A enxaqueca e uma entidade clinica classica com caracteristicas bem definidas, mas tambem com alg... more A enxaqueca e uma entidade clinica classica com caracteristicas bem definidas, mas tambem com alguma variabilidade. Tem um perfil temporal paroxistico, com episodios de frequencia e duracao variaveis, intervalados por periodos totalmente assintomaticos. A prevalencia da enxaqueca no adulto situa-se entre 10% e 15%, com consequencias socio-economicas importantes. E aceite uma maior prevalencia da enxaqueca no sexo feminino; a razao homem:mulher e, consoante os estudos, de 1:2-3. A historia de enxaqueca inicia-se habitualmente em adolescentes ou jovens adultos, podendo surgir na infância. Rapazes e meninas serao igualmente atingidos; o predominio do sexo feminino so aparece na adolescencia. No entanto, em cerca de 10% dos casos a enxaqueca aparece depois dos 40 anos. Uma primeira crise depois dos 45 anos, sendo possivel, obriga a investigacao clinica para exclusao de uma cefaleia sintomatica.
Introduction Neuropsychological symptoms are rare in familial hemiplegic migraine (FHM). There ar... more 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. Keywords ATP1A2 gene Á Familial hemiplegic migraine type 2 Á M731T mutation Á Neuropsychological aura Á Psychosis Á Time travel
Migraine is a common neurological episodic disorder with a female-to-male prevalence 3-to 4-fold ... more Migraine is a common neurological episodic disorder with a female-to-male prevalence 3-to 4-fold higher, suggesting a possible X-linked genetic component. Our aims were to assess the role of common variants of gammaaminobutyric acid A receptor (GABA A R) genes, located in the X-chromosome, in migraine susceptibility and the possible interaction between them. An association study with 188 unrelated cases and 286 migraine-free controls age-and ethnic matched was performed. Twenty-three tagging SNPs were selected in three genes (GABRE, GABRA3 and GABRQ). Allelic, genotypic and haplotypic frequencies were compared between cases and controls. We also focused on gene-gene interactions. The AT genotype of rs3810651 of GABRQ gene was associated with an increased risk for migraine (OR: 4.07; 95% CI: 1.71-9.73, p=0.002), while the CT genotype of rs3902802 (OR: 0.41; 95% CI: 0.21-0.78, p=0.006) and GA genotype of rs2131190 of GABRA3 gene (OR: 0.53; 95% CI: 0.32-0.88, p=0.013) seem to be protective factors. All associations were found in the female group and maintained significance after Bonferroni correction. We also found three nominal associations in the allelic analyses although there were no significant results in the haplotypic analyses. Strikingly, we found strong interactions between six SNPs encoding for different subunits of GABA A R, all significant after permutation correction. To our knowledge, we show for the first time, the putative involvement of polymorphisms in GABA A R genes in migraine susceptibility and more importantly we unraveled a role for novel gene-gene interactions opening new perspectives for the development of more effective treatments.
Background: Since the mid-19th century, epistaxis and migraine have been occasionally associated ... more Background: Since the mid-19th century, epistaxis and migraine have been occasionally associated with each other. Nevertheless, we found only two cases in the contemporary medical literature. Sporadic hemiplegic migraine is a subtype of migraine with reversible motor deficits, without similar episodes in relatives. Case: We describe a 47-year-old male with a history of migraine with a scintillating scotoma starting at the age of 20. In some of the episodes, he developed epistaxis in the resolution phase of migraine. At the age of 35, he experienced a visual aura followed by transient aphasia, left crural weakness and headache. Contralateral similar episodes occurred in the subsequent months. Neurological examination and MRI were normal. Mutations in CACNA1A, ATP1A2, SCN1A and NOTCH3 were excluded. Discussion: Three distinct aspects deserve our consideration. This is the first report of migraine-induced epistaxis involving aura; the scarcity of similar reports may be due to the lack of a guided anamnesis. The complex aura presented had a peculiar topography, inconsistent with the classical analytical neurological semiology. This may suggest that the spreading depression affects the brain bilaterally but in an uneven and elective manner. Lastly, the present report conveys that the late appearance of complex auras requires improbable interactions between environmental and endogenous conditions in individuals with a genetic predisposition.
