Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic migraine 1 increase the susceptibility for cortical spreading depolarization and seizures and worsen outcome after experimental traumatic brain injury

Patients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the CACNA1A gene that encodes the α1A subunit of neuronal voltage-gated CaV2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact (CCI) and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure was more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here we show that gain of CaV2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers.

Hemiplegic Migraine Associated With PRRT2 Mutations: A Clinical and Genetic Study

Background and objective:PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of PRRT2 in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.Methods:PRRT2 was analyzed in 860 probands with hemiplegic migraine and PRRT2 mutations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with mutations whose clinical manifestations were detailed.Results:PRRT2 mutations were found in 12 of 163 probands previously tested negative for CACNA1A, ATP1A2 and SCN1A mutations, and in 18 of 697 consecutive probands screened simultaneously on the four genes. In this second group, pathogenic variants were found in 105 subjects, mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%) and SCN1A (15%). The PRRT2 mutations included seven distinct variants, five of which already described in persons with paroxysmal kinesigenic dyskinesia, and two new variants. Eight probands had a deletion of the whole PRRT2 gene.Among the 49 PRRT2 mutated patients, 26 had pure hemiplegic migraine, 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4) or abnormal movement (3). Three patients had epilepsy without migraine, two had paroxysmal kinesigenic dyskinesia without migraine, and one was asymptomatic.Conclusion:PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine, and screened in any affected patient, together with the three other main genes. Further studies are needed to understand how the same loss of function PRRT2 mutations can lead to a wide range of neurologic phenotypes including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder and hemiplegic migraine.

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.

Differentiating stroke, transient ischemic attack, or hemiplegic migraine in a teenager: a case report

Background: The symptoms of stroke in the pediatric population are less evaluated than in adults. Although certain indicators are characteristic of stroke – acute drooping of the mouth corners, hemiparesis, and headache – they are not pathognomonic. Other diseases may manifest with similar symptoms, such as the first episode of hemiplegic migraine, and should be differentiated from stroke at an emergency department. Aim of the study: We present the differential diagnosis between stroke, transient ischemic attack, and first episode of hemiplegic migraine in a teenager with alarming focal symptoms. Case report: We present a case of 15-year-old patient with acute headache, drooping of the right mouth corners, and hemiparesis of the right upper and lower limb. He was brought by ambulance to the emergency department under suspicion of a stroke. A series of diagnostic tests performed at the Emergency Department did not reveal any vascular incident. Further diagnosis was performed at the Neurology Department. The patient was discharged from the hospital with a suspicion of first attack of hemiplegic migraine or transient ischemic attack. Conclusions: Differentiating stroke from other conditions in young patients is a significant challenge. The stroke diagnostic process in children requires further research to support accurate diagnosis and, if necessary, treatment as rapidly as possible.

CACNA1A-p.Thr501Met mutation associated with familial hemiplegic migraine: a family report

Background and aims Hemiplegic migraine (HM) is a rare form of migraine characterized by the presence of a motor and other types of aura. HM can be sporadic or familial. Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, classified into 3 subtypes, based on the gene involved (CACNA1A in FHM1, ATP1A2 in FHM2 and SCN1A in FHM3). The clinical presentation is highly heterogeneous and some attacks may be severe. We report the clinical characteristics and genetic analysis of 12 patients belonging to a family with CACNA1A-p.Thr501Met gene mutation. Methods We screened for mutations in CACNA1A gene 15 patients belonging to the same family. The exonic sequences of CACNA1A were analyzed using a Tru-seq® Custom Amplicon (TSCA) (Illumina Inc., San Diego, CA) targeted capture and paired end library kit. Sanger sequencing was used to confirm CACNA1A variants and segregation analysis. Results CACNA1A-p.Thr501Met mutation was found in 12 of the 15 patients screened, which was compatible with the diagnosis of FHM1. Attacks of hemiplegic migraine were reported by 10 of the 12 subjects (83.33%). Only one subject developed persistent mild cerebellar symptoms and none of the subjects developed cerebellar atrophy. Discussion The variant p.Thr501Met was described previously in association with episodic ataxia and rarely with FHM related to cerebellar symptoms. FHM1 has a broad clinical spectrum and about half of the families have cerebellar involvement. In our study, only one patient developed persistent cerebellar deficits. These data suggest that CACNA1A-p.Thr501Met mutation can occur prevalently as hemiplegic migraine.