A genetic interaction of NRXN2 with GABRE, SYT1 and CASK in migraine patients: a case-control study.

BACKGROUND: Migraine is a multifactorial disorder that is more frequent (two to four times) in women than in men. In recent years, our research group has focused on the role of neurotransmitter release and its regulation. Neurexin (NRXN2) is one of the components of the synaptic vesicle machinery, responsible for connecting intracellular fusion proteins and synaptic vesicles. Our aim was to continue exploring the role and interaction of proteins involved in the control and promotion of neurotransmission in migraine susceptibility. METHODS: A case-control study was performed comprising 183 migraineurs (148 females and 35 males) and 265 migraine-free controls (202 females and 63 males). Tagging single nucleotide polymorphisms of NRXN2 were genotyped to assess the association between NRXN2 and migraine susceptibility. The χ2 test was used to compare allele frequencies in cases and controls and odds ratios were estimated with 95% confidence intervals. Haplotype frequencies were compared between groups. Gene-gene interactions were analysed using the Multifactor Dimensionality Reduction v2.0. RESULTS: We found a statistically significant interaction model (p = 0.009) in the female group between the genotypes CG of rs477138 (NRXN2) and CT of rs1158605 (GABRE). This interaction was validated by logistic regression, showing a significant risk effect [OR = 4.78 (95%CI: 1.76-12.97)] after a Bonferroni correction. Our data also supports a statistically significant interaction model (p = 0.011) in the female group between the GG of rs477138 in NRXN2 and, the rs2244325's GG genotype and rs2998250's CC genotype of CASK. This interaction was also validated by logistic regression, with a protective effect [OR = 0.08 (95%CI: 0.01-0.75)]. A weak interaction model was found between NRXN2-SYT1. We have not found any statistically significant allelic or haplotypic associations between NRXN2 and migraine susceptibility. CONCLUSIONS: This study unravels, for the first time, the gene-gene interactions between NRXN2, GABRE - a GABAA-receptor - and CASK, importantly it shows the synergetic effect between those genes and its relation with migraine susceptibility. These gene interactions, which may be a part of a larger network, can potentially help us in better understanding migraine aetiology and in development of new therapeutic approaches.

[Chronic and Refractory Migraine: How to Diagnose and Treat]. / Enxaqueca Crónica e Refratária: Como Diagnosticar e Tratar.

Migraine is highly prevalent and carries a significant personal, social and economic burden. It is the second cause of disability (years living with disability) worldwide and the first cause under 50 years of age. Chronic migraine (occurring for more than 15 days a month) and refractory migraine (treatment resistant), especially when there is also analgesic overuse, are the most disabling forms of migraine. These three disorders (chronic migraine, refractory migraine and medication overuse headache) are particularly difficult to treat. This article reviews their epidemiology, clinical presentation, diagnostic criteria, risk factors, comorbidities and social and personal impact. The therapeutic options available are discussed and focused on a multidisciplinary approach, non-pharmacological interventions treatment of comorbidities and avoiding analgesic overuse. Prophylactic treatments are mandatory and include the oral prophylactic treatments (topiramate), botulinum toxin type A and the novel monoclonal antibodies against calcitonin gene related peptide or its receptor, which are the first migraine preventive medicines developed specifically to target migraine pathogenesis. In refractory cases, multiple therapies are required including neurostimulation.