To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar a... more To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar ataxia, hemiplegic migraine, and related syndromes caused by missense mutation c.1748 (p.R583Q) in the CACNA1A gene. Design: Observational 12-year follow-up study. Setting: Community and hospital care. Patients: Sixteen patients in a 4-generation family were identified in 1998 in a population-based survey. The follow-up revealed 28 patients (25 of whom were observed) and 32 unaffected relatives with an a priori risk of 50%. Results: Four major phenotypes (migraine with multiple auras, transient focal neurological deficits without headache, coma triggered by minor head trauma, and slowly progressive cerebellar ataxia) were present in various combinations. The initial manifestation was ataxia in 16 patients and a transient episode in 12 patients. Eighteen patients did not have migraine, and 11 showed only ataxia. The c.1748 (p.R583Q) mutation in CACNA1A was confirmed in all 23 of the patients who were tested but was not found in any of the 27 adult relatives. The CACNA1A CAG repeat expansion was excluded. Conclusions: A unique missense mutation in the CACNA1A gene, which exhibits a very high penetrance and expressivity, may present a phenotypic spectrum that is broader than current descriptions. Single-gene disorders can behave as complex traits, which reinforces the importance of genetic modifiers in the tightly regulated function of P/Q-type calcium channels. The clinical spectrum of missense mutation CACNA1A-related disorders is much broader than strictly familial hemiplegic migraine.
Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP... more Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are scarce. To present the prevalence and distribution of HCA and HSP in Portugal. Population-based, nationwide, systematic survey, from January 1, 1994, through April 15, 2004, in Portugal. Multiple sources of information were used (review of clinical files, active collaboration of neurologists and geneticists, and investigation of affected families), but the main source was active collaboration of general practitioners. Patients were examined by the same team of neurologists, using homogeneous inclusion criteria. The clinical data were registered, and all families were genetically tested. Overall, 1336 patients from a population of 10,322 million were diagnosed as having HCA or HSP, a prevalence of 12.9 per 100,000 population. Hereditary cerebellar ataxia was more prevalent (prevalence, 8.9 per 100,000 population; 5.6 for dominant and 3.3 for recessive ataxias) than HSP (prevalence, ...
Background: The high concordance rate of migraine in monozygotic twin pairs has long been recogni... more Background: The 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 presentations: We 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. Conclusions: Familial 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.
Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from re... more Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo-ponto-cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.
Neuroepidemiology increase in power at slower test speed was showed in all subjects for both maxi... more Neuroepidemiology increase in power at slower test speed was showed in all subjects for both maximal knee extension and flexion. (4) A slight headache was showed in two patients as a side effect while administering DS. Conclusions: The improvement of ADL was demonstrated by administering DS to the patients of DM, which was accompanied by not only the reduction of myotonia but also the increase of muscular strength, and DS administration suggested a effective treatment method.
CACNA1A gene disorders present a variable familial phenotype of ataxia, migraine with aura, and/o... more CACNA1A gene disorders present a variable familial phenotype of ataxia, migraine with aura, and/or hemiplegic migraine. Prevalence data for these conditions are scarce. The aim of this study is to report a minimal prevalence estimate for familial hemiplegic migraine with cerebellar ataxia and spinocerebellar ataxia type 6 in Portugal. This is a multisource population-based prevalence study. Patients and families with spinocerebellar ataxia type 6 and familial hemiplegic migraine and cerebellar ataxia identified through the Portuguese survey of hereditary ataxias and spastic paraplegias were re-evaluated. Prevalent patients were confirmed to be alive and affected at the 1st of January 2013. One family with spinocerebellar ataxia type 6 and 2 families with other CACNA1A gene mutations were identified. From these families, 23 patients were alive and living in Portugal in the prevalence day, for an estimated national prevalence per 100,000 inhabitants of 0.21 for familial hemiplegic migraine with cerebellar ataxia and of 0.01 for spinocerebellar ataxia type 6. The prevalence of familial hemiplegic migraine with cerebellar ataxia and spinocerebellar ataxia type 6 are both probably low in Portugal.
Our aim was to evaluate familial aggregation of migraine in a large group of Portuguese families,... more Our aim was to evaluate familial aggregation of migraine in a large group of Portuguese families, and to assess if familial aggregation differs between MA and MO.
