Familial Hemiplegic Migraine Genes Research Articles

Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine.

Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, CACNA1A, SCN1A, and ATP1A2, have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the CACNA1I gene encoding the T-type calcium channel Cav3.3. Burden testing of CACNA1I variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, P = 0.00005) and the UK Biobank (OR = 2.32, P = 0.0004) databases. Dysfunction in T-type calcium channels, including Cav3.3, has been implicated in a range of neurological conditions, suggesting a potential role in HM. Using patch-clamp electrophysiology, we compared the biophysical properties of five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, and p.Q1158H) to wild-type (WT) channels expressed in HEK293T cells. We observed numerous functional alterations across the channels with Cav3.3-Q1158H showing the greatest differences compared to WT channels, including reduced current density, right-shifted voltage dependence of activation and inactivation, and slower current kinetics. Interestingly, we also found significant differences in the conductance properties exhibited by the Cav3.3-R307H and -Q1158H variants compared to WT channels under conditions of acidosis and alkalosis. In light of these data, we suggest that rare variants in CACNA1I may contribute to HM etiology.

Exploring Neuronal Vulnerability to Head Trauma Using a Whole Exome Approach.

Brain injuries are associated with oxidative stress and a need to restore neuronal homeostasis. Mutations in ion channel genes, in particular CACNA1A, have been implicated in familial hemiplegic migraine (FHM) and in the development of concussion-related symptoms in response to trivial head trauma. The aim of this study was to explore the potential role of variants in other ion channel genes in the development of such responses. We conducted whole exome sequencing (WES) on16 individuals who developed a range of neurological and concussion-related symptoms following minor or trivial head injuries. All individuals were initially tested and shown to be negative for mutations in known FHM genes.Variants identified from the WES results were filtered to identify rare variants (minor allele frequency [MAF] <0.01) in genes related to neural processes as well as genes highly expressed in the brain using a combination of in silico prediction tools (SIFT, PolyPhen, PredictSNP, Mutation Taster, and Mutation Assessor). Rare (MAF <0.001) or novel heterozygous variants in 7 ion channel genes were identified in 37.5% (6/16) of the cases (CACNA1I, CACNA1C, ATP10A, ATP7B, KCNAB1, KCNJ10, and SLC26A4), rare variants in neurotransmitter genes were found in 2 cases (GABRG1 and GRIK1), and rare variants in 3 ubiquitin-related genes identified in 4 cases (SQSTM1, TRIM2, and HECTD1).In this study, the largest proportion of potentially pathogenic variants in individuals with severe responses to minor head trauma were identified in genes previously implicated in migraine and seizure-related autosomal recessive neurological disorders. Together with results implicating variants in the hemiplegic migraine genes, CACNA1A and ATP1A2, in severe head trauma response, our results support a role for heterozygous deleterious mutations in genes implicated in neurological dysfunction and potentially increasing the risk of poor response to trivial head trauma.

