Severe attacks of familial hemiplegic migraine, childhood epilepsy and ATP1A2 mutation

We studied four members of a family suffering from typical attacks of familial hemiplegic migraine (FHM) caused by a new mutation, R548C, of ATP1A2 gene in exon 12. One individual had also childhood absence epilepsy and generalized tonic-clonic seizures (GTCS). GTCS were followed by a severe attack of hemiplegic migraine at four times. Sodium valproate enabled control of both the epileptic seizures and the most severe FHM attacks. This association of FHM and epileptic seizures and their control with the same treatment suggest similar pathophysiological mechanisms.     

A novel ATP1A2 gene mutation in an Irish familial hemiplegic migraine kindred

OBJECTIVE: We studied a large Irish Caucasian pedigree with familial hemiplegic migraine (FHM) with the aim of finding the causative gene mutation. BACKGROUND: FHM is a rare autosomal-dominant subtype of migraine with aura, which is linked to 4 loci on chromosomes 19p13, 1q23, 2q24, and 1q31. The mutations responsible for hemiplegic migraine have been described in the CACNA1A gene (chromosome 19p13), ATP1A2 gene (chromosome 1q23), and SCN1A gene (chromosome 2q24). METHODS: We performed linkage analyses in this family for chromosome 1q23 and performed mutation analysis of the ATP1A2 gene. RESULTS: Linkage to the FHM2 locus on chromosome 1 was demonstrated. Mutation screening of the ATP1A2 gene revealed a G to C substitution in exon 22 resulting in a novel protein variant, D999H, which co-segregates with FHM within this pedigree and is absent in 50 unaffected individuals. This residue is also highly conserved across species. CONCLUSIONS: We propose that D999H is a novel FHM ATP1A2 mutation.     

Ⅰ型电压依赖型钠通道基因突变嵌合体的检测

目的:寻找鉴定Ⅰ型电压依赖型钠通道基因(SCN1A)突变嵌合体的有效方法,降低癫痫伴热性惊厥附加症的再发风险.方法:抽取携带已知突变c.5768A＞ G/p.Q1923R的患儿及无突变的患儿母亲的外周血全基因组DNA,将患儿的DNA与母亲的DNA以1∶0、1∶1、1∶3、1∶7、1∶15、1∶31及0∶1混合,对包含该突变位点的片段进行PCR扩增后,进行变性高效液相色谱(dHPLC)技术分析、常规测序及焦磷酸测序(pyrosequencing).结果:常规测序仅能检测出1∶0及1∶1混合样本的突变,而dHPLC及焦磷酸测序均能检测出低至1∶15混合样本的突变,且后者能对突变进行定量.结论:利用dHPLC结合焦磷酸测序的方法能有效快速地检测出低至3％左右的突变,可以避免绝大多数SCN1A基因嵌合突变的漏检.     

Alternating hemiplegia of childhood: no mutations in the familial hemiplegic migraine CACNA1A gene

INTRODUCTION: Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterized by attacks of hemiplegia and mental retardation. It has been often associated with migraine. The CACNA1A gene on chromosome 19 is involved in familial hemiplegic migraine and other episodic cerebral disorders, but also with progressive neuronal damage. METHODS: We performed mutation analysis in this gene in four AHC patients, using single strand conformation polymorphism analysis. RESULTS: We found nine polymorphisms, but no mutations in any of the 47 exons. CONCLUSIONS: Other cerebral ion channel genes remain candidate genes for AHC.     

Acute striatal necrosis in hemiplegic migraine with de novo CACNA1A mutation

We report the case of a 9-year-old girl with early-onset developmental delay, chronic ataxia and prolonged hemiplegic migraine episodes bringing about progressive deterioration. Two days into one episode, diffusion-weighted magnetic resonance imaging disclosed unilateral striatal abnormal signal consistent with cytotoxic edema, which evolved into atrophy on follow-up scans. Mutational screen of CACNA1A gene identified a de novo p.Tyr1387Cys mutation.     

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.     

Prolonged sporadic hemiplegic migraine associated with a novel de novo missense ATP1A2 gene mutation

Hemiplegic migraine is a rare form of migraine characterized by periodic attacks of migraine with neurologic aura and transient hemiplegia. There are familial and sporadic cases, both on a genetic basis; we describe the case of a 6-year-old boy affected by sporadic hemiplegic migraine, showing a novel ATP1A2 gene missense mutation (p.Gly715Arg) in exon 16. Long-term treatment with flunarizine resulted in good clinical response and prevention of further attacks.     

Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4

BACKGROUND: Migrainous vertigo (MV) is increasingly recognized as a common cause of episodic vertigo. MV displays several clinical similarities with familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA-2), which have been linked to mutations in 3 genes, CACNA1A, encoding a neuronal calcium channel alpha subunit, ATP1A2, encoding a catalytic subunit of a Na(+)/K(+)-ATPase, and most recently the voltage-gated sodium channel SCN1A. The present study explored the hypothesis that mutations in CACNA1A, ATP1A2, SCN1A, and the calcium channel beta(4) subunit CACNB4 confer susceptibility to MV. METHODS: Mutation analysis of the coding exons and exon/intron junctions of CACNA1A, ATP1A2, SCN1A, and CACNB4 was performed in 14 unrelated MV patients by conformation sensitive gel electrophoresis and automated sequence analysis. RESULTS: Analysis of the 4 candidate genes in the 14 MV patients resulted in the identification of a total of 26 sequence variants. The silent substitution D29D in CACNB4 was observed in 2 MV patients and was not present in 46 ethnically matched control DNA samples. The remaining variants were also observed in control DNA samples and the allele frequencies of variants that resulted in amino acid substitutions were not significantly different between patients and controls. CONCLUSIONS: Based on this group of patients there is no evidence that the genes causing FHM and EA-2 represent major susceptibility loci for MV.     

Beat-to-Beat repolarization variability in LQTS patients with the SCN5A sodium channel gene mutation

Current techniques evaluating beat-to-beat variability of repolarization rely on accurate determination of T wave endpoints. This study proposes a T wave endpoint-independent method to quantify repolarization variability in a standard 12-lead ECG using a wavelet transformation. Our method was used to identify repolarization variability in long QT syndrome patients (LQTS) with the SCN5A sodium channel gene mutation. Using wavelet transformations based on the second Gaussian derivative, we evaluated repolarization variability in 11 LQTS patients with the mutation, 13 noncarrier family members, and 28 unrelated healthy subjects. Time-domain repolarization variability parameters (SDRTo, SDRTm) and wavelet parameters describing temporal (beat-to-beat) variability of repolarization in time (TVT) and in amplitude (TVA) were analyzed. Reproducibility of wavelet parameters and relationship of wavelet-based variability with heart rate and preceding RR interval were investigated. The wavelet-based method quantified beat-to-beat variability of the entire repolarization segment (regardless of QT interval identification) providing insight into variability in repolarization morphology. Our method showed that SCN5A carriers have significantly increased repolarization variability in amplitude (23% +/14% vs 8 +/- 4%, P < 0.001) and in time (14 +/- 17 ms vs 3 +/-2 ms, P < 0.004) compared to noncarriers. Variability of repolarization amplitude was found to be heart rate dependent with variability decreasing with increasing heart rate. Relative error describing reproducibility of TVA and TVT was < or = 5% and < or =10%, respectively. Our method quantifies repolarization variability in amplitude and in time without the need to identify T or U wave endpoints. Wavelet-detected repolarization variability contributes to phenotypic identification of SCN5A carriers, with more pronounced beat-to-beat variability in repolarization amplitude than in time.     

SCN5A基因突变致扩张型心肌病伴房室传导阻滞的家系调查

目的:通过对已发现的心脏钠通道基因SCN5A A1180V突变相关的扩张型心肌病(dilated cardiomyopathy,DCM)伴房室传导阻滞(atrioventricular block,AVB)家系进行随访,分析SCN5A基因A1180V突变致DCM的临床特征及病情演变特点,为制订该类突变携带者临床防治策略...     