BACKGROUND AND PURPOSE: Migraine is a common neurological disabling disorder, and anomalies of va... more BACKGROUND AND PURPOSE: Migraine is a common neurological disabling disorder, and anomalies of vascular function have been implied in its pathophysiology. Several findings point to a possible role of the endothelin receptor type A (EDNRA) in migraine. We aim to assess the involvement of endothelin receptor type A (EDNRA) in migraine susceptibility in a sample of Portuguese migraineurs. METHODS: Three tagging SNPs (rs702757, rs5333 and rs5335) were analysed in 188 cases-111 without aura (MO) and 77 with aura (MA)-and 287 controls. A multivariable logistic regression was performed, including the three SNPs, adjusted for gender. Allelic and haplotypic frequencies were compared between cases and controls. Significant or promising results were confirmed by a multifactor dimensionality reduction analysis (MDR).
To the Editor: The CACNA1A gene encodes the highly conserved brain-specific P/Q-type voltage-gate... more To the Editor: The CACNA1A gene encodes the highly conserved brain-specific P/Q-type voltage-gated calcium-channel a1A-subunit, expressed mainly in the cerebellum. This channel mediates the entry of calcium ions into cells. This gene is involved in spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1), which have been considered as distinct clinical entities (1, 2). Recent studies have shown extensive clinical and genetic overlaps between these diseases (3–6). Here, we report a novel missense mutation, located in a region considered to be the voltage sensor of the P/Q-type calcium channel, responsible for both progressive cerebellar ataxia and hemiplegic migraine in all patients from one affected family. We ascertained a Portuguese family with both progressive cerebellar ataxia and hemiplegic migraine, during a population-based survey on hereditary ataxias (7). This family had three patients, two of whom were clinically examined, in two consecutive generations. The proband was a 32-year-old woman presenting with slowly progressive ataxia since her childhood. She experienced a 24-h coma, at the age of 18, after a car accident without head trauma. Magnetic resonance imaging study in this patient showed atrophy of the cerebellum. Nine years later, she had the first episode of hemiplegic migraine that occurred again at a later time. Her brother had the first symptoms at 11 years of age with hemiparesis and aphasia, triggered by physical effort. Hemiparesis and aphasia have recovered after 1week, whereas the signs of gait ataxia have persisted and slowly progressed. No headache was present. Their mother, already deceased, has never been clinically evaluated. We were told by her family members that she had attacks of hemiparesis and aphasia precipitated by physical effort, mainly during the summer season, since she was 11 years of age. By the age of 13, she began to exhibit signs of a slowly progressive ataxia. Mutation analysis of the CACNA1A gene in this family revealed a mobility variant at exon 25 in the two affected sibs but not in their healthy relatives. By direct sequencing, a G-to-A substitution at position 4315 was identified, which produces an arginine-to-glutamine change, at codon 1347, in the CACNA1A gene; this was not present in 100 control chromosomes from the Portuguese general population. This Arg1347 is evolutionarily conserved among a1A-subunits from other species such as Rattus norvegicus, Mus musculus, Drosophila melanogaster and Caenorhabditis elegans, as well as in other a1-subunits. Other mobility variants were detected in this family, indicative of several polymorphisms (Table 1). In the present study, we report a new mutation in the P/Q-type calcium-channel a1A-subunit gene, in a Portuguese family with both slowly progressive cerebellar ataxia and hemiplegic migraine. This mutation replaces a polar positively charged highly conserved arginine by a neutral glutamine, at codon 1347. The two previously described mutations R192Q (1) and R583Q (6, 8) are located in the S4-transmembrane segments of protein domains I and II, respectively (Fig. 1), which are considered to be the voltage sensor segments, both replacing highly conserved positively charged arginines by neutral glutamines. The missense mutation in this family is similar and is also located in the S4-transmembrane segment but of protein domain III. Functional studies performed in channels with the two previously Clin Genet 2004: 65: 70–72 Copyright # Blackwell Munksgaard 2004 Printed inDenmark. All rights reserved CLINICALGENETICS
A retrospective chart review of all patients with cerebrovascular diseases attending the outpatie... more A retrospective chart review of all patients with cerebrovascular diseases attending the outpatients' clinic during a 5-year period was performed to identify patients with seizures secondary to cerebrovascular diseases, in order to evaluate the routine clinical management of these patients. We found 57 epileptic patients out of 985 cases regularly followed for cerebrovascular diseases. The clinical characteristics of these 57
Background SCN1A is the most relevant gene in epilepsy. Only seven SCN1A mutations have been iden... more Background SCN1A is the most relevant gene in epilepsy. Only seven SCN1A mutations have been identified in 10 familial hemiplegic migraine (FHM) kindreds worldwide. Cases and kindreds In 2009, we presented a kindred with FHM due to the L263V SCN1A mutation. In the current study, we report a novel FHM3 kindred from the same village. The first family exhibited the co-occurrence of FHM and epilepsy. No case of epilepsy was observed in the new kindred. An L263V mutation was found in all patients, and the haplotype analysis supports a unique mutational event. Comments Despite its bioelectric activity, the SCN1A L263V mutation most likely requires a combination of several endogenous or environmental induction stimuli to attain an epileptogenic threshold.