Familial hemiplegic migraine: A model for the genetic studies of migraine

FHM3 is a rare subtype of familial hemiplegic migraine (FHM) caused by mutations in the neuronal sodium channel gene SCN1A (1). Only five FHM3 mutations have been described in a few families since the identification of SCN1A as the third FHM gene in 2005 (1–4). In the present issue of Cephalalgia, Weller et al. (5) report the identification of two novel SCN1A FHM3 mutations in two families with pure FHM. This study is important for clinicians managing patients with FHM, and should also encourage geneticists to consider or reconsider FHM as one of the major targets in the continuing quest for migraine genes. Despite extensive studies, migraine genes remain difficult to identify (6). The common migraines (migraine without aura and migraine with aura) are characterized by high prevalence in the general population, high phenotypic variability, absence of any objective diagnosis marker and polygenic inheritance. Therefore, a successful approach in the search for migraine genes has been the study of FHM, a rare autosomal dominant subform of migraine with aura characterized by the presence of a motor weakness during the aura phase. However, studies of FHM have shown that being monogenic does not imply being a ‘‘simple’’ model. Indeed, FHM is genetically heterogeneous, i.e. mutations in different genes can cause the same phenotype of recurrent migraine attacks with complex aura. From 1996 to 2005, three FHM genes have been identified that all encode ion transporters: a neuronal calcium channel (CACNA1A, FHM1) (7), a glial sodium/potassium pump (ATP1A2, FHM2) (8) and a neuronal sodium channel (SCN1A, FHM3) (1). In 2012, the proline-rich transmembrane protein 2 gene (PRRT2), encoding a protein associated with the exocytosis complex, was proposed as the fourth FHM gene (9,10). Mutations in CACNA1A, ATP1A2 and PRRT2 have also been found in patients with sporadic hemiplegic migraine (SHM) and are often de novo mutations (9,11–13). Study of cellular and murine models have shown that FHM mutations in CACNA1A and ATP1A2 facilitated the initiation of cortical spreading depression waves, the mechanism underlying the migraine aura, and increased neuronal excitability with an excess of glutamatergic neurotransmission (11,13). A proportion of cases with FHM or SHM do not harbor a mutation in the four known genes, indicating that other FHM genes are still to be discovered. Furthermore, genotype-phenotype correlations studies have described the wide clinical spectrum of FHM and the high clinical variability among patients with the same mutation (13). While most cases have so-called ‘‘pure’’ hemiplegic migraine, a small subset of familial and sporadic cases have associated manifestations including permanent cerebellar signs (nystagmus and/ or ataxia), epilepsy, cognitive impairment, elicited repetitive daily blindness and paroxysmal dyskinesia. Some patients can present with early-onset severe attacks with coma, prolonged hemiplegia, fever and brain edema (13). Moreover, different mutations in FHM genes induce other monogenic neurological disorders. CACNA1A mutations can cause episodic ataxia type 2 and spinocerebellar ataxia type 6 (7,13). PRRT2 mutations are associated with benign familial infantile convulsions, infantile convulsions with choreoathetosis, and paroxysmal dyskinesias (10). SCN1A was already known as an epilepsy gene previous to its identification as the FHM3 gene (1). Diagnosing HM might be a challenge. The first step relies on a detailed description of the aura (13). Apart from the presence of a motor weakness during the aura and the frequency of prolonged auras, most HM attacks are similar to attacks of migraine with typical or with brain stem aura. Single cases are diagnosed as sporadic HM, while at least two affected firstand/or

Two novel SCN1A mutations identified in families with familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by motor auras. The majority of FHM families have mutations in the CACNA1A and ATP1A2 genes; less than 5% of FHM families are explained by mutations in the SCN1A gene. Here we screened two Spanish FHM families for mutations in the FHM genes. We assessed the clinical features of both FHM families and performed direct sequencing of all coding exons (and adjacent sequences) of the CACNA1A, ATP1A2, PRRT2 and SCN1A genes. FHM patients in both families had pure hemiplegic migraine with highly variable severity and frequency of attacks. We identified a novel SCN1A missense mutation p.Ile1498Met in all three tested hemiplegic migraine patients of one family. In the other family, novel SCN1A missense mutation p.Phe1661Leu was identified in six out of eight tested hemiplegic migraine patients. Both mutations affect amino acid residues that either reside in an important functional domain (in the case of Ile(1498)) or are known to be important for kinetic properties of the NaV1.1 channel (in the case of Phe(1661)). We identified two mutations in families with FHM. SCN1A mutations are an infrequent but important cause of FHM. Genetic testing is indicated in families when no mutations are found in other FHM genes.

Migraine Genetics: Part II

Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21-23. The defect is a new mutation in the α2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an α1 subunit of a neuronal voltage-gated Na+ channel. Genome-wide association studies have identified many non-coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two-pore domain potassium channel, TWIK-related spinal cord potassium channel. TWIK-related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.

