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R. R. Frants - One of the best experts on this subject based on the ideXlab platform.
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Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine
Journal of Human Genetics, 2007Co-Authors: Maria-josé Castro, Anine H. Stam, Kaate R. J. Vanmolkot, Jan B. Koenderink, Carolina Lemos, José Barros, Raquel G. Gouveia, Isabel Pavão Martins, Alexandre P. Mendes, R. R. FrantsAbstract:Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura. Three genes have been identified, all involved in ion transport. There is considerable clinical variation associated with FHM mutations. Genotype–phenotype correlation studies are needed, but are challenging mainly because the number of carriers of individual mutations is low. One exception is the recurrent T666M mutation in the FHM1 CACNA1A gene that was identified in almost one-third of FHM families and showed variable associated clinical features and severity, both within and among FHM families. Similar studies in the FHM2 ATP1A2 gene have not been performed because of the low number of carriers with individual mutations. Here we report on the recurrence of ATP1A2 mutations M731T and T376M that affect sodium–potassium pump functioning in two Portuguese FHM families. Considerably increasing the number of mutation carriers with these mutations indicated a clear genotype–phenotype correlation: both mutations are associated with pure FHM. In addition, we show that recurrent mutations for ATP1A2 are more frequent than previously thought, which has implications for genotype–phenotype correlations and genetic testing.
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Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes.
Clinical genetics, 2007Co-Authors: Maria-josé Castro, Kaate R. J. Vanmolkot, B. Nunes, B. B. A. De Vries, Carolina Lemos, J. J. M. W. Van Den Heuvel, T. Temudo, José Barros, Jorge Sequeiros, R. R. FrantsAbstract:Mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na+,K+-ATPase, are associated with familial hemiplegic migraine type 2. The majority of ATP1A2 mutations were reported in patients with hemiplegic migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with hemiplegic migraine and interesting additional clinical features. The proband's of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to hemiplegic migraine; more severe mental retardation was observed in his brother, who also had hemiplegic migraine and carried the same mutation. Cell-survival assays clearly showed abnormal functioning of mutant Na+,K+-ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.
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two novel functional mutations in the na k atpase alpha2 subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes
Clinical Genetics, 2007Co-Authors: Maria-josé Castro, Kaate R. J. Vanmolkot, B. Nunes, Carolina Lemos, J. J. M. W. Van Den Heuvel, T. Temudo, José Barros, Jorge Sequeiros, B De Vries, R. R. FrantsAbstract:Mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na+,K+-ATPase, are associated with familial hemiplegic migraine type 2. The majority of ATP1A2 mutations were reported in patients with hemiplegic migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with hemiplegic migraine and interesting additional clinical features. The proband's of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to hemiplegic migraine; more severe mental retardation was observed in his brother, who also had hemiplegic migraine and carried the same mutation. Cell-survival assays clearly showed abnormal functioning of mutant Na+,K+-ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.
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Mutation analysis of CACNA1A and ATP1A2 genes in Brazilian FHM families.
Arquivos de neuro-psiquiatria, 2006Co-Authors: Luciana R Lopes, Arn M. J. M. Van Den Maagdenberg, R. R. Frants, Kaate R. J. Vanmolkot, Mario Fernando Prieto Peres, Patrícia R Tobo, Eliova Zukerman, Carlos Alberto Moreira-filhoAbstract:Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with aura. This disease has been associated with missense mutations in the CACNA1A and ATP1A2 genes. The aim of this study was to identify whether CACNA1A and ATP1A2 are or not related to Brazilian FHM. Here we screened four Brazilian FHM families (total of 26 individuals--13 affected and 13 asymptomatic or normal) for mutations in both genes. We found an amino acid change in a member of family FHM-D (Arg2206Gly). However since this alteration is not present in all affected individuals and is present in one asymptomatic individual it should be considered a polymorphism. Further studies with additional families will be necessary to reveal the importance of both CACNA1A and ATP1A2 genes on the pathogeneses of FHM in Brazil and to test the third gene (SCN1A) in these FHM families.
