Recurrent coma and fever in familial hemiplegic migraine type 2. A prospective 15-year follow-up of a large family with a novel ATP1A2 mutation.

Background Familial hemiplegic migraine (FHM) is a rare monogenic migraine subtype characterised by attacks associated with transient motor weakness. Clinical information is mainly based on reports of small families with only short follow-up. Here, we document a prospective 15-year follow-up of an extended family with FHM type 2. Patients and methods After diagnosing FHM in a patient with severe attacks associated with coma and fever, we identified eight more family members with FHM and one with possible FHM. All family members were prospectively followed for 15 years. In total 13 clinically affected and 21 clinically non-affected family members were genetically tested and repeatedly investigated. Results A novel p.Arg348Pro ATP1A2 mutation was found in 14 family members: 12 with clinical FHM, one with psychomotor retardation and possible FHM, and one without FHM features. In 9/12 (75%) family members with genetically confirmed FHM, attacks were severe, long-lasting, and often associated with impaired consciousness and fever. Such attacks were frequently misdiagnosed and treated as viral meningitis or stroke. Epilepsy was reported in three family members with FHM and in the one with psychomotor retardation and possible FHM. Ataxia was not observed. Conclusion FHM should be considered in patients with recurrent coma and fever.

Validation of the web-based LUMINA questionnaire for recruiting large cohorts of migraineurs.

OBJECTIVE: To assess validity of a self-administered web-based migraine-questionnaire in diagnosing migraine aura for the use of epidemiological and genetic studies. METHODS: Self-reported migraineurs enrolled via the LUMINA website and completed a web-based questionnaire on headache and aura symptoms, after fulfilling screening criteria. Diagnoses were calculated using an algorithm based on the International Classification of Headache Disorders (ICHD-2), and semi-structured telephone-interviews were performed for final diagnoses. Logistic regression generated a prediction rule for aura. Algorithm-based diagnoses and predicted diagnoses were subsequently compared to the interview-derived diagnoses. RESULTS: In 1 year, we recruited 2397 migraineurs, of which 1067 were included in the validation. A seven-question subset provided higher sensitivity (86% vs. 45%), slightly lower specificity (75% vs. 95%), and similar positive predictive value (86% vs. 88%) in assessing aura when comparing with the ICHD-2-based algorithm. CONCLUSIONS: This questionnaire is accurate and reliable in diagnosing migraine aura among self-reported migraineurs and enables detection of more aura cases with low false-positive rate.

Early seizures and cerebral oedema after trivial head trauma associated with the CACNA1A S218L mutation.

OBJECTIVE: To study the clinical spectrum of CACNA1A S218L mutation carriers with special attention to "early seizures and cerebral oedema after trivial head trauma (ESCEATHT)", a combination of symptoms which resembles the "juvenile head trauma syndrome". PATIENTS AND METHODS: In two patients with ESCEATHT all exons of CACNA1A were sequenced. Both patients also had hemiplegic migraine and ataxia. Subsequently, we screened the literature for S218L mutation carriers. RESULTS: In both patients, a de novo S218L mutation in the CACNA1A gene was found. In addition, we identified 11 CACNA1A S218L carriers from the literature. Of these 13 S218L mutation carriers, 12 (92%) had ataxia or cerebellar symptoms and nine (69%) had hemiplegic migraine that could be triggered by trivial head trauma. Three mutation carriers had the complete ESCEATHT phenotype. Seven (54%) had seizures (four had early post-traumatic seizures) and five (38%) had oedema as detected by MRI/CT. CONCLUSIONS: The CACNA1A S218L mutation is associated with familial hemiplegic migraine, ataxia and/or ESCEATHT. A minority of S218L mutation carriers have the complete ESCEATHT phenotype but a high percentage of patients had one or more ESCEATHT symptoms. As the S218L mutation enhances the propensity for cortical spreading depression (CSD), we postulate a role for CSD not only in hemiplegic migraine but also in early seizures and cerebral oedema after trivial head trauma. As this combination of symptoms is part of the unexplained "juvenile head trauma syndrome", a similar molecular mechanism may underlie this disorder.

Migraine and genetic and acquired vasculopathies.

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and hereditary infantile hemiparessis, retinal arteriolar tortuosity and leukoencephalopahty (HIHRATL). The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. Common genetic susceptibility, increased susceptibility to cortical spreading depression (CSD) and vascular endothelial dysfunction are among the possible explanations. The relation between migraine and acquired vasculopathies such as ischaemic stroke and coronary heart disease has long been established, further supporting a role of the (cerebral) blood vessels in migraine. This review focuses on genetic and acquired vasculopathies associated with migraine. We speculate how genetic and acquired vascular mechanisms might be involved in migraine.

First mutation in the voltage-gated Nav1.1 subunit gene SCN1A with co-occurring familial hemiplegic migraine and epilepsy.

Almost all mutations in the SCN1A gene, encoding the alpha(1) subunit of neuronal voltage-gated Na(V)1.1 sodium channels, are associated with severe childhood epilepsy. Recently, two mutations were identified in patients with pure familial hemiplegic migraine (FHM). Here, we identified a novel SCN1A L263V mutation in a Portuguese family with partly co-segregating hemiplegic migraine and epilepsy. The L263V mutation segregated in five FHM patients, three of whom also had epileptic attacks, occurring independently from their hemiplegic migraine attacks. L263V is the first SCN1A mutation associated with FHM and co-occurring epilepsy in multiple mutation carriers, and is the clearest molecular link between migraine and epilepsy thus far. The results extend the clinical spectrum associated with SCN1A mutations and further strengthen the molecular evidence that FHM and epilepsy share, at least in part, similar molecular pathways.

CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine.

Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype-phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.

A review of the genetic relation between migraine and epilepsy.

A possible relation between migraine and epilepsy has been a matter of debate for many decades. Clinical, epidemiological and therapeutic similarities may be coincidental and are no proof of a common aetiological background. However, a genetically determined dysfunction of ion channels seems to point to a common underlying mechanism for both paroxysmal disorders. For example, mutations in the three known genes for familial hemiplegic migraine can cause epilepsy. It is likely that the development of specific drugs aimed at restoring ion-channel function and/or related cellular signalling pathways might benefit patients with epilepsy as well as those with migraine. This review will briefly summarize the clinical, epidemiological, pathophysiological and therapeutic similarities between migraine and epilepsy. Most attention will be paid to the genetic relationship between these two paroxysmal disorders.

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.

Shared genetic factors in migraine and depression: evidence from a genetic isolate.

OBJECTIVE: To investigate the co-occurrence of migraine and depression and assess whether shared genetic factors may underlie both diseases. METHODS: Subjects were 2,652 participants of the Erasmus Rucphen Family genetic isolate study. Migraine was diagnosed using a validated 3-stage screening method that included a telephone interview. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). The contribution of shared genetic factors in migraine and depression was investigated by comparing heritability estimates for migraine with and without adjustment for symptoms of depression, and by comparing the heritability scores of depression between migraineurs and controls. RESULTS: We identified 360 migraine cases: 209 had migraine without aura (MO) and 151 had migraine with aura (MA). Odds ratios for depression in patients with migraine were 1.29 (95% confidence interval [CI] 0.98-1.70) for MO and 1.70 (95% CI 1.28-2.24) for MA. Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96), and decreased after adjustment for symptoms of depression or use of antidepressant medication, in particular for MA. Comparison of the heritability scores for depression between patients with migraine and controls showed a genetic correlation between HADS-D score and MA. CONCLUSIONS: There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors.

Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine.

BACKGROUND: Familial (FHM) and sporadic (SHM) hemiplegic migraine are severe subtypes of migraine associated with transient hemiparesis. For FHM, three genes have been identified encoding subunits of a calcium channel (CACNA1A), a sodium-potassium pump (ATP1A2), and a sodium channel (SCN1A). Their role in SHM is unknown. Establishing a genetic basis for SHM may further the understanding of its pathophysiology and relationship with common types of migraine. It will also facilitate the often difficult differential diagnosis from other causes of transient hemiparesis. METHODS: We systematically scanned 39 well-characterized patients with SHM without associated neurologic features for mutations in the three FHM genes. Functional assays were performed for all new sequence variants. RESULTS: Sequence variants were identified in seven SHM patients: one CACNA1A mutation, five ATP1A2 mutations, and one SCN1A polymorphism. All six mutations caused functional changes in cellular assays. One SHM patient later changed to FHM because another family member developed FHM attacks. CONCLUSION: We show that FHM genes are involved in at least a proportion of SHM patients without associated neurologic symptoms. Screening of ATP1A2 offers the highest likelihood of success. Because FHM gene mutations were also found in family members with "nonhemiplegic" typical migraine with and without aura, our findings reinforce the hypothesis that FHM, SHM, and "normal" migraine are part of a disease spectrum with shared pathogenetic mechanisms.

Alternating hemiplegia of childhood: no mutations in the glutamate transporter EAAT1.

Alternating hemiplegia of childhood (AHC) is a severe brain disorder, mainly characterised by episodes of hemiplegia, progressive mental retardation, and other severe paroxysmal and permanent neurological symptoms. Clinically and genetically, there is some overlap with sporadic (SHM) and familial (FHM) hemiplegic migraine, a severe monogenic subtype of migraine. Although no mutations were detected in the FHM1 CACNA1A and FHM2 ATP1A2 genes in sporadic AHC patients, a mutation was found in the FHM2 ATP1A2 gene in a family with AHC. Recently, a missense mutation was found in the SLC1A3 gene that encodes the glutamate transporter EAAT1, in a patient with alternating hemiplegia, episodic ataxia, seizures, and headache. Because of the remarkable clinical similarities and the potential role of glutamate in AHC, we analysed six sporadic patients with AHC for mutations in the SLC1A3 gene. No mutations were found. The SLC1A3 EAAT1 glutamate transporter gene does not seem to be involved in the pathogenesis of AHC.

Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation.

OBJECTIVE: Attacks of familial hemiplegic migraine (FHM) are usually associated with transient, completely reversible symptoms. Here, we studied the ATP1A2 FHM2 gene in a young girl with episodes of both very severe and transient neurological symptoms that were triggered by mild head trauma as well as permanent mental retardation. Her family members suffered from hemiplegic and confusional migraine attacks. METHODS: Mutation analysis of the ATP1A2 gene was performed by direct sequencing of all exons and flanking intronic regions, using genomic DNA of the proband. Functional consequences of the mutation were analyzed by cellular survival assays. RESULTS: We identified a novel G615R ATP1A2 mutation in the proband and several of her family members. Functional analysis of mutant Na,K-ATPase in cellular survival assays showed a complete loss-of-function effect. INTERPRETATION: Permanent mental retardation in children may be caused by ATP1A2 mutations.