中国南方人群家族性偏瘫型偏头痛家系CACNA1A基因多态性相关研究

背景：偏头痛与遗传学之间的联系早已受到关注，遗传流行病学和分离研究证实，偏头痛存在显著的遗传危险性。目的：通过检测偏头痛患者和家族性偏瘫型偏头痛家族外周血CACNA1A基因3个常见的突变位点，分析探讨中国南方人群家族性偏瘫型偏头痛与CACNA1A基因突变之间的关系。 设计：抽样调查。 单位：中山大学附属第一医院和深圳市宝安西乡人民医院。 对象：所有病例均来源中山大学附属第一医院门诊和深圳市宝安西乡人民医院。①家族性偏瘫型偏头痛患者组10例患者。②家族性偏瘫型偏头痛亲属组：家系A和B共12例。③无家族性偏瘫型偏头痛家族史的偏头痛患者组53例。④健康对照10名。 方法：采用聚合酶链反应扩增CACNL1A4-基因的第13，16，17外显子。采用SSCP方法对2个家族性偏瘫型偏头痛家族10例患者及12名无症状亲属和53例无家族性偏瘫型偏头痛家族史的有先兆偏头痛患者及10名健康对照的外周血标本进行检测，分析CACNA1A基因的3个常见突变位点（T666M，R583Q和D715E）在家族性偏瘫型偏头痛家族中的表现形式。 主要观察指标：①聚合酶链反应扩增CACNL1A4基因第13，16，17外显子的结果。②SSCP分析13，16，17外显子的突变结果。 结果：参加实验的家族性偏瘫型偏头痛患者10例，家族性偏瘫型偏头痛亲属12例，无家族性偏瘫型偏头痛家族史的偏头痛患者53例。健康对照组10名，均进入结果分析。①第13，16，17外显子的目的片段长度分别为247，268，204bp。③CACNA1A基因3个常见的突变T666M。R583Q和D715E在2个家族性偏瘫型偏头痛家族10例家族性偏瘫型偏头痛患者，12名无症状亲属和53例无家族性偏瘫型偏头痛家族史的有先兆偏头痛患者及10名健康对照者中均未检测到。 结论：在中国人群家族性偏瘫型偏头痛家族中未发现有T666M，RS83Q和D715E3个突变。     

中国南方人群家族性偏瘫型偏头痛家系CACNA1A基因多态性相关研究

背景:偏头痛与遗传学之间的联系早已受到关注,遗传流行病学和分离研究证实,偏头痛存在显著的遗传危险性。目的:通过检测偏头痛患者和家族性偏瘫型偏头痛家族外周血CAC-NA1A基因3个常见的突变位点,分析探讨中国南方人群家族性偏瘫型偏头痛与CACNA1A基因突变之间的关系。设计:抽样调查。单位:中山大学附属第一医院和深圳市宝安西乡人民医院。对象:所有病例均来源中山大学附属第一医院门诊和深圳市宝安西乡人民医院。①家族性偏瘫型偏头痛患者组10例患者。②家族性偏瘫型偏头痛亲属组:家系A和B共12例。③无家族性偏瘫型偏头痛家族史的偏头痛患者组53例。④健康对照10名。方法:采用聚合酶链反应扩增CACNL1A4基因的第13,16,17外显子。采用SSCP方法对2个家族性偏瘫型偏头痛家族10例患者及12名无症状亲属和53例无家族性偏瘫型偏头痛家族史的有先兆偏头痛患者及10名健康对照的外周血标本进行检测,分析CACNA1A基因的3个常见突变位点(T666M,R583Q和D715E)在家族性偏瘫型偏头痛家族中的表现形式。主要观察指标:①聚合酶链反应扩增CACNL1A4基因第13,16,17外显子的结果。②SSCP分析13,16,17外显子的突变结果。结果:参加实验的家族性偏瘫型偏头痛患者10例,家族性偏瘫型偏头痛亲属12例,无家族性偏瘫型偏头痛家族史的偏头痛患者53例,健康对照组10名,均进入结果分析。①第13,16,17外显子的目的片段长度分别为247,268,204bp。②CACNA1A基因3个常见的突变T666M,R583Q和D715E在2个家族性偏瘫型偏头痛家族10例家族性偏瘫型偏头痛患者,12名无症状亲属和53例无家族性偏瘫型偏头痛家族史的有先兆偏头痛患者及10名健康对照者中均未检测到。结论:在中国人群家族性偏瘫型偏头痛家族中未发现有T666M,R583Q和D715E3个突变。     

Familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

BackgroundThe mechanisms of genotype-phenotype interaction in Familiar Hemiplegic migraine type 2 (FHM2) are still far from clear. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe. No genotype-phenotype correlations have been attempted.Case presentationWe describe an Italian family with FHM and a missense ATP1A2 variant (L425H) not previously described. The clinical picture was mild in all the affected members.ConclusionsCo-segregation of the variant with the aura phenotype was complete in this family, suggesting a 100% penetrance. In silico protein prediction softwares indicate that this variant may change the 3D structure of ATPA1A2 at the cytoplasmic loop between the two central transmembrane helices. Milder FHM phenotypes are rarely reported in literature, likely because case reports are biased towards the most severe phenotypes, with milder forms possibly misdiagnosed as sporadic migraine with aura forms (MAs), even with complex auras. Further studies taking into account intra-familiar variability and functional consequences on the channel protein may help clarify genotype-phenotype correlations.     

