Familial hemiplegic migraine in Indian children-a tertiary center experience.

Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.

Migraine with prolonged aphasic aura associated with a CACNA1A mutation: A case report and narrative review.

OBJECTIVE: To demonstrate that a known CACNA1A variant is associated with a phenotype of prolonged aphasic aura without hemiparesis. BACKGROUND: The usual differential diagnosis of prolonged aphasia without hemiparesis includes vascular disease, seizure, metabolic derangements, and migraine. Genetic mutations in the CACNA1A gene can lead to a myriad of phenotypes, including familial hemiplegic migraine (FHM) type 1, an autosomal dominant disorder characterized by an aura of unilateral, sometimes prolonged weakness. Though aphasia is a common feature of migraine aura, with or without hemiparesis, aphasia without hemiparesis has not been reported with CACNA1A mutations. METHODS: We report the case of a 51-year-old male who presented with a history of recurrent episodes of aphasia without hemiparesis lasting days to weeks. His headache was left sided and was heralded by what his family described as "confusion." On examination, he had global aphasia without other focal findings. Family history revealed several relatives with a history of severe headaches with neurologic deficits including aphasia and/or weakness. Imaging revealed T2 hyperintensities in the left parietal/temporal/occipital regions on MRI scan with corresponding hyperperfusion on SPECT. Genetic testing revealed a missense mutation in the CACNA1A gene. CONCLUSIONS: This case expands the phenotypic spectrum of the CACNA1A mutation and FHM to include prolonged aphasic aura without hemiparesis. Our patient's SPECT imaging demonstrated hyperperfusion in areas correlating with aura symptoms which can occur in prolonged aura.

Familial hemiplegic migraine in pediatric patients: A genetic, clinical, and follow-up study.

OBJECTIVE: The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype-phenotype correlations may suggest prognostic factors associated with severe phenotypes. BACKGROUND: Hemiplegic migraine is a rare disease and data concerning the pediatric population are even more rare as they are often extrapolated from mixed cohorts. METHODS: We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first attack occurred under the age of 18 years. RESULTS: We enrolled nine patients (seven males and two females) first referred to our three centers. Three of the nine (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both genetic mutations. The patients experienced at least one aura feature other than hemiplegia during the first attack. The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h; 3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range) duration of follow-up was 7.4 (2.2, 3-10) years. During the first year from the disorder's onset, only four patients had additional attacks. Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2). CONCLUSION: The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time. Furthermore, the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning.

Hemiplegic Migraine.

PURPOSE OF REVIEW: In this article, we review recent updates to the epidemiology, diagnostic testing, genetics, pathophysiology, and management of hemiplegic migraine. RECENT FINDINGS: While three genes have been historically associated with hemiplegic migraine, recent studies suggest two additional genes may also be implicated including PPRT2 and SLC1A3. Hemiplegic migraine is a severe subset of migraine with aura with symptoms including reversible hemiparesis in addition to other aura symptoms such as visual, sensory, or speech. The exact pathophysiology of hemiplegic migraine is not clear, but it is thought that this phenomenon is due to neuronal and glial depolarization causing cortical spreading depression. Due to the severity of presentation as well as the numerous mimickers, it is important to know a comprehensive differential and work-up. Given the low prevalence of the disease, most studies regarding treatment are limited to case studies. There is still an important need for further and larger studies regarding management of these cases.

A novel CACNA1A R2201W variant in a woman with hemiplegic migraine.

INTRODUCTION: Familial hemiplegic migraine type 1 (FHM1) is a monogenic rare disease that is characterized by migraine attacks accompanied by unilateral weakness and is caused by mutations in the CACNA1A gene. We report the case of a patient with a clinical history consistent with hemiplegic migraine who underwent genetic testing that revealed a variant in the CACNA1A gene. CASE PRESENTATION: A 68-year-old woman was evaluated for progressive postural instability and subjective cognitive decline. She had suffered from recurrent migraine episodes accompanied by fully reversible unilateral weakness that had started around the age of thirty and had fully disappeared at the time of evaluation. Magnetic resonance imaging (MRI) showed an extensive leukoencephalopathy, with features suggestive of small vessel disease, significantly progressing over the years. Exome sequencing revealed the heterozygous variant c.6601C>T (p.Arg2201Trp) in the CACNA1A gene. This variant, located in a highly conserved region, causes the substitution of arginine with tryptophan at codon 2202 of exon 47, with a high likelihood of a damaging effect on protein activity and/or structure. DISCUSSION: This is the first report describing the missense mutation c.6601C>T (p.Arg2201Trp) in heterozygosity in the CACNA1A gene in a patient with clinical features of hemiplegic migraine. The presence of a diffuse leukoencephalopathy on MRI is not typical of hemiplegic migraine and may suggest a phenotypic variant related to this mutation or result from the combined effect of the patient's comorbidities.

CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options.

