scholarly journals Detection of a Novel Mutation in the CACNA1A gene

2012 ◽  
Vol 15 (1) ◽  
pp. 120-125 ◽  
Author(s):  
Shani Stuart ◽  
Bishakha Roy ◽  
Gail Davies ◽  
Nevene Maksemous ◽  
Robert Smith ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Novel Mutation ◽  
Diagnostic Procedures ◽  
Familial Hemiplegic Migraine ◽  
Therapeutic Agents ◽  
Phenotypic Effect ◽  
Hemiplegic Migraine ◽  
New Information ◽  
Cacna1a Gene ◽  
Improving Accuracy

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. It is divided into three subtypes FHM1, FHM2 and FHM3, which are caused by mutations in the CACNA1A, ATP1A2 and SCN1A genes respectively. As part of a regular diagnostic service, we investigated 168 patients with FHM symptoms. Samples were tested for mutations contained within the CACNA1A gene. Some tested samples (4.43%) showed an FHM1 mutation, with five of the mutations found in exon 5, one mutation in exon 16 and one in exon 17. Four polymorphisms were also detected, one of which occurred in a large percentage of samples (14.88%). The exon 16 2094G>A polymorphism, however, has been found to occur in healthy Caucasian control populations up to a frequency of 16% and is not considered to be significantly associated with FHM. A finding of significance, found in a single patient, was the detection of a novel mutation in exon 5 that results in a P225H change. The affected individual was an 8-year-old female. The exact phenotypic effect of this mutation is unknown, and further studies are needed to understand the pathophysiology of this mutation in FHM1. New information will allow for diagnostic procedures to be constantly updated, thus improving accuracy of diagnosis. It is possible that new information will also aid the development of new therapeutic agents for the treatment of FHM.

The FHM1 Mutation S218L: A Severe Clinical Phenotype? A Case Report and Review of the Literature

Cephalalgia ◽  
2009 ◽  
Vol 29 (12) ◽  
pp. 1337-1339 ◽  
Author(s):  
S Debiais ◽  
C Hommet ◽  
I Bonnaud ◽  
MA Barthez ◽  
S Rimbaux ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Cerebral Oedema ◽  
Clinical Phenotype ◽  
Pregnant Patient ◽  
Familial Hemiplegic Migraine ◽  
Review Of The Literature ◽  
Severe Phenotype ◽  
Hemiplegic Migraine ◽  
Motor Weakness ◽  
Cacna1a Gene

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura that is characterized by motor weakness during attacks. FHM1 is associated with mutations in the CACNA1A gene located on chromosome 19. We report a severe, prolonged HM attack in a young pregnant patient who had the S218L FHM1. This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma. The case history we report suggests a specific, severe phenotype and the co-occurrence of HM and epilepsy related to the S218L FHM1 mutation.

A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

Cephalalgia ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 1382-1395
Author(s):  
Wenjing Tang ◽  
Meichen Zhang ◽  
Enchao Qiu ◽  
Shanshan Kong ◽  
Yingji Li ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Pathogenic Mutation ◽  
Familial Hemiplegic Migraine ◽  
Chinese Family ◽  
Hemiplegic Migraine ◽  
Pathogenic Potential ◽  
The Family

Background ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation. Methods Clinical manifestations in the family were recorded. Blood samples from patients and the unaffected members were collected for whole-exome sequencing to identify the pathogenic mutation. Seven online softwares (SIFT, PolyPhen-2, PROVEAN, PANTHER, MutationTaster2, MutationAssessor and PMut) were used for predicting the pathogenic potential of the mutation. PredictProtein, Jpred 4 and PyMOL were used to analyze structural changes of the protein. The mutation function was further tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Results All patients in the family had typical hemiplegic migraine attacks. Co-segregation of the mutation with the migraine phenotype in four generations, with 10 patients, was completed. The identified novel mutation, G762S in ATP1A2, exhibited the disease-causing feature by all the predictive softwares. The mutation impaired the local structure of the protein and decreased cell viability. Conclusion G762S in ATP1A2 is a novel pathogenic mutation identified in a Chinese family with familial hemiplegic migraine, which causes loss of function by changing the protein structure of the Na+/K+-ATPase α2 subunit.

scholarly journals Early-onset familial hemiplegic migraine due to a novel SCN1A mutation

Cephalalgia ◽  
2016 ◽  
Vol 36 (13) ◽  
pp. 1238-1247 ◽  
Author(s):  
Chunxiang Fan ◽  
Stefan Wolking ◽  
Frank Lehmann-Horn ◽  
Ulrike BS Hedrich ◽  
Tobias Freilinger ◽  
...  
Keyword(s):  
Early Onset ◽  
Novel Mutation ◽  
Familial Hemiplegic Migraine ◽  
Inhibitory Neurons ◽  
Clinical Genetic ◽  
Hemiplegic Migraine ◽  
Gene Encoding ◽  
Whole Cell Patch Clamp ◽  
Steady State Inactivation ◽  
Epilepsy Gene

Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with β1 and β2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.

scholarly journals Familial Hemiplegic Migraine Type 1 Associated with Parkinsonism: A Case Report

