1 channels efficiently participate in spike generation induced by ATP and 5-HT supported by NaV1.6 channels. Of the various FHM3 mutations tested, the L263V missense mutation, with a longer activation state and lower activation voltage, resulted in the most pronounced spiking activity. In contrast, mutations that result in a loss of NaV1.1 function largely reduced firing of trigeminal nerve fibers. The combined activation of P2X3 and 5-HT3 receptors and branching of nerve fibers resulted in very prolonged and high-frequency spiking activity in the mutants compared to WT. We identified, in silico, key determinants of long-lasting nociceptive activity in FHM3-mutated Aδ-fibers that naturally express P2X3 and 5-HT3 receptors and suggest mutant-specific correction options. Modeled trigeminal nerve firing was significantly higher for FHM3 mutations, compared to WT, suggesting that pronounced nociceptive signaling may contribute to migraine pain.

Late sodium current blocker GS967 inhibits persistent currents induced by familial hemiplegic migraine type 3 mutations of the SCN1A gene.

BACKGROUND: Familial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura. Three causative different genes have been identified, all of which are involved in membrane ion transport. Among these, SCN1A encodes the voltage-gated Na+ channel Nav1.1, and FHM caused by mutations of SCN1A is named FHM3. For 7 of the 12 known FHM3-causing SCNA1 mutations functional consequences have been investigated, and even if gain of function effect seems to be a predominant phenotype, for several mutations conflicting results have been obtained and the available data do not reveal a univocal FHM3 pathomechanism. METHODS: To obtain a more complete picture, here, we characterized by patch clamp approach the remaining 5 mutations (Q1489H, I1498M, F1499 L, M1500 V, F1661 L) in heterologous expression systems. RESULTS: With the exception of I1498M, all mutants exhibited the same current density as WT and exhibited a shift of the steady state inactivation to more positive voltages, an accelerated recovery from inactivation, and an increase of the persistent current, revealing that most FHM3 mutations induce a gain of function. We also determined the effect of GS967, a late Na+ current blocker, on the above mentioned mutants as well as on previously characterized ones (L1649Q, L1670 W, F1774S). GS967 inhibited persistent currents of all SCNA1 FMH3-related mutants and dramatically slowed the recovery from fast inactivation of WT and mutants, consistent with the hypothesis that GS967 specifically binds to and thereby stabilizes the fast inactivated state. Simulation of neuronal firing showed that enhanced persistent currents cause an increase of ionic fluxes during action potential repolarization and consequent accumulation of K+ and/or exhaustion of neuronal energy resources. In silico application of GS967 largely reduced net ionic currents in neurons without impairing excitability. CONCLUSION: In conclusion, late Na+ current blockers appear a promising specific pharmacological treatment of FHM3.

Gain of function of sporadic/familial hemiplegic migraine-causing SCN1A mutations: Use of an optimized cDNA.

INTRODUCTION: Familial hemiplegic migraine 3 is an autosomal dominant headache disorder associated with aura and transient hemiparesis, caused by mutations of the neuronal voltage-gated sodium channel Nav1.1. While a gain-of function phenotype is generally assumed to underlie familial hemiplegic migraine, this has not been fully explored. Indeed, a major obstacle in studying in vitro neuronal sodium channels is the difficulty in propagating and mutagenizing expression plasmids containing their cDNAs. The aim of this work was to study the functional effect of two previously uncharacterized hemiplegic migraine causing mutations, Leu1670Trp (L1670W) and Phe1774Ser (F1774S). METHODS: A novel SCN1A containing-plasmid was designed in silico and synthesized, and migraine mutations were inserted in this background. Whole-cell patch clamp was performed to investigate the functional properties of mutant Nav1.1 transiently expressed in Human Embryonic Kidney 293 cells. RESULTS AND CONCLUSIONS: We generated an optimized Nav1.1 expression plasmid that was extremely simple to handle and used the novel plasmid to study the functional effects of two migraine mutations. We observed that L1670W, but not F1774S, reduced current density and that both mutations led to a dramatic increase in persistent sodium currents, a depolarizing shift of the steady state-inactivation voltage-dependence, and a faster recovery from inactivation. The results are consistent with a major gain-of function effect underlying familial hemiplegic migraine 3. Our optimization strategy will help to characterize in an efficient manner the effect in vitro of mutations of neuronal voltage-gated sodium channels.

Early-onset familial hemiplegic migraine due to a novel SCN1A mutation.

Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with ß1 and ß2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.