Pearls and pitfalls in genetic studies of migraine

Migraine is a prevalent neurovascular brain disorder with a strong genetic component, and different methodological approaches have been implemented to identify the genes involved. This review focuses on pearls and pitfalls of these approaches and genetic findings in migraine. Common forms of migraine (i.e. migraine with and without aura) are thought to have a polygenic make-up, whereas rare familial hemiplegic migraine (FHM) presents with a monogenic pattern of inheritance. Until a few years ago only studies in FHM yielded causal genes, which were identified by a classical linkage analysis approach. Functional analyses of FHM gene mutations in cellular and transgenic animal models suggest abnormal glutamatergic neurotransmission as a possible key disease mechanism. Recently, a number of genes were discovered for the common forms of migraine using a genome-wide association (GWA) approach, which sheds first light on the pathophysiological mechanisms involved. Novel technological strategies such as next-generation sequencing, which can be implemented in future genetic migraine research, may aid the identification of novel FHM genes and promote the search for the missing heritability of common migraine.

Novel SCN1A mutation in the IFMT motif of the α1 subunit of the voltage-gated NaV1.1 channel causing familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a monogenic subtype of migraine with aura. So far three FHM genes are identified; the CACNA1A gene, the ATP1A2 gene and the SCN1A gene.

Migraine Genes and the Relation to Gender

Migraine is an episodic brain disorder that is characterized by recurrent attacks of severe unilateral headache that are accompanied by various neurological symptoms. In addition, many patients have what is called an aura with visual and sensory disturbances. The majority of patients are female, suggesting that female hormones play an important role in the pathophysiology of the disorder. The molecular mechanisms, however, underlying this female preponderance are not well understood. It can be expected that the field of genetics that aims at identifying genetic factors that cause migraine by lowering the threshold for attacks will unravel some of these mechanisms. The 3 best known migraine genes encode ion transporters and were identified in families with familial hemiplegic migraine (FHM), a rare subtype of migraine with aura. FHM gene mutations cause alterations in mechanisms that control and modulate the neurotransmitter balance in the brain. Transgenic mice knock-in with human pathogenic mutations that were shown to exhibit some migraine-relevant features were very helpful in dissecting molecular mechanisms of migraine and pointed to a central role for cortical glutamate. In addition, transgenic mice that overexpress human RAMP1 exist and exhibit an increased sensitivity to calcitonin gene-related peptide. Findings from genetic and animal experiments on gender differences in migraine are discussed. Recently, a role for glutamate also came forward from a genome-wide association study in common migraine. By deciphering genetic and pathogenic migraine pathways, it can be expected that in the near future we will better understand mechanisms behind the female preponderance in migraine.

Familial hemicrania continua

There are now three known causative genes for familial hemiplegic migraine and increasing evidence to support a genetic predisposition to the more common types of migraine with and without aura, and for cluster headache. We present the first reported case of familial hemicrania continua. A mother and daughter developed hemicrania continua at the same time of life. Both showed an absolute response to indometacin and at similar doses. Both also suffered from migraine with aura. We discuss the increasing support for a genetic predisposition to dysfunction of the pain system within the brain manifesting as primary headache.

Defective membrane expression of the Na + -HCO 3 − cotransporter NBCe1 is associated with familial migraine

Homozygous mutations in SLC4A4, encoding the electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1, have been known to cause proximal renal tubular acidosis (pRTA) and ocular abnormalities. In this study, we report two sisters with pRTA, ocular abnormalities, and hemiplegic migraine. Genetic analysis ruled out pathological mutations in the known genes for familial hemiplegic migraine, but identified a homozygous 65-bp deletion (Delta65bp) in the C terminus of NBCe1, corresponding to the codon change S982NfsX4. Several heterozygous members of this family also presented glaucoma and migraine with or without aura. Despite the normal electrogenic activity in Xenopus oocytes, the Delta65bp mutant showed almost no transport activity due to a predominant cytosolic retention in mammalian cells. Furthermore, coexpression experiments uncovered a dominant negative effect of the mutant through hetero-oligomer formation with wild-type NBCe1. Among other pRTA pedigrees with different NBCe1 mutations, we identified four additional homozygous patients with migraine. The immunohistological and functional analyses of these mutants demonstrate that the near total loss of NBCe1 activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH.