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From gene to disease; familial hemiplegic migraine as a result of mutations in a sodium-potassium pump gene
Nederlands tijdschrift voor geneeskunde, 2004Co-Authors: Ee Kors, Joost Haan, Arn M. J. M. Van Den Maagdenberg, R. R. Frants, K. R. J. Vanmolkot, M. D. FerrariAbstract:Familial hemiplegic migraine (FHM) is a rare, autosomal dominant subtype of migraine, associated in half of the families with mutations in the CACNA1A gene located on chromosome 19p13, which encodes the Cav2.1-subunit of brain-specific P/Q-type calcium channels. Recently, mutations in a second gene, ATP1A2 on chromosome 1q23, which encodes a sodium-potassium exchange pump subunit, have been identified. The first functional studies indicate that A TP1A2 FHM mutations result in a loss of function of the pump, leading to an increase in extracellular potassium. This is known to evoke cortical spreading depression, the underlying mechanism of migraine aura.
Anine H. Stam - One of the best experts on this subject based on the ideXlab platform.
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Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation.
Neurology, 2018Co-Authors: Nadine Pelzer, Anine H. Stam, Joost Haan, Arn M. J. M. Van Den Maagdenberg, Michel D. Ferrari, Boukje De Vries, L. S. Vijfhuizen, Stephany C. Koelewijn, Amber Smagge, Gisela M. TerwindtAbstract:Objective To investigate whether the clinical characteristics of patients with hemiplegic migraine with and without autosomal dominant mutations in CACNA1A , ATP1A2 , or SCN1A differ, and whether the disease may be caused by mutations in other genes. Methods We compared the clinical characteristics of 208 patients with familial (n = 199) or sporadic (n = 9) hemiplegic migraine due to a mutation in CACNA1A , ATP1A2 , or SCN1A with those of 73 patients with familial (n = 49) or sporadic (n = 24) hemiplegic migraine without a mutation in these genes. In addition, 47 patients (familial: n = 33; sporadic: n = 14) without mutations in CACNA1A , ATP1A2 , or SCN1A were scanned for mutations in novel genes using whole exome sequencing. Results Patients with mutations in CACNA1A , ATP1A2 , or SCN1A had a lower age at disease onset, larger numbers of affected family members, and more often attacks (1) triggered by mild head trauma, (2) with extensive motor weakness, and (3) with brainstem features, confusion, and brain edema. Mental retardation and progressive ataxia were exclusively found in patients with a mutation. Whole exome sequencing failed to identify pathogenic mutations in new genes. Conclusions Most patients with hemiplegic migraine without a mutation in CACNA1A , ATP1A2 , or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. A major fourth autosomal dominant gene for hemiplegic migraine remains to be identified. Our observations might guide physicians in selecting patients for mutation screening and in providing adequate genetic counseling.
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Genetics of migraine: an update with special attention to genetic comorbidity.
Current opinion in neurology, 2008Co-Authors: Anine H. Stam, Joost Haan, Arn M. J. M. Van Den Maagdenberg, Gisela M. Terwindt, Michel D. FerrariAbstract:Purpose of review To highlight recent genetic findings in migraine and discuss, new mutations in hemiplegic migraine genes in familial and sporadic cases and relevant candidate gene association studies. Special attention will be given to comorbid diseases of migraine. Recent findings Familial hemiplegic migraine (FHM) is genetically heterogeneous with mutations in the CACNA1A (FHM1), ATP1A2 (FHM2) and SCN1A (FHM3) genes. Nineteen novel ATP1A2 mutations were identified last year, eleven of them in FHM2 families. A systematic genetic analysis of patients with sporadic hemiplegic migraine revealed five mutations in this gene, which has implications for genetic counselling. The identification of a second FHM3 SCN1A mutation definitely established SCN1A as a migraine gene. The identification of TREX1 mutations in families with retinal vasculopathy and associated diseases such as migraine may provide new insights in migraine pathophysiology. Summary Many novel ATP1A2 mutations were identified in patients with familial and sporadic hemiplegic migraine. In sporadic patients, ATP1A2 screening has the highest chance of finding a causal mutation. A second FHM3 mutation definitely established the epilepsy SCN1A gene as a migraine gene. The discovery of genes in monogenic diseases in which migraine is prominent may lead to new insights in the molecular pathways involved in migraine pathophysiology.