In the last decade, variants in the Ca2+ channel gene CACNA1A emerged as a frequent aetiology of rare neurological phenotypes sharing a common denominator of variable paroxysmal manifestations and chronic cerebellar dysfunction. The spectrum of paroxysmal manifestations encompasses migraine with hemiplegic aura, episodic ataxia, epilepsy and paroxysmal non-epileptic movement disorders. Additional chronic neurological symptoms range from severe developmental phenotypes in early-onset cases to neurobehavioural disorders and chronic cerebellar ataxia in older children and adults.In the present review we systematically approach the clinical manifestations of CACNA1A variants, delineate genotype-phenotype correlations and elaborate on the emerging concept of an age-dependent phenotypic spectrum in CACNA1A disease. We furthermore reflect on different therapy options available for paroxysmal symptoms in CACNA1A and address open issues to prioritize in the future clinical research.

Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations.

Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Genetics of migraine: where are we now?

Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes code for proteins expressed in neurons, glial cells, or vessels, all of which increase susceptibility to cortical spreading depression. The study of monogenic migraines has shown that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified numerous susceptibility variants that each result in only a small increase in overall migraine risk. The more than 180 known variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also highlighted the importance of shared genetic factors between migraine and its major co-morbidities, including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes.

Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations.

BACKGROUND: ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. AIM: We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. METHODS: A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. RESULTS: Patients (age 2.5-20 years) had symptom onset at an early age (6 days-1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks-4.8 years) with some improvements reported in all five. CONCLUSIONS: Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure-function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.

Genetics of migraine.

Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes encode proteins expressed in neurons, astrocytes or vessels, which all increase the susceptibility to cortical spreading depression. Study of monogenic migraines showed that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified multiple susceptibility variants that only cause a small increase of the global migraine risk. The variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also underscored the importance of genetic factors shared between migraine and its major co-morbidities including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes. Thanks to the advent of new technologies such as induced pluripotent stem cells, genetic data will hopefully finally be able to lead to therapeutic progress.

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms.

BACKGROUND: Mutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear. METHODS: Ten ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations. RESULTS: Compared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain. CONCLUSIONS: ATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.

SCN1A variants from bench to bedside-improved clinical prediction from functional characterization.

Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed. We review the functional SCN1A work performed to date, critically appraise electrophysiological measurements, compare this to in silico predictions, and relate our findings to the clinical phenotype. Our results show, regardless of the underlying phenotype, that conventional in silico software correctly predicted benign from pathogenic variants in nearly 90%, however was unable to differentiate within the disease spectrum (DS vs. GEFS+ vs. FHM). In contrast, patch-clamp data from mammalian expression systems revealed functional differences among missense variants allowing discrimination between disease severities. Those presenting with milder phenotypes retained a degree of channel function measured as residual whole-cell current, whereas those without any whole-cell current were often associated with DS (p = .024). These findings demonstrate that electrophysiological data from mammalian expression systems can serve as useful disease biomarker when evaluating SCN1A variants, particularly in view of new and emerging treatment options in DS.

Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 2.

BACKGROUND: Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in ATP1A2 exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the Atp1a2 orthologous gene. OBJECTIVE: To investigate the characteristics of cortical spreading depression in a mouse model with E700K mutation in the Atp1a2. METHODS: Cortical spreading depression was induced by applying stepwise increases of KCl concentration or electrical stimulation intensity to C57BL/6J-Tg(Atp1a2*E700K)9151Kwk mice (Tg, both sexes) and corresponding wild-type animals. Under urethane anesthesia, the responsiveness and threshold to cortical spreading depression were examined and the distribution of c-Fos expression, a neuronal activity marker, was immunohistochemically determined. RESULTS: Overall, Tg mice showed significantly faster propagation velocity (p < 0.01) and longer full-width-at-half-maximum (p < 0.01) than wild-type animals, representing a slower recovery from direct current potential deflection. The cortical spreading depression threshold tended to be lower in Tg, especially in females. c-Fos-positive cells were significantly enhanced in the ipsilateral somatosensory cortex, piriform cortex, amygdala and striatum (each p < 0.05 vs. contralateral side). Numbers of c-Fos positive cells were significantly higher in the ipsilateral amygdala of Tg, as compared with wild-type animals (p < 0.01). CONCLUSION: The effect of cortical spreading depression may be greater in E700K transgenic mice than that in wild-type animals, while the threshold for cortical spreading depression shows little change. Higher c-Fos expression in the amygdala may indicate alterations of the limbic system in Tg, suggesting an enhanced linkage between cortical spreading depression and amygdala connectivity in familial hemiplegic migraine 2 patients.

Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant.

BACKGROUND: To investigate the genetic and environmental factors responsible for phenotype variability in a family carrying a novel CACNA1A missense mutation. Mutations in the CACNA1A gene were identified as responsible for at least three autosomal dominant disorders: FHM1 (Familial Hemiplegic Migraine), EA2 (Episodic Ataxia type 2), and SCA6 (Spinocerebellar Ataxia type 6). Overlapping clinical features within individuals of some families sharing the same CACNA1A mutation are not infrequent. Conversely, reports with distinct phenotypes within the same family associated with a common CACNA1A mutation are very rare. CASE PRESENTATION: A clinical, molecular, neuroradiological, neuropsychological, and neurophysiological study was carried out in proband and his carrier mother. The new heterozygous missense variant c.4262G > A (p.Arg1421Gln) in the CACNA1A gene was detected in the two affected family members. The proband showed a complex clinical presentation characterized by developmental delay, poor motor coordination, hemiplegic migraine attacks, behavioral dysregulation, and EEG abnormalities. The mother showed typical episodic ataxia attacks during infancy with no other comorbidities and mild cerebellar signs at present neurological evaluation. CONCLUSIONS: The proband and his mother exhibit two distinct clinical phenotypes. It can be hypothesized that other unknown modifying genes and/or environmental factors may cooperate to generate the wide intrafamilial variability.