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine

Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.

A long-term follow-up study of 18 patients with sporadic hemiplegic migraine

Our objective was to study the long-term prognosis of sporadic hemiplegic migraine (SHM). We performed a longitudinal follow-up study in 18 patients who were diagnosed with SHM between 1993 and 1996. Follow-up time between the first and second survey ranged from nine to 14 years. These patients were included as part of a genetic study in which we systematically analysed the role of the three known familial hemiplegic migraine (FHM) genes. In 12 out of 18 patients the clinical diagnosis was unchanged. In two of the six remaining patients the attacks were no longer associated with hemiplegia; one of them had an ATP1A2 gene mutation (E120A). In the four other patients, the diagnosis changed into FHM, because a family member had developed hemiplegic migraine since the initial diagnosis was made. In two of the four patients a mutation was demonstrated (CACNA1A [R583Q] and ATP1A2 [R834X]). This study shows that the diagnosis of SHM changes into FHM in a considerable percentage of patients (22% [4 of 18]), almost a decade after the initial diagnosis. This indicates that a careful follow-up of SHM patients and their families is advisable for optimal care and counseling. Diagnostic screening of FHM genes in SHM patients can be of value. Our genetic and clinical follow-up studies reinforce the evidence that FHM and SHM are part of the same spectrum of migraine.

Sporadic hemiplegic migraine and delayed cerebral oedema after minor head trauma: a novel de novo CACNA1A gene mutation