Objectives: Migraine pathophysiology involves several pathways. Our aims were to explore a possib... more Objectives: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene ( BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene-related peptide gene ( CGRP); and a possible interaction between the two. Methods: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP—rs1553005—of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable-logistic regression and confirmed by a multifactor dimensionality reduction analysis. Results: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT-genotype of rs2049046 and the GC-genoty...
A enxaqueca e uma entidade clinica classica com caracteristicas bem definidas, mas tambem com alg... more A enxaqueca e uma entidade clinica classica com caracteristicas bem definidas, mas tambem com alguma variabilidade. Tem um perfil temporal paroxistico, com episodios de frequencia e duracao variaveis, intervalados por periodos totalmente assintomaticos. A prevalencia da enxaqueca no adulto situa-se entre 10% e 15%, com consequencias socio-economicas importantes. E aceite uma maior prevalencia da enxaqueca no sexo feminino; a razao homem:mulher e, consoante os estudos, de 1:2-3. A historia de enxaqueca inicia-se habitualmente em adolescentes ou jovens adultos, podendo surgir na infância. Rapazes e meninas serao igualmente atingidos; o predominio do sexo feminino so aparece na adolescencia. No entanto, em cerca de 10% dos casos a enxaqueca aparece depois dos 40 anos. Uma primeira crise depois dos 45 anos, sendo possivel, obriga a investigacao clinica para exclusao de uma cefaleia sintomatica.
Introduction Neuropsychological symptoms are rare in familial hemiplegic migraine (FHM). There ar... more 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. Keywords ATP1A2 gene Á Familial hemiplegic migraine type 2 Á M731T mutation Á Neuropsychological aura Á Psychosis Á Time travel
Migraine is a common neurological episodic disorder with a female-to-male prevalence 3-to 4-fold ... more Migraine is a common neurological episodic disorder with a female-to-male prevalence 3-to 4-fold higher, suggesting a possible X-linked genetic component. Our aims were to assess the role of common variants of gammaaminobutyric acid A receptor (GABA A R) genes, located in the X-chromosome, in migraine susceptibility and the possible interaction between them. An association study with 188 unrelated cases and 286 migraine-free controls age-and ethnic matched was performed. Twenty-three tagging SNPs were selected in three genes (GABRE, GABRA3 and GABRQ). Allelic, genotypic and haplotypic frequencies were compared between cases and controls. We also focused on gene-gene interactions. The AT genotype of rs3810651 of GABRQ gene was associated with an increased risk for migraine (OR: 4.07; 95% CI: 1.71-9.73, p=0.002), while the CT genotype of rs3902802 (OR: 0.41; 95% CI: 0.21-0.78, p=0.006) and GA genotype of rs2131190 of GABRA3 gene (OR: 0.53; 95% CI: 0.32-0.88, p=0.013) seem to be protective factors. All associations were found in the female group and maintained significance after Bonferroni correction. We also found three nominal associations in the allelic analyses although there were no significant results in the haplotypic analyses. Strikingly, we found strong interactions between six SNPs encoding for different subunits of GABA A R, all significant after permutation correction. To our knowledge, we show for the first time, the putative involvement of polymorphisms in GABA A R genes in migraine susceptibility and more importantly we unraveled a role for novel gene-gene interactions opening new perspectives for the development of more effective treatments.