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Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine
Journal of Human Genetics, 2007Co-Authors: Maria-josé Castro, Anine H. Stam, Kaate R. J. Vanmolkot, Jan B. Koenderink, Carolina Lemos, José Barros, Raquel G. Gouveia, Isabel Pavão Martins, Alexandre P. Mendes, R. R. FrantsAbstract:Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura. Three genes have been identified, all involved in ion transport. There is considerable clinical variation associated with FHM mutations. Genotype–phenotype correlation studies are needed, but are challenging mainly because the number of carriers of individual mutations is low. One exception is the recurrent T666M mutation in the FHM1 CACNA1A gene that was identified in almost one-third of FHM families and showed variable associated clinical features and severity, both within and among FHM families. Similar studies in the FHM2 ATP1A2 gene have not been performed because of the low number of carriers with individual mutations. Here we report on the recurrence of ATP1A2 mutations M731T and T376M that affect sodium–potassium pump functioning in two Portuguese FHM families. Considerably increasing the number of mutation carriers with these mutations indicated a clear genotype–phenotype correlation: both mutations are associated with pure FHM. In addition, we show that recurrent mutations for ATP1A2 are more frequent than previously thought, which has implications for genotype–phenotype correlations and genetic testing.
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First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.
European journal of human genetics : EJHG, 2007Co-Authors: Kaate R. J. Vanmolkot, Anine H. Stam, Boukje De Vries, Ashok Raman, Jan B. Koenderink, Eelke H Van Den Boogerd, Judith Van Vark, Jeroen J. M. W. Van Den Heuvel, Nin Bajaj, Gisela M. TerwindtAbstract:Familial hemiplegic migraine (FHM) is a rare autosomal-dominant subtype of migraine with aura, associated with hemiparesis during the aura. Here we describe a unique FHM family in which two novel allelic missense mutations in the Na,K-ATPase gene ATP1A2 segregate in the proband with hemiplegic migraine. Both mutations show reduced penetrance in family members of the proband. Cellular survival assays revealed Na,K-ATPase dysfunction for both ATP1A2 mutants, indicating that both mutations are disease causative. This is the first case of compound heterozygosity for any of the known FHM genes.
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Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation.
Annals of neurology, 2006Co-Authors: K. R. J. Vanmolkot, Anine H. Stam, Joost Haan, Ee Kors, H. Stroink, Jan B. Koenderink, Eelke H Van Den Boogerd, B. B. A. De Vries, J. J. M. W. Van Den Heuvel, Gisela M. TerwindtAbstract: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. Ann Neurol 2006;59:310–314
Gisela M. Terwindt - One of the best experts on this subject based on the ideXlab platform.
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Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation.
Neurology, 2018Co-Authors: Nadine Pelzer, Anine H. Stam, Joost Haan, Arn M. J. M. Van Den Maagdenberg, Michel D. Ferrari, Boukje De Vries, L. S. Vijfhuizen, Stephany C. Koelewijn, Amber Smagge, Gisela M. TerwindtAbstract:Objective To investigate whether the clinical characteristics of patients with hemiplegic migraine with and without autosomal dominant mutations in CACNA1A , ATP1A2 , or SCN1A differ, and whether the disease may be caused by mutations in other genes. Methods We compared the clinical characteristics of 208 patients with familial (n = 199) or sporadic (n = 9) hemiplegic migraine due to a mutation in CACNA1A , ATP1A2 , or SCN1A with those of 73 patients with familial (n = 49) or sporadic (n = 24) hemiplegic migraine without a mutation in these genes. In addition, 47 patients (familial: n = 33; sporadic: n = 14) without mutations in CACNA1A , ATP1A2 , or SCN1A were scanned for mutations in novel genes using whole exome sequencing. Results Patients with mutations in CACNA1A , ATP1A2 , or SCN1A had a lower age at disease onset, larger numbers of affected family members, and more often attacks (1) triggered by mild head trauma, (2) with extensive motor weakness, and (3) with brainstem features, confusion, and brain edema. Mental retardation and progressive ataxia were exclusively found in patients with a mutation. Whole exome sequencing failed to identify pathogenic mutations in new genes. Conclusions Most patients with hemiplegic migraine without a mutation in CACNA1A , ATP1A2 , or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. A major fourth autosomal dominant gene for hemiplegic migraine remains to be identified. Our observations might guide physicians in selecting patients for mutation screening and in providing adequate genetic counseling.
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Genetics of migraine: an update with special attention to genetic comorbidity.