SIR–Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura in which attacks are associated with some degree of motor weakness or hemiparesis during the aura phase. Sporadic hemiplegic migraine (SHM) differs from FHM by the absence of affected family members.1, 2 Mutations have been reported in three genes: CACNA1A (19p13 – FHM1) coding for the α1 sub-unit of a calcium channel, ATP1A2 (1q23 – FHM2) coding for the Na+/K+ATP1A2α1 sub-unit, and SCN1A (FHM3 – 2q24) coding for the α1 sub-unit of a sodium channel. Patients with SHM only rarely have mutations in the FHM gene CACNA1A.3 The female patient was born at term by normal vaginal delivery after an uneventful pregnancy. Motor delay became apparent, with hypotonia, ataxia, and dysarthria. She sat at 3 years, and was unable to walk. She normally used a chair for mobility and had limited communication. Neurological signs were consistent with ataxic cerebral palsy, but with no causative diagnosis apparent. Comprehensive investigations, including magnetic resonance imaging (MRI) of the brain and muscle biopsy, were normal. At age 5 the patient sustained a head injury after her wheelchair was accidentally tipped over, causing her to strike the left side of her head. Over the course of a few hours she developed a reduced level of consciousness and was admitted to hospital. There was no focal neurological sign and a brain computed tomography was normal. Her level of consciousness returned to normal. However after 24 hours she developed a fever of 39°C. No infective focus was apparent and routine investigations, including cerebrospinal fluid examination, were unremarkable. Over the subsequent 48 hours she developed increasing right-sided weakness, with decreased tone, increased deep tendon reflexes, an extensor plantar response on the right, and unilateral upper motor neuron facial nerve palsy. She had a right-sided focal seizure on day 8, and on day 10 following the injury MRI demonstrated marked enlargement of the left cerebral hemisphere with generalized sulcal effacement and significant mass effect (Fig. 1). T2 weighted image D10 after injury showing left-sided cerebral oedema. Subsequently she developed a mild right hemiparesis, but otherwise she returned to her previous clinical state. Repeat MRI 7 months after the episode showed residual abnormal signal in the left caudate and lenticular nucleus (Fig. 2). There was no family history of migraine or disability. She continued to have migrainous attacks, some associated with brief episodes of hemiplegia. T2 weighted image 8 months after trauma with abnormal signal in the left caudate and lenticular nucleus (arrow). DNA of the patient was extracted from peripheral blood using standard procedures. The exons of CACNA1A coding for the segments S4, S5, S6, and the P-loop of the four domains of the protein were screened by a combination of single strand conformation polymorphism and direct sequencing. This screening identified a nucleotide substitution in exon 25 (c.4046G>A) leading to the missense mutation p.Arg1349Gln. This mutation affects a highly conserved residue within the domain III-S4 and was not present in a panel of 280 control chromosomes. This mutation was absent in her parents. We describe a novel de novo mutation in CACNA1A (p. Arg1349Gln) in a child with severe hemiplegic migraine induced by minor head trauma. There was no clinically affected first-degree relative, and neither parent carried the Arg1349Gln mutation confirming the de novo occurrence and leading to a diagnosis of genetic SHM. CACNA1A mutations have been reported only in a very small number of SHM patients prior to our case.4-11 SHM after minor head injury has been previously described. Curtain et al.10 described a previously well child with no relevant family history who developed delayed cerebral oedema following a fall of less than 3 feet, leading to coma and permanent disability. Kors et al. reported three patients who developed cerebral oedema following minor head trauma. Two patients were from the same family with severe FHM, but in the other patient there was no family history. All three were found to have the same C-to-T substitution of serine for lysine at codon 218 in the CACNA1A gene (S218L).11 The broad clinical spectrum of SHM may cause diagnostic difficulties. Clinical features in the patient described (severe motor delay, hypotonia and ataxia, and the absence of any paroxysmal neurological episodes) were non-specific. Her first recognized hemiplegic migraine attack occurred at age 5 after relatively minor head trauma, and only then was the diagnosis suspected. We would suggest that CACNA1A gene screening be considered when a child presents similarly in the absence of another causative diagnosis.

Molecular genetics of migraine

Migraine is an episodic neurovascular disorder that is clinically divided into two main subtypes that are based on the absence or presence of an aura: migraine without aura (MO) and migraine with aura (MA). Current molecular genetic insight into the pathophysiology of migraine predominantly comes from studies of a rare monogenic subtype of migraine with aura called familial hemiplegic migraine (FHM). Three FHM genes have been identified, which all encode ion transporters, suggesting that disturbances in ion and neurotransmitter balances in the brain are responsible for this migraine type, and possibly the common forms of migraine. Cellular and animal models expressing FHM mutations hint toward neuronal hyperexcitability as the likely underlying disease mechanism. Additional molecular insight into the pathophysiology of migraine may come from other monogenic syndromes (for instance cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is caused by NOTCH3 mutations), in which migraine is prominent. Investigating patients with common forms of migraine has had limited successes. Except for 5',10'-methylenetetrahydrolate reductase, an enzyme in folate metabolism, the large majority of reported genetic associations with candidate migraine genes have not been convincingly replicated. Genetic linkage studies using migraine subtypes as an end diagnosis did not yield gene variants thus far. Clinical heterogeneity in migraine diagnosis may have hampered the identification of such variants. Therefore, the recent introduction of more refined methods of phenotyping, such as latent-class analysis and trait component analysis, may be certainly helpful. Combining the new phenotyping methods with genome-wide association studies may be a successful strategy toward identification of migraine susceptibility genes. Likely the identification of reliable biomarkers for migraine diagnosing will make these efforts even more successful.

Migraine and epilepsy: genetically linked?