Background: Since the mid-19th century, epistaxis and migraine have been occasionally associated ... more Background: Since the mid-19th century, epistaxis and migraine have been occasionally associated with each other. Nevertheless, we found only two cases in the contemporary medical literature. Sporadic hemiplegic migraine is a subtype of migraine with reversible motor deficits, without similar episodes in relatives. Case: We describe a 47-year-old male with a history of migraine with a scintillating scotoma starting at the age of 20. In some of the episodes, he developed epistaxis in the resolution phase of migraine. At the age of 35, he experienced a visual aura followed by transient aphasia, left crural weakness and headache. Contralateral similar episodes occurred in the subsequent months. Neurological examination and MRI were normal. Mutations in CACNA1A, ATP1A2, SCN1A and NOTCH3 were excluded. Discussion: Three distinct aspects deserve our consideration. This is the first report of migraine-induced epistaxis involving aura; the scarcity of similar reports may be due to the lack of a guided anamnesis. The complex aura presented had a peculiar topography, inconsistent with the classical analytical neurological semiology. This may suggest that the spreading depression affects the brain bilaterally but in an uneven and elective manner. Lastly, the present report conveys that the late appearance of complex auras requires improbable interactions between environmental and endogenous conditions in individuals with a genetic predisposition.
To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar a... more To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar ataxia, hemiplegic migraine, and related syndromes caused by missense mutation c.1748 (p.R583Q) in the CACNA1A gene. Design: Observational 12-year follow-up study. Setting: Community and hospital care. Patients: Sixteen patients in a 4-generation family were identified in 1998 in a population-based survey. The follow-up revealed 28 patients (25 of whom were observed) and 32 unaffected relatives with an a priori risk of 50%. Results: Four major phenotypes (migraine with multiple auras, transient focal neurological deficits without headache, coma triggered by minor head trauma, and slowly progressive cerebellar ataxia) were present in various combinations. The initial manifestation was ataxia in 16 patients and a transient episode in 12 patients. Eighteen patients did not have migraine, and 11 showed only ataxia. The c.1748 (p.R583Q) mutation in CACNA1A was confirmed in all 23 of the patients who were tested but was not found in any of the 27 adult relatives. The CACNA1A CAG repeat expansion was excluded. Conclusions: A unique missense mutation in the CACNA1A gene, which exhibits a very high penetrance and expressivity, may present a phenotypic spectrum that is broader than current descriptions. Single-gene disorders can behave as complex traits, which reinforces the importance of genetic modifiers in the tightly regulated function of P/Q-type calcium channels. The clinical spectrum of missense mutation CACNA1A-related disorders is much broader than strictly familial hemiplegic migraine.
Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP... more Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are scarce. To present the prevalence and distribution of HCA and HSP in Portugal. Population-based, nationwide, systematic survey, from January 1, 1994, through April 15, 2004, in Portugal. Multiple sources of information were used (review of clinical files, active collaboration of neurologists and geneticists, and investigation of affected families), but the main source was active collaboration of general practitioners. Patients were examined by the same team of neurologists, using homogeneous inclusion criteria. The clinical data were registered, and all families were genetically tested. Overall, 1336 patients from a population of 10,322 million were diagnosed as having HCA or HSP, a prevalence of 12.9 per 100,000 population. Hereditary cerebellar ataxia was more prevalent (prevalence, 8.9 per 100,000 population; 5.6 for dominant and 3.3 for recessive ataxias) than HSP (prevalence, ...
Background: The high concordance rate of migraine in monozygotic twin pairs has long been recogni... more Background: The 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 presentations: We 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. Conclusions: Familial 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.
Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from re... more Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo-ponto-cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.
Neuroepidemiology increase in power at slower test speed was showed in all subjects for both maxi... more Neuroepidemiology increase in power at slower test speed was showed in all subjects for both maximal knee extension and flexion. (4) A slight headache was showed in two patients as a side effect while administering DS. Conclusions: The improvement of ADL was demonstrated by administering DS to the patients of DM, which was accompanied by not only the reduction of myotonia but also the increase of muscular strength, and DS administration suggested a effective treatment method.
CACNA1A gene disorders present a variable familial phenotype of ataxia, migraine with aura, and/o... more CACNA1A gene disorders present a variable familial phenotype of ataxia, migraine with aura, and/or hemiplegic migraine. Prevalence data for these conditions are scarce. The aim of this study is to report a minimal prevalence estimate for familial hemiplegic migraine with cerebellar ataxia and spinocerebellar ataxia type 6 in Portugal. This is a multisource population-based prevalence study. Patients and families with spinocerebellar ataxia type 6 and familial hemiplegic migraine and cerebellar ataxia identified through the Portuguese survey of hereditary ataxias and spastic paraplegias were re-evaluated. Prevalent patients were confirmed to be alive and affected at the 1st of January 2013. One family with spinocerebellar ataxia type 6 and 2 families with other CACNA1A gene mutations were identified. From these families, 23 patients were alive and living in Portugal in the prevalence day, for an estimated national prevalence per 100,000 inhabitants of 0.21 for familial hemiplegic migraine with cerebellar ataxia and of 0.01 for spinocerebellar ataxia type 6. The prevalence of familial hemiplegic migraine with cerebellar ataxia and spinocerebellar ataxia type 6 are both probably low in Portugal.