A enxaqueca é uma cefaleia muito prevalente na população com importantes custos pessoais, sociais e económicos e é a segunda causa a nível mundial de anos vividos com incapacidade. As suas variantes, crónica (aquela que ocorre mais de 15 dias por mês) e refratária (resistente ao tratamento), sobretudo quando se complicam de uso excessivo de analgésicos, embora mais raras, constituem as formas que causam maior incapacidade. Os autores revêm estes três tipos de cefaleias (enxaqueca refratária, enxaqueca crónica e cefaleia secundária a utilização excessiva de analgésicos) que constituem um grupo de cefaleias de difícil terapêutica. São revistos a epidemiologia, os aspetos clínicos, os critérios de diagnóstico, as comorbilidades, os fatores de agravamento e o impacto destas cefaleias sobre a qualidade de vida dos doentes. O tratamento de cada uma destas entidades é abordado, ressalvando a importância de uma abordagem abrangente, considerando o tratamento das comorbilidades, a utilidade de medidas não farmacológicas, o imperativo de evitar o abuso de analgésicos e a necessidade absoluta de tratamento profilático. São revistos os diferentes tratamentos profiláticos disponíveis (e a evidência científica da sua eficácia), tais como os fármacos preventivos orais (neuromodeladores como o topiramato), a toxina botulínica tipo A e os novos medicamentos preventivos para a enxaqueca (anticorpos monoclonais que atuam sobre o péptido relacionado com o gene da calcitonina ou o seu recetor, e que são os primeiros medicamentos preventivos desenvolvidos especificamente para atuar na fisiopatogenia da enxaqueca. Para os casos refratários são consideradas outras alternativas terapêuticas como a neuroestimulação.

Going Deep into Synaptic Vesicle Machinery Genes and Migraine Susceptibility - A Case-Control Association Study.

OBJECTIVE: A number of observations, including among our study population, have implicated variants in the syntaxin-1A, a component of the synaptic vesicles, in migraine susceptibility. Therefore, we hypothesize that variants in other components of the vesicle machinery are involved in migraine. BACKGROUND: Migraine is a common and complex neurologic disorder that affects approximately 15-18% of the general population. The exact cause of migraine is unknown; however, genetic studies have made possible substantial progress toward the identification of underlying molecular pathways. Neurotransmitters have been for long considered to have a key role in migraine pathophysiology; so we investigated common variants in genes involved in the synaptic vesicle machinery and their impact in migraine susceptibility. METHODS: We performed a case-control study comprising 188 unrelated patients with headache and 286 healthy controls in a population from the north of Portugal. Benefiting from the presence of linkage disequilibrium, we selected and genotyped 119 tagging single-nucleotide polymorphisms in 18 genes. RESULTS: We found significant associations between single-nucleotide variants and migraine in 7 genes, SYN1, SYN2, SNAP25, VAMP2, STXBP1, STXBP5, and UNC13A, either conferring an increased risk or protection of migraine. Due to SYN1 X-chromosomal location, we performed the statistical analysis separated by gender and, in the female group, the C allele of rs5906435 increased the risk for migraine susceptibility (P = .021; OR = 1.69; 95% CI: 1.21-2.34). In contrast, the TT genotype of the same variant emerged as a potential protective factor (P = .003; OR = 0.45; 95% CI: 0.27-0.74). The SYN2 analysis supported the rs3773364's G allele (P = .014) as a risk factor for migraine, and although not statistically significant after correction, the AG genotype (P = .006; OR = 1.86; 95% CI: 1.20-2.90) reinforced the allelic findings. Additionally, we found the SNAP25-rs363039's CT genotype (P = .001; OR = 2.14; 95% CI: 1.36-3.34), the STXBP5-rs1765028's T allele (P = .041; OR = 1.46; 95% CI: 1.13-1.90), and the UNC13B-rs7851161's TT genotype (P = .001; OR = 2.14; 95% CI: 1.36-3.34) as statistically significant risk factors for migraine liability. VAMP2-rs1150's G allele revealed a risk association to migraine, not statistically significant after correction (P = .068). Additionally, we found haplotypes in SYN1, SYN2, STXBP1, and UNC13B to be associated with migraine. CONCLUSIONS: Overall, this study provides a new insight into migraine liability, identifying possible starting points for functional studies.

SUNCT syndrome: A cohort of 15 Portuguese patients.

BACKGROUND: In this paper, we describe a cohort of patients with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), a rare trigeminal autonomic headache, managed in the outpatient clinic of a tertiary hospital. METHODS: Patients were identified through review of individual records between January 1, 2008 and June 30, 2014. RESULTS: Fifteen patients were identified (eight males:seven females), with mean age at onset of 49.7 years, mean number of attacks per day of 7.5 and mean attack duration of 54.6 seconds. Pain was mostly orbital, periorbital or temporal. Cranial autonomic signs/symptoms were universally present; one patient reported ipsilateral epistaxis. Two symptomatic cases were identified and treated surgically. Most patients responded to lamotrigine, one to topiramate and another to eslicarbazepine. CONCLUSION: Our case series is among the largest reported, with findings similar to others already published, but the first to report epistaxis during SUNCT attack and response to eslicarbazepine.

