Abstract:Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura with an autosomal dominant pattern of inheritance. Six FHM families underwent extensive clinical and genetic investigation. The authors identified a novel ATP1A2 mutation (E700K) in three patients from one family. In the patients, attacks were triggered by several factors including minor head trauma. In one subject a 3-day coma developed after a cerebral angiography. Overall, the phenotype of the patients closely resembles that of previ… Show more
“…These residues have been mapped onto a common structure for clarity. Citations for human ATP1A2 mutations: Ambrosini et al (2005), Castro et al (2008), De Fusco et al (2003), Fernandez et al (2008), Gallanti et al (2008), Jen et al (2007), Jurkat-Rott et al (2004), Kaunisto et al (2004), Koenderink et al (2005), Pierelli et al (2006), Riant et al (2005), Segall et al (2004, 2005), Spadaro et al (2004), Swoboda et al (2004), Todt et al (2005), Vanmolkot et al (2003, 2006a, b, 2007). Citations for human ATP1A3 mutations: Brashear et al (2007), de Carvalho Aguiar et al (2004), Kamm et al (2008), Zanotti-Fregonara et al (2008)Fig.…”
Mutations affecting the Na+, K+ ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na+, K+ ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na+, K+ ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na+, K+ ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. Importantly, all of these mutations cause neurological phenotypes and, akin to the mutations that cause RDP and FHM, these new alleles are missense mutations. All of these alleles exhibit progressive stress-induced locomotor impairment suggesting neuromuscular dysfunction, yet neurodegeneration is observed in an allele-specific manner. Surprisingly, studies of longevity demonstrate that mild hypomorphic mutations in the sodium pump significantly improve longevity, which was verified using the Na+, K+ ATPase antagonist ouabain. The isolation and characterization of a series of new missense alleles of ATPalpha in Drosophila provides the foundation for further studies of these neurological diseases and the role of sodium pump impairment in animal longevity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-009-0673-2) contains supplementary material, which is available to authorized users.
“…These residues have been mapped onto a common structure for clarity. Citations for human ATP1A2 mutations: Ambrosini et al (2005), Castro et al (2008), De Fusco et al (2003), Fernandez et al (2008), Gallanti et al (2008), Jen et al (2007), Jurkat-Rott et al (2004), Kaunisto et al (2004), Koenderink et al (2005), Pierelli et al (2006), Riant et al (2005), Segall et al (2004, 2005), Spadaro et al (2004), Swoboda et al (2004), Todt et al (2005), Vanmolkot et al (2003, 2006a, b, 2007). Citations for human ATP1A3 mutations: Brashear et al (2007), de Carvalho Aguiar et al (2004), Kamm et al (2008), Zanotti-Fregonara et al (2008)Fig.…”
Mutations affecting the Na+, K+ ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na+, K+ ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na+, K+ ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na+, K+ ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. Importantly, all of these mutations cause neurological phenotypes and, akin to the mutations that cause RDP and FHM, these new alleles are missense mutations. All of these alleles exhibit progressive stress-induced locomotor impairment suggesting neuromuscular dysfunction, yet neurodegeneration is observed in an allele-specific manner. Surprisingly, studies of longevity demonstrate that mild hypomorphic mutations in the sodium pump significantly improve longevity, which was verified using the Na+, K+ ATPase antagonist ouabain. The isolation and characterization of a series of new missense alleles of ATPalpha in Drosophila provides the foundation for further studies of these neurological diseases and the role of sodium pump impairment in animal longevity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-009-0673-2) contains supplementary material, which is available to authorized users.
“…2). 10,52,[63][64][65][66][67][68][69][70] All produce substitutions of conserved amino acids in important functional regions including the intracellular 4-5 loop, where…”
Section: Familial Hemiplegic Migraine Type 2 (Fhm2)mentioning
Summary: Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.
“…However, the presence of dizziness in FHM has been previously described; several authors have claimed that migraine with brainstem aura is a subtype of FHM [18,19]. …”
BackgroundThe high concordance rate of migraine in monozygotic twin pairs has long been recognised. In the current study, we present a monozygotic twin pair discordant for familial hemiplegic migraine (FHM).Case presentationsWe evaluated 12 adult family members in 2012. The twin pair was separately examined by neurologists at different time points. Mutation screening was performed for known FHM-related genes. The monozygosity of the twins was verified. Eleven individuals had a history of migraine or paroxysmal neurological symptoms, including four patients with motor aura. No mutations were detected in the CACNA1A, ATP1A2, SCN1A, PRRT2 or NOTCH3 genes. The monozygotic twin sisters, aged 52, were discordant for age of onset, motor aura and neuropsychological aura (forced thinking). Overall, the family members presented a wide range of phenotypical features.ConclusionsFamilial hemiplegic migraine is a monogenic disorder that is distinct from migraine with typical aura. However, in certain families with motor aura, such as this one, it is possible that the most severe phenotype is caused by an unlikely combination of polygenic traits and non-genetic factors. In these kindreds, we propose that hemiplegic aura is only a severe and complex form of typical aura.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