Our aim was to evaluate familial aggregation of migraine in a large group of Portuguese families,... more Our aim was to evaluate familial aggregation of migraine in a large group of Portuguese families, and to assess if familial aggregation differs between MA and MO.
BACKGROUND AND PURPOSE: Migraine is a common neurological disabling disorder, and anomalies of va... more BACKGROUND AND PURPOSE: Migraine is a common neurological disabling disorder, and anomalies of vascular function have been implied in its pathophysiology. Several findings point to a possible role of the endothelin receptor type A (EDNRA) in migraine. We aim to assess the involvement of endothelin receptor type A (EDNRA) in migraine susceptibility in a sample of Portuguese migraineurs. METHODS: Three tagging SNPs (rs702757, rs5333 and rs5335) were analysed in 188 cases-111 without aura (MO) and 77 with aura (MA)-and 287 controls. A multivariable logistic regression was performed, including the three SNPs, adjusted for gender. Allelic and haplotypic frequencies were compared between cases and controls. Significant or promising results were confirmed by a multifactor dimensionality reduction analysis (MDR).
To the Editor: The CACNA1A gene encodes the highly conserved brain-specific P/Q-type voltage-gate... more To the Editor: The CACNA1A gene encodes the highly conserved brain-specific P/Q-type voltage-gated calcium-channel a1A-subunit, expressed mainly in the cerebellum. This channel mediates the entry of calcium ions into cells. This gene is involved in spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1), which have been considered as distinct clinical entities (1, 2). Recent studies have shown extensive clinical and genetic overlaps between these diseases (3–6). Here, we report a novel missense mutation, located in a region considered to be the voltage sensor of the P/Q-type calcium channel, responsible for both progressive cerebellar ataxia and hemiplegic migraine in all patients from one affected family. We ascertained a Portuguese family with both progressive cerebellar ataxia and hemiplegic migraine, during a population-based survey on hereditary ataxias (7). This family had three patients, two of whom were clinically examined, in two consecutive generations. The proband was a 32-year-old woman presenting with slowly progressive ataxia since her childhood. She experienced a 24-h coma, at the age of 18, after a car accident without head trauma. Magnetic resonance imaging study in this patient showed atrophy of the cerebellum. Nine years later, she had the first episode of hemiplegic migraine that occurred again at a later time. Her brother had the first symptoms at 11 years of age with hemiparesis and aphasia, triggered by physical effort. Hemiparesis and aphasia have recovered after 1week, whereas the signs of gait ataxia have persisted and slowly progressed. No headache was present. Their mother, already deceased, has never been clinically evaluated. We were told by her family members that she had attacks of hemiparesis and aphasia precipitated by physical effort, mainly during the summer season, since she was 11 years of age. By the age of 13, she began to exhibit signs of a slowly progressive ataxia. Mutation analysis of the CACNA1A gene in this family revealed a mobility variant at exon 25 in the two affected sibs but not in their healthy relatives. By direct sequencing, a G-to-A substitution at position 4315 was identified, which produces an arginine-to-glutamine change, at codon 1347, in the CACNA1A gene; this was not present in 100 control chromosomes from the Portuguese general population. This Arg1347 is evolutionarily conserved among a1A-subunits from other species such as Rattus norvegicus, Mus musculus, Drosophila melanogaster and Caenorhabditis elegans, as well as in other a1-subunits. Other mobility variants were detected in this family, indicative of several polymorphisms (Table 1). In the present study, we report a new mutation in the P/Q-type calcium-channel a1A-subunit gene, in a Portuguese family with both slowly progressive cerebellar ataxia and hemiplegic migraine. This mutation replaces a polar positively charged highly conserved arginine by a neutral glutamine, at codon 1347. The two previously described mutations R192Q (1) and R583Q (6, 8) are located in the S4-transmembrane segments of protein domains I and II, respectively (Fig. 1), which are considered to be the voltage sensor segments, both replacing highly conserved positively