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.     

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

Background and aimsHemiplegic 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.MethodsWe 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.ResultsCACNA1A-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.DiscussionThe 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.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01297-5.     

Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients

The aim of this study was to investigate the involvement of the CACNA1A and ATP1A2 gene in a population-based sample of sporadic hemiplegic migraine (SHM). Patients with SHM ( n  = 105) were identified in a nationwide search in the Danish population. We sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes in 100 patients with SHM to search for possible SHM mutations. Novel DNA variants were discovered in eight SHM patients, four in exons of the CACNA1A gene and four in exons of the ATP1A2 gene. Six of the variants were considered non-pathogenic. The causal role of the two remaining DNA variants is unknown until functional studies have been made or independent genetic evidence is discovered. Only very few DNA variants were identified in 100 SHM patients, and regardless of whether the identified variants are causal the CACNA1A and ATP1A2 genes are not major genes in SHM.     

Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine.

Int J Psychophysiol . 2002 Jun;44(3):239-249
The modulation of trigeminal reflex excitability in migraine patients was evaluated during the asymptomatic phase by studying the effects of attention, habituation and preconditioning stimulus on the R2 and R3 components of the blink reflex (BR). Fifty patients suffering from migraine without aura, 20 affected by migraine with aura and 35 sex- and age-matched controls were selected. In subgroups of migraine with-aura and without-aura patients, and normal controls, the blink reflex was elicited during different cognitive situations: (a) spontaneous mental activity; (b) stimulus anticipation; (c) recognition of target numbers. In the remaining subjects, R2 and R3 habituation was evaluated by repetitive stimulation at 1, 5, 10, 15, 20, 25 and 30 s intervals. The R2 and R3 recovery curves were also computed. A reduced R3 threshold with a normal pain threshold was found in migraine with-aura and without-aura patients; the R3 component was not significantly correlated with the pain thresholds in patients and controls. The R2 and R3 components were less influenced by the warning of the stimulus in migraine without-aura and migraine with-aura patients, in comparison with the control group. A slight increase of both R2 and R3 recovery after preconditioning stimulus was also observed in migraine patients, probably caused by a phenomenon of trigeminal hyperexcitability persisting after the last attack. The abnormal BR modulation by alerting expresses in migraine a dysfunction of adaptation capacity to environmental conditions, probably predisposing to migraine.
Comment: Further physiologic and functional evidence for the interictal hyperexcitability of neurons in patients with migraine, in this case trigeminal neurons involved in the blink reflex. SJT     

Electrocardiogram changes and atrial arrhythmias in individuals carrying sodium channel SCN5A D1275N mutation

Introduction: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular depolarization as well as cardiac conduction. Patients with cardiac electrical abnormalities have an increased risk of sudden cardiac death (SCD) and cardio-embolic stroke. Optimal management of cardiac disease includes the understanding of association between the causative mutations and the clinical phenotype. A 12-lead electrocardiogram (ECG) is an easy and inexpensive tool for finding risk patients.

Materials and methods: A blood sample for DNA extraction was obtained in a Finnish family with 43 members; systematic 12-lead ECG analysis was performed in 13 of the family members carrying an SCN5A D1275N mutation. Conduction defects and supraventricular arrhythmias, including atrial fibrillation/flutter, atrioventricular nodal re-entry tachycardia (AVNRT) and junctional rhythm were searched for.

Results: Five (38%) mutation carriers had fascicular or bundle branch block, 10 had atrial arrhythmias; no ventricular arrhythmias were found. Notching of the R- and S waves – including initial QRS fragmentation – and prolonged S-wave upstroke were present in all the affected family members. Notably, four (31%) affected family members had a stroke before the age of 31 and two experienced premature death.

Conclusions: A 12-lead ECG can be used to predict arrhythmias in SCN5A D1275N mutation carriers.

• Key messages

• The 12-lead ECG may reveal cardiac abnormalities even before clinical symptoms occur.

• Specific ECG findings – initial QRS fragmentation, prolonged S-wave upstroke as well as supraventricular arrhythmias – were frequently encountered in all SCN5A D1257N mutation carriers.

• ECG follow-up is recommended for all SCN5A D1275N mutation carriers.