CADASIL: MRI may be normal in the fourth decade of life - a case report.

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifests by migraine with aura, cerebral ischemic events, mood disturbances and dementia. Brain MRI lesions typically precede the symptoms from 10 to 15 years and previous evidence showed all CADASIL patients above 35 years old have an abnormal MRI, supporting the clinical diagnosis. Case results We present a 37-year-old female patient with migraine without aura, a family history of CADASIL, normal brain 3-Tesla MRI and normal skin biopsy, even though a pathogenic NOTCH3 gene mutation (allele 2, exon 11, c.1672 C\gtT, p.Arg558Cys) was detected. Conclusions When CADASIL is strongly suspected, a normal brain MRI, even in the fourth decade of life, does not rule out the diagnosis and should not discourage the genetic test.

Familial hemiplegic migraine due to L263V SCN1A mutation: discordance for epilepsy between two kindreds from Douro Valley.

BACKGROUND: SCN1A is the most relevant gene in epilepsy. Only seven SCN1A mutations have been identified in 10 familial hemiplegic migraine (FHM) kindreds worldwide. CASES AND KINDREDS: In 2009, we presented a kindred with FHM due to the L263V SCN1A mutation. In the current study, we report a novel FHM3 kindred from the same village. The first family exhibited the co-occurrence of FHM and epilepsy. No case of epilepsy was observed in the new kindred. An L263V mutation was found in all patients, and the haplotype analysis supports a unique mutational event. COMMENTS: Despite its bioelectric activity, the SCN1A L263V mutation most likely requires a combination of several endogenous or environmental induction stimuli to attain an epileptogenic threshold.

Interaction between γ-aminobutyric acid A receptor genes: new evidence in migraine susceptibility.

Migraine is a common neurological episodic disorder with a female-to-male prevalence 3- to 4-fold higher, suggesting a possible X-linked genetic component. Our aims were to assess the role of common variants of gamma-aminobutyric acid A receptor (GABAAR) genes, located in the X-chromosome, in migraine susceptibility and the possible interaction between them. An association study with 188 unrelated cases and 286 migraine-free controls age- and ethnic matched was performed. Twenty-three tagging SNPs were selected in three genes (GABRE, GABRA3 and GABRQ). Allelic, genotypic and haplotypic frequencies were compared between cases and controls. We also focused on gene-gene interactions. The AT genotype of rs3810651 of GABRQ gene was associated with an increased risk for migraine (OR: 4.07; 95% CI: 1.71-9.73, p=0.002), while the CT genotype of rs3902802 (OR: 0.41; 95% CI: 0.21-0.78, p=0.006) and GA genotype of rs2131190 of GABRA3 gene (OR: 0.53; 95% CI: 0.32-0.88, p=0.013) seem to be protective factors. All associations were found in the female group and maintained significance after Bonferroni correction. We also found three nominal associations in the allelic analyses although there were no significant results in the haplotypic analyses. Strikingly, we found strong interactions between six SNPs encoding for different subunits of GABAAR, all significant after permutation correction. To our knowledge, we show for the first time, the putative involvement of polymorphisms in GABAAR genes in migraine susceptibility and more importantly we unraveled a role for novel gene-gene interactions opening new perspectives for the development of more effective treatments.

Monozygotic twin sisters discordant for familial hemiplegic migraine.

BACKGROUND: The high concordance rate of migraine in monozygotic twin pairs has long been recognised. In the current study, we present a monozygotic twin pair discordant for familial hemiplegic migraine (FHM). CASE PRESENTATIONS: We evaluated 12 adult family members in 2012. The twin pair was separately examined by neurologists at different time points. Mutation screening was performed for known FHM-related genes. The monozygosity of the twins was verified. Eleven individuals had a history of migraine or paroxysmal neurological symptoms, including four patients with motor aura. No mutations were detected in the CACNA1A, ATP1A2, SCN1A, PRRT2 or NOTCH3 genes. The monozygotic twin sisters, aged 52, were discordant for age of onset, motor aura and neuropsychological aura (forced thinking). Overall, the family members presented a wide range of phenotypical features. CONCLUSIONS: Familial hemiplegic migraine is a monogenic disorder that is distinct from migraine with typical aura. However, in certain families with motor aura, such as this one, it is possible that the most severe phenotype is caused by an unlikely combination of polygenic traits and non-genetic factors. In these kindreds, we propose that hemiplegic aura is only a severe and complex form of typical aura.