Most molecular genetic knowledge in migraine so far comes from the study of a rare subtype, familial hemiplegic migraine (FHM). The three known FHM genes (CACNA1A, ATP1A2 and SCN1A) are ion transporter genes. Mutations in all three FHM genes can also be associated with epilepsy. Of the many epilepsy genes that have been discovered, an association with migraine has been reported only for SCN1A. There is probably a lack of systematic studies of migraine in epilepsy families. A genetically determined dysfunction of ion transporters seems to point, at least to certain extent, at a common underlying mechanism for both paroxysmal disorders. The effect of ion channel mutations on neuronal neurotransmitter release is probably of major importance. In this article, we will discuss the arguments for a genetic relationship between migraine and epilepsy. A possible genetic link could give insight into the pathophysiology of both syndromes, and offer possibilities to develop specific preventive treatment aimed at the underlying ion transporter dysfunction and its consequences.

A high-density association screen of 155 ion transport genes for involvement with common migraine

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.

CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood

Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.

The primary headaches: genetics, epigenetics and a behavioural genetic model.

The primary headaches, migraine with (MA) and without aura (MO) and cluster headache, all carry a substantial genetic liability. Familial hemiplegic migraine (FHM), an autosomal dominant mendelian disorder classified as a subtype of MA, is due to mutations in genes encoding neural channel subunits. MA/MO are considered multifactorial genetic disorders, and FHM has been proposed as a model for migraine aetiology. However, a review of the genetic studies suggests that the FHM genes are not involved in the typical migraines and that FHM should be considered as a syndromic migraine rather than a subtype of MA. Adopting the concept of syndromic migraine could be useful in understanding migraine pathogenesis. We hypothesise that epigenetic mechanisms play an important role in headache pathogenesis. A behavioural model is proposed, whereby the primary headaches are construed as behaviours, not symptoms, evolutionarily conserved for their adaptive value and engendered out of a genetic repertoire by a network of pattern generators present in the brain and signalling homeostatic imbalance. This behavioural model could be incorporated into migraine genetic research.

Monogenic migraine syndromes highlight novel drug targets

AbstractIn the post‐genomic era, the paradigm for drug discovery has changed, as every gene may become a potential target. Genetic diseases provide a special window into gene target selection. This approach is being applied to migraine making use of the genes and mutations causing familial hemiplegic migraine (FHM). FHM is caused by missense mutations in CACNA1A, altering a neuronal P/Q Ca2+ channel, in ATP1A2, altering α2 Na,K‐ATPase, and in SCN1A, altering a neuronal sodium channel. These genes provide insights into migraine pathogenesis that likely extend to other forms of migraine as well. Since the three FHM genes are only co‐expressed in neurons, FHM is a neuronal, not a vascular, disease and because they all encode ion transport proteins, FHM is a neuronal channelopathy—meaning meta‐stable neuronal hyperexcitability is the substrate of migraine, much as it is for genetic epilepsy syndromes. This similarity is reinforced, since different mutations of all three FHM genes can produce seizure syndromes. This has implications for drug discovery in that seizure medications already known to modulate the FHM channel mechanisms warrant more targeted development, and that drugs targeted to vascular headaches, such as the historically effective triptans, or experimental botulinum toxin, may well work by similar nonvascular mechanisms. Finally, in model neurogenetic systems such as Caenorhabditis elegans, the FHM genes also provide both a comprehensive means to discover all genes involved in their signaling pathway—genes potentially involved in common forms of the disease, and an in vivo whole animal means to screen rapidly for novel therapeutics. Drug Dev Res 68:432–440, 2007. © 2008 Wiley‐Liss, Inc.

First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare autosomal-dominant subtype of migraine with aura, associated with hemiparesis during the aura. Here we describe a unique FHM family in which two novel allelic missense mutations in the Na,K-ATPase gene ATP1A2 segregate in the proband with hemiplegic migraine. Both mutations show reduced penetrance in family members of the proband. Cellular survival assays revealed Na,K-ATPase dysfunction for both ATP1A2 mutants, indicating that both mutations are disease causative. This is the first case of compound heterozygosity for any of the known FHM genes.