Current opinion in neurology, 2008Co-Authors: Anine H. Stam, Joost Haan, Arn M. J. M. Van Den Maagdenberg, Gisela M. Terwindt, Michel D. FerrariAbstract:Purpose of review To highlight recent genetic findings in migraine and discuss, new mutations in hemiplegic migraine genes in familial and sporadic cases and relevant candidate gene association studies. Special attention will be given to comorbid diseases of migraine. Recent findings Familial hemiplegic migraine (FHM) is genetically heterogeneous with mutations in the CACNA1A (FHM1), ATP1A2 (FHM2) and SCN1A (FHM3) genes. Nineteen novel ATP1A2 mutations were identified last year, eleven of them in FHM2 families. A systematic genetic analysis of patients with sporadic hemiplegic migraine revealed five mutations in this gene, which has implications for genetic counselling. The identification of a second FHM3 SCN1A mutation definitely established SCN1A as a migraine gene. The identification of TREX1 mutations in families with retinal vasculopathy and associated diseases such as migraine may provide new insights in migraine pathophysiology. Summary Many novel ATP1A2 mutations were identified in patients with familial and sporadic hemiplegic migraine. In sporadic patients, ATP1A2 screening has the highest chance of finding a causal mutation. A second FHM3 mutation definitely established the epilepsy SCN1A gene as a migraine gene. The discovery of genes in monogenic diseases in which migraine is prominent may lead to new insights in the molecular pathways involved in migraine pathophysiology.
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First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.
European journal of human genetics : EJHG, 2007Co-Authors: Kaate R. J. Vanmolkot, Anine H. Stam, Boukje De Vries, Ashok Raman, Jan B. Koenderink, Eelke H Van Den Boogerd, Judith Van Vark, Jeroen J. M. W. Van Den Heuvel, Nin Bajaj, Gisela M. TerwindtAbstract:Familial hemiplegic migraine (FHM) is a rare autosomal-dominant subtype of migraine with aura, associated with hemiparesis during the aura. Here we describe a unique FHM family in which two novel allelic missense mutations in the Na,K-ATPase gene ATP1A2 segregate in the proband with hemiplegic migraine. Both mutations show reduced penetrance in family members of the proband. Cellular survival assays revealed Na,K-ATPase dysfunction for both ATP1A2 mutants, indicating that both mutations are disease causative. This is the first case of compound heterozygosity for any of the known FHM genes.
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Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation.
Annals of neurology, 2006Co-Authors: K. R. J. Vanmolkot, Anine H. Stam, Joost Haan, Ee Kors, H. Stroink, Jan B. Koenderink, Eelke H Van Den Boogerd, B. B. A. De Vries, J. J. M. W. Van Den Heuvel, Gisela M. TerwindtAbstract: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. Ann Neurol 2006;59:310–314
Nereo Bresolin - One of the best experts on this subject based on the ideXlab platform.
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amino acid changes in the amino terminus of the na k adenosine triphosphatase alpha 2 subunit associated to familial and sporadic hemiplegic migraine
Clinical Genetics, 2007Co-Authors: Alessandra Tonelli, A. Gallanti, Anna Bersano, Veronica Cardin, E Ballabio, Giovanni Airoldi, Francesca Redaelli, Livia Candelise, Nereo BresolinAbstract:Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura inherited with an autosomal dominant pattern. Here, we report the genetic analysis of four families and one sporadic case with hemiplegic migraine (HM) in whom we searched for mutations in the three genes associated with the disease CACNA1A, ATP1A2 and SCN1A. Two novel amino acid changes p.Arg65Trp and p.Tyr9Asn, in the Na,K-adenosine triphosphatase (ATPase) alpha-2 subunit encoded by the ATP1A2 gene, were found in one FHM family and in the sporadic case, respectively. These mutations are peculiar for their location in the extreme N-terminus, an uncommon mutation target in this protein. Low frequency of migraine attacks in all our mutant patients with low complexity of the associated aura symptoms in the sporadic case is also observed. Besides the two novel mutations, the data here reported confirm the involvement of ATP1A2 gene in the sporadic form of HM, while the negative results on the other families tested for all genes known in HM strengthen the hypothesis of the existence of at least another locus involved in FHM.
Kaate R. J. Vanmolkot - One of the best experts on this subject based on the ideXlab platform.