Cerebellar ataxia, hemiplegic migraine, and related phenotypes due to a CACNA1A missense mutation: 12-year follow-up of a large Portuguese family.

OBJECTIVE: To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar ataxia, hemiplegic migraine, and related syndromes caused by missense mutation c.1748 (p.R583Q) in the CACNA1A gene. DESIGN: Observational 12-year follow-up study. SETTING: Community and hospital care. PATIENTS: Sixteen patients in a 4-generation family were identified in 1998 in a population-based survey. The follow-up revealed 28 patients (25 of whom were observed) and 32 unaffected relatives with an a priori risk of 50%. RESULTS: Four major phenotypes (migraine with multiple auras, transient focal neurological deficits without headache, coma triggered by minor head trauma, and slowly progressive cerebellar ataxia) were present in various combinations. The initial manifestation was ataxia in 16 patients and a transient episode in 12 patients. Eighteen patients did not have migraine, and 11 showed only ataxia. The c.1748 (p.R583Q) mutation in CACNA1A was confirmed in all 23 of the patients who were tested but was not found in any of the 27 adult relatives. The CACNA1A CAG repeat expansion was excluded. CONCLUSIONS: A unique missense mutation in the CACNA1A gene, which exhibits a very high penetrance and expressivity, may present a phenotypic spectrum that is broader than current descriptions. Single-gene disorders can behave as complex traits, which reinforces the importance of genetic modifiers in the tightly regulated function of P/Q-type calcium channels. The clinical spectrum of missense mutation CACNA1A -related disorders is much broader than strictly familial hemiplegic migraine.

Assessing risk factors for migraine: differences in gender transmission.

AIM: Our aim was to assess which specific factors are contributing to an increased risk of migraine in a group of 131 Portuguese families. METHODS: We studied 319 first-degree relatives, using a multilevel approach to account for the dependency among members from the same family. We included in the model relative's gender, the proband's gender and age-at-onset, to evaluate if any of these variables were associated with relative's affection status. We also included in the model proband's migraine subtype. We further assessed female and male transmissions within the proband nuclear family. RESULTS: Relatives' gender was found to be a risk factor for migraine (Odds Ratio = 2.86; 95% CI = 1.75-4.67), with females at a higher risk. When splitting probands according to their migraine subtype, we found that none of the variables studied contributed to relatives of MA-probands affection-status. Our results also show a significant difference between proband's transmission and the gender of the parents and offspring. CONCLUSIONS: With this study, we showed that gender is truly a risk factor for migraine and that a gender-biased transmission is also observed. This reinforce the importance of identifying genes associated with migraine that are modulated by genes located in the sex chromosomes and the study of mitochondrial DNA or X-chromosome and hormonal-related effects associated with migraine susceptibility.

Migraine-induced epistaxis and sporadic hemiplegic migraine: unusual features in the same patient.

BACKGROUND: Since the mid-19th century, epistaxis and migraine have been occasionally associated with each other. Nevertheless, we found only two cases in the contemporary medical literature. Sporadic hemiplegic migraine is a subtype of migraine with reversible motor deficits, without similar episodes in relatives. CASE: We describe a 47-year-old male with a history of migraine with a scintillating scotoma starting at the age of 20. In some of the episodes, he developed epistaxis in the resolution phase of migraine. At the age of 35, he experienced a visual aura followed by transient aphasia, left crural weakness and headache. Contralateral similar episodes occurred in the subsequent months. Neurological examination and MRI were normal. Mutations in CACNA1A, ATP1A2, SCN1A and NOTCH3 were excluded. DISCUSSION: Three distinct aspects deserve our consideration. This is the first report of migraine-induced epistaxis involving aura; the scarcity of similar reports may be due to the lack of a guided anamnesis. The complex aura presented had a peculiar topography, inconsistent with the classical analytical neurological semiology. This may suggest that the spreading depression affects the brain bilaterally but in an uneven and elective manner. Lastly, the present report conveys that the late appearance of complex auras requires improbable interactions between environmental and endogenous conditions in individuals with a genetic predisposition.