Familial "Diplegic" Migraine - Description of a Family With a Novel CACNA1A Mutation.

OBJECTIVE: To characterize phenotypes of a novel CACNA1A mutation causing familial hemiplegic migraine type 1. BACKGROUND: Familial hemiplegic migraine is a rare monogenic form of migraine associated with attacks of fully reversible unilateral motor weakness. We now report a novel CACNA1A gene mutation associated with fully reversible bilateral motor weakness (diplegia). METHODS: The proband underwent genotyping which identified a novel CACNA1A missense mutation (c.622 [isoform 1] G > A [p.Gly208Arg]). To characterize phenotypes associated with this novel mutation, the proband and 8 of her similarly affected family members underwent a semi-structured interview. RESULTS: All 9 subjects who were interviewed met ICHD-3 phenotypic diagnostic criteria for FHM, including reporting attacks with reversible unilateral motor weakness. Additionally, 7 of 9 subjects reported attacks including reversible motor weakness affecting both sides of the body simultaneously. CONCLUSIONS: We describe a novel CACNA1A mutation associated with migraine attacks including reversible diplegia.

In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures.

Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wild-type (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the CaV2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of CaV2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.

The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature.

BACKGROUND AND PURPOSE: CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS: Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS: Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS: Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.

Familial Hemiplegic Migraines and Baseline Neuropsychological Testing: A Case Report.

OBJECTIVE: To explore the neuropsychological correlates and implications of familial hemiplegic migraines (FHMs). BACKGROUND: FMH is a rare, autosomal dominant subtype of migraine that only occurs in 0.01% of the population. Little is known about the neuropsychological impact of FHMs; however, cognitive impairment associated with cerebellar syndrome has been identified in some cases. METHOD: A single case study involving a 24-year-old male who recently endured an atypical, prolonged FHM episode. RESULTS: The patient's overall neuropsychological functioning was intact with low average semantic fluency and processing speed, and mild indications of executive dysfunction. CONCLUSION: Baseline and serial neuropsychological testing in individuals with FHM may help identify the potential progression and course of cognitive impairment associated with this condition.

Ten years of follow-up in a large family with familial hemiplegic migraine type 1: Clinical course and implications for treatment.

Background Familial hemiplegic migraine (FHM) is a rare, genetic form of migraine with aura. The severity of the aura imposes an effective prophylaxis that is currently based on standard anti-migraine drugs. To this concern, only short-term reports are currently available. Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic. Medical history, general and neurological examination as well as therapeutic approaches were recorded regularly on a routine basis for an average period of 13 years (range 9-15 years). Brain imaging studies and EEG data were also collected. Results Our long-term follow-up revealed that ictal manifestations, which usually improve after the adolescence, may reoccur later in the adulthood. Permanent neurological signs as assessed by means of clinical evaluation as well as follow-up MRIs, EEGs and neuropsychological testing remained stable. Interval therapy with non-selective calcium antagonists reduced the burden of migraine attacks and was well tolerated in the long term.

Enhanced susceptibility to cortical spreading depression in two types of Na+,K+-ATPase α2 subunit-deficient mice as a model of familial hemiplegic migraine 2.

Background Patients with familial hemiplegic migraine type 2 (FHM2) have a mutated ATP1A2 gene (encoding Na+,K+-ATPase α2 subunit) and show prolonged migraine aura. Cortical spreading depression (CSD), which involves mass depolarization of neurons and astrocytes that propagates slowly through the gray matter, is profoundly related to aura. Methods In two types of Atp1a2-defective heterozygous mice, Atp1a2tm1Kwk (C-KO) and Atp1a2tm2Kwk (N-KO), the sensitivity and responsiveness to CSD were examined under urethane anesthesia. Results In both cases, heterozygotes exhibited a low threshold for induction of CSD, faster propagation rate, slower recovery from DC deflection, and profound suppression of the electroencephalogram, compared to wild-type mice. A high dose of KCl elicited repeated CSDs for a longer period, with a tendency for a greater frequency of CSD occurrence in heterozygotes. The difference of every endpoint was slightly greater in N-KO than C-KO. Change of regional cerebral blood flow in response to CSD showed no significant difference. Conclusion Heterozygotes of Atp1a2-defective mice simulating FHM2 demonstrated high susceptibility to CSD rather than cortical vasoreactivity, and these effects may differ depending upon the knockout strategy for the gene disruption. These results suggest that patients with FHM2 may exhibit high susceptibility to CSD, resulting in migraine.