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Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine
Journal of Human Genetics, 2007Co-Authors: Maria-josé Castro, Anine H. Stam, Kaate R. J. Vanmolkot, Jan B. Koenderink, Carolina Lemos, José Barros, Raquel G. Gouveia, Isabel Pavão Martins, Alexandre P. Mendes, R. R. FrantsAbstract:Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura. Three genes have been identified, all involved in ion transport. There is considerable clinical variation associated with FHM mutations. Genotype–phenotype correlation studies are needed, but are challenging mainly because the number of carriers of individual mutations is low. One exception is the recurrent T666M mutation in the FHM1 CACNA1A gene that was identified in almost one-third of FHM families and showed variable associated clinical features and severity, both within and among FHM families. Similar studies in the FHM2 ATP1A2 gene have not been performed because of the low number of carriers with individual mutations. Here we report on the recurrence of ATP1A2 mutations M731T and T376M that affect sodium–potassium pump functioning in two Portuguese FHM families. Considerably increasing the number of mutation carriers with these mutations indicated a clear genotype–phenotype correlation: both mutations are associated with pure FHM. In addition, we show that recurrent mutations for ATP1A2 are more frequent than previously thought, which has implications for genotype–phenotype correlations and genetic testing.
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two novel functional mutations in the na k atpase alpha2 subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes
Clinical Genetics, 2007Co-Authors: Maria-josé Castro, Kaate R. J. Vanmolkot, B. Nunes, Carolina Lemos, J. J. M. W. Van Den Heuvel, T. Temudo, José Barros, Jorge Sequeiros, B De Vries, R. R. FrantsAbstract:Mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na+,K+-ATPase, are associated with familial hemiplegic migraine type 2. The majority of ATP1A2 mutations were reported in patients with hemiplegic migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with hemiplegic migraine and interesting additional clinical features. The proband's of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to hemiplegic migraine; more severe mental retardation was observed in his brother, who also had hemiplegic migraine and carried the same mutation. Cell-survival assays clearly showed abnormal functioning of mutant Na+,K+-ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.
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Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes.
Clinical genetics, 2007Co-Authors: Maria-josé Castro, Kaate R. J. Vanmolkot, B. Nunes, B. B. A. De Vries, Carolina Lemos, J. J. M. W. Van Den Heuvel, T. Temudo, José Barros, Jorge Sequeiros, R. R. FrantsAbstract:Mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na+,K+-ATPase, are associated with familial hemiplegic migraine type 2. The majority of ATP1A2 mutations were reported in patients with hemiplegic migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with hemiplegic migraine and interesting additional clinical features. The proband's of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to hemiplegic migraine; more severe mental retardation was observed in his brother, who also had hemiplegic migraine and carried the same mutation. Cell-survival assays clearly showed abnormal functioning of mutant Na+,K+-ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.
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First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.
European journal of human genetics : EJHG, 2007Co-Authors: Kaate R. J. Vanmolkot, Anine H. Stam, Boukje De Vries, Ashok Raman, Jan B. Koenderink, Eelke H Van Den Boogerd, Judith Van Vark, Jeroen J. M. W. Van Den Heuvel, Nin Bajaj, Gisela M. TerwindtAbstract:Familial hemiplegic migraine (FHM) is a rare autosomal-dominant subtype of migraine with aura, associated with hemiparesis during the aura. Here we describe a unique FHM family in which two novel allelic missense mutations in the Na,K-ATPase gene ATP1A2 segregate in the proband with hemiplegic migraine. Both mutations show reduced penetrance in family members of the proband. Cellular survival assays revealed Na,K-ATPase dysfunction for both ATP1A2 mutants, indicating that both mutations are disease causative. This is the first case of compound heterozygosity for any of the known FHM genes.
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Mutation analysis of CACNA1A and ATP1A2 genes in Brazilian FHM families.
Arquivos de neuro-psiquiatria, 2006Co-Authors: Luciana R Lopes, Arn M. J. M. Van Den Maagdenberg, R. R. Frants, Kaate R. J. Vanmolkot, Mario Fernando Prieto Peres, Patrícia R Tobo, Eliova Zukerman, Carlos Alberto Moreira-filhoAbstract:Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with aura. This disease has been associated with missense mutations in the CACNA1A and ATP1A2 genes. The aim of this study was to identify whether CACNA1A and ATP1A2 are or not related to Brazilian FHM. Here we screened four Brazilian FHM families (total of 26 individuals--13 affected and 13 asymptomatic or normal) for mutations in both genes. We found an amino acid change in a member of family FHM-D (Arg2206Gly). However since this alteration is not present in all affected individuals and is present in one asymptomatic individual it should be considered a polymorphism. Further studies with additional families will be necessary to reveal the importance of both CACNA1A and ATP1A2 genes on the pathogeneses of FHM in Brazil and to test the third gene (SCN1A) in these FHM families.