2015 ◽  
Vol 7 (1) ◽  
pp. 84-89 ◽  
Author(s):  
Marie Bruun ◽  
Lena Elisabeth Hjermind ◽  
Carsten Thomsen ◽  
Else Danielsen ◽  
Lise Lykke Thomsen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Familial Hemiplegic Migraine ◽  
Spinocerebellar Ataxia Type ◽  
Emission Computed Tomography ◽  
Idiopathic Parkinson’S Disease ◽  
Hemiplegic Migraine ◽  
Idiopathic Parkinson's Disease ◽  
Cacna1a Gene

Familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are allelic disorders caused by mutations in the CACNA1A gene on chromosome 19p13. It is well described that FHM1 can present with cerebellar signs, but parkinsonism has not previously been reported in FHM1 or EA2 even though parkinsonism has been described in SCA6. We report a 63-year-old woman with FHM1 caused by an R583Q mutation in the CACNA1A gene, clinically presenting with migraine and permanent cerebellar ataxia. Since the age of 60 years, the patient also developed parkinsonism with rigidity, bradykinesia and a resting tremor. An MRI showed a normal substantia nigra, but a bilateral loss of substance in the basal ganglia, which is in contrast to the typically normal MRI in idiopathic Parkinson's disease. Dopamine transporter (DAT) imaging with single-photon emission computed tomography demonstrated a decreased DAT-binding potential in the putamen. We wish to draw attention to FHM1 associated with parkinsonism; however, whether the reported case is a consequence of FHM1 being allelic to SCA6, unknown modifiers to the specific R583Q CACNA1A mutation or idiopathic Parkinson's disease remains unanswered.

A novel ATP1A2 gene mutation in familial hemiplegic migraine and epilepsy

Cephalalgia ◽  
2013 ◽  
Vol 34 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Cinzia Costa ◽  
Paolo Prontera ◽  
Paola Sarchielli ◽  
Alessandra Tonelli ◽  
Maria Teresa Bassi ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Febrile Seizures ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Specific Symptom ◽  
Motor Weakness ◽  
Generation Family ◽  
Atp1a2 Gene ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

Background Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fully reversible motor weakness as a specific symptom of aura. Mutations in the ion transportation coding genes CACNA1A, ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy. Case Here we report on a three-generation family with five patients having a novel ATP1A2 mutation on exon 19, causing guanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co-segregated in the five living relatives with migraine, four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalized epilepsy with febrile seizures plus (GEFS+). Conclusions The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine and epilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders.

Intracellular and Plasma Magnesium in Familial Hemiplegic Migraine and Migraine With and Without Aura

Cephalalgia ◽  
1994 ◽  
Vol 14 (1) ◽  
pp. 29-32 ◽  
Author(s):  
MC Smeets ◽  
CB Vernooy ◽  
JHM Souverijn ◽  
MD Ferrari
Keyword(s):  
Spreading Depression ◽  
Autosomal Dominant ◽  
Study Groups ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Dominant Type ◽  
Intracellular Magnesium ◽  
Migraine Pathophysiology ◽  
Plasma Magnesium ◽  
Autosomal Dominant Type

Familial hemiplegic migraine (FHM) is an autosomal dominant type of migraine and probably represents the most extreme end of migraine with aura. Reduced magnesium facilitates the development of spreading depression and possibly aura. Cellular magnesium levels are under genetic control. We hypothesized that FHM patients would have significantly reduced intracellular magnesium levels. We determined intracellular and plasma magnesium levels in blood of 38 afflicted and 11 non-afflicted members of three families with FHM and, in 32 migraine patients (9 with and 23 without aura) and 32 age and sex matched healthy controls. We found no significant differences between the magnesium levels in the five study groups. We conclude that reduced blood magnesium is unlikely to be related to migraine pathophysiology.

CACNA1A Gene Polymorphisms in Cluster Headache

Cephalalgia ◽  
2001 ◽  
Vol 21 (10) ◽  
pp. 953-958 ◽  
Author(s):  
C Sjöstrand ◽  
V Giedratis ◽  
K Ekbom ◽  
E Waldenlind ◽  
J Hillert
Keyword(s):  
Cluster Headache ◽  
Primary Headache ◽  
Headache Disorder ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Promising Candidate ◽  
Primary Headache Disorder ◽  
Increased Risk ◽  
Ihs Criteria ◽  
Cacna1a Gene

Cluster headache (CH) is a primary headache disorder where the aetiological and pathophysiological mechanisms still are largely unknown. An increased risk of CH in first- and second-degree relatives suggests the importance of genetic factors. Mutations of the P/Q type calcium channel alpha 1 subunit (CACNA1A) gene on chromosome 19p13 have been shown to cause several neurological disorders with a wide clinical spectrum, mainly episodic diseases. Missence mutations of the gene cause familial hemiplegic migraine (FHM) and it is also likely to be involved in the more common forms of migraine. The CACNA1A gene is thus a promising candidate gene for CH. In this study we performed an association analysis of an intragenic polymorphic (CA)n-repeat with marker D19S1150 and a (CAG)n-repeat in the 3′UTR region, in 75 patients with CH according to IHS criteria and 108 matched controls. Genotypes and allele frequencies were similarly distributed in patients and controls. Linkage disequilibrium between the two markers was similar in patients and controls. We conclude that an importance of the CACNA1A gene in sporadic CH is unlikely.

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