Psychotic aura symptoms in familial hemiplegic migraine type 2 (ATP1A2).

INTRODUCTION: Neuropsychological symptoms are rare in familial hemiplegic migraine (FHM). There are no reports of psychotic symptoms in FHM type 2 (ATP1A2). We examined a family with a FHM phenotype due to a M731T mutation in ATP1A2. A 10-year follow-up allowed us to observe complex auras, including psychotic symptoms in two siblings. CASE REPORT: Male, 48 years old, with an aura that included complex illusions with a feeling of time travelling, coincident with other aura features. The aura was regarded as mystical by the patient. Female, 38 years old, with a complex migraine aura, during which she believed she had the ability to time travel and was being followed by lobbyists who wanted to steal this ability from her. DISCUSSION: FHM type 2 must be included in the list of differential diagnoses of acute psychosis in patients with a previous history of migraine aura.

Sporadic hemiplegic migraine with normal imaging as the initial manifestation of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be present with negative family history and, especially in younger patients, with normal brain magnetic resonance. For this reason, those CADASIL patients that present only with migraine may be misdiagnosed. In the case of migraine with motor aura, sporadic hemiplegic migraine (SHM) is one of the possible misdiagnoses. CASE RESULTS: We present a case of a patient who, in the first years of her disease, met the clinical criteria for SHM. A diagnosis of CADASIL was considered only when her sister presented with headache and an unknown leukoencephalopathy. CONCLUSIONS: This case illustrates the need for a careful review of the clinical and family history during the follow-up of primary headaches.

BDNF and CGRP interaction: implications in migraine susceptibility.

OBJECTIVES: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene (BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene-related peptide gene (CGRP); and a possible interaction between the two. METHODS: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP-rs1553005-of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable-logistic regression and confirmed by a multifactor dimensionality reduction analysis. RESULTS: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT-genotype of rs2049046 and the GC-genotype of rs1553005 (odds ratio=1.88, 95% confidence interval: 1.20-2.93) for migraineurs. CONCLUSION: Our data support the hypothesis of an interaction between BDNF and CGRP in migraine susceptibility that should be further explored.

A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.

Evidence of syntaxin 1A involvement in migraine susceptibility: a Portuguese study.

OBJECTIVE: To confirm syntaxin 1A as a risk factor for migraine, given that syntaxin 1A interacts with several factors in migraine pathophysiology. DESIGN: Case-control approach. SETTING: An outpatient clinic. PARTICIPANTS: In a sample of 188 migraineurs (111 without aura and 77 with aura) and 287 migraine-free controls, 3 tagging SNPs of STX1A (rs3793243, rs941298, and rs6951030) were analyzed. A backward stepwise multiple logistic regression was performed. Allelic and haplotypic frequencies were compared between cases and controls. RESULTS: We found that rs941298 and rs6951030 were risk factors for migraines. In particular, the TT genotype of rs941298 is associated with an increased risk of both migraine in general and migraine without aura; the GG and GT genotypes for rs6951030 are also associated with migraine, while the GT genotype of rs6951030 was found to be significant in the migraine without aura group. The single-nucleotide polymorphism rs3793243 did not show any significant association. In the haplotype-based analysis, we found an underrepresentation of the T-C-T haplotype (rs3793243-rs941298-rs6951030) in the global sample and in migraine without aura group. We found an enrichment of the G allele of rs6951030 for female migraineurs only. CONCLUSIONS: We confirmed the involvement of syntaxin 1A in migraine susceptibility regarding rs941298. In addition, we found rs6951030 to also be associated in Portuguese migraine patients. Sex differences should be further explored to disentangle a possible sex susceptibility in syntaxin 1A.

Guidelines for telematic second opinion consultation on headaches in Europe: on behalf of the European Headache Federation (EHF).

The seeking of a second opinion is the long-established process whereby a physician or expert from the same or a similar specialty is invited to assess a clinical case in order to confirm or reject a diagnosis or treatment plan. Seeking a second opinion has become more common in recent years, and the trend is associated with significant changes in the patient-doctor relationship. Telemedicine is attractive because it is not only fast but also affordable and thus makes it possible to reach highly qualified centres and experts that would otherwise be inaccessible, being impossible, or too expensive, to reach by any surface transport. In Europe, the European Headache Federation (EHF), being able to draw on a group of headache experts covering all the European languages, is the organisation best placed to provide qualified second-opinion consultation on difficult headache cases and to develop a Headache Medical Opinion Service Centre. The provision of good quality clinical information is crucial to the formulation of a valid, expert second opinion. This preliminary step can be properly accomplished only by the primary health care provider through the furnishing of an appropriate clinical report, together with the results of all available tests, including original films of all imaging studies already performed. On receiving the EHF's proposed standardised data collection form, properly filled in, we may be sure that we have all the relevant data necessary to formulate a valid expert second opinion. This form can be accessed electronically and downloaded from the EHF website. Once finalised, the EHF second opinion project should be treated as a pilot strategy that requires careful monitoring (for the first year at least), so that appropriate changes, as suggested by the retrospective analysis and its quality control, can be implemented.

Familial clustering of migraine: further evidence from a Portuguese study.

OBJECTIVE: Our aim was to evaluate familial aggregation of migraine in a large group of Portuguese families, and to assess if familial aggregation differs between MA and MO. METHODS: Familial aggregation was evaluated by estimating relative risk (RR) of migraine in 143 first-degree relatives of 50 probands with MA, in 196 first-degree relatives of 94 probands with MO and also in proband's spouses. Probands were enrolled in the study from a clinical sample and a population sample was used as reference. RESULTS: A significantly increased risk of migraine was found in both first-degree relatives of MO probands (RR = 3.7; 95% CI: 3.2-4.3) and of MA probands (RR = 3.6; 95% CI: 3.1-4.3), comparatively to the general population. Risk for spouses was not increased. First-degree relatives of MA probands and MO probands had a significantly increased risk of both MA and MO compared to the general population. In the group of MA probands, RR of MA in first-degree relatives reached a significant 4-fold increase when compared with RR of MO (RR(MA|MA) = 12.2, 95%CI: 7.7-19.5; RR(MO|MA) = 3.1, 95%CI: 2.5-3.8), while, in the group of MO probands, RR of MA was not significantly increased when compared with RR of MO (RR(MA|MO) = 5.3, 95%CI: 3.1-9.2; RR(MO|MO) = 4.0, 95%CI: 3.5-4.7). CONCLUSIONS: The present study focus on familial aggregation of migraine in a Portuguese population. Our results demonstrate a substantial familial risk of migraine with evidence of both common and specific etiologic mechanisms for either migraine subtypes.

The C677T polymorphism in MTHFR is not associated with migraine in Portugal.

Migraine is a debilitating disorder affecting a large proportion of the population. The effect of methylenetetrahydrofolate reductase (GeneID: 4524) polymorphisms in migraine etiology and development has been a theme of great interest. Several populations were evaluated with contradictory results. In this case-control study, we investigated the effect of the C677T polymorphism in MTHFR, as a genetic risk factor for migraine, in the Portuguese population. We observed that, overall, there was no significant difference in the frequencies of MTHFR C677T genotypes or of the T-allele among the Portuguese migraineurs when compared to controls. There was also no association of migraine with aura with MTHFR genotypes or with the T-allele, in contrast with previous studies. Regarding the risk of the T-allele homozygote carriers, there was an equal probability to develop migraine with aura over migraine without aura in our patients. Thus, we conclude that the C677T MTHFR polymorphism, responsible for a reduction of the MTHFR activity in folate metabolism, is not a major genetic susceptibility factor for migraine in the Portuguese population.

Divergent sodium channel defects in familial hemiplegic migraine.

Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel Na(V)1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human beta(1) and beta(2) accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na(V)1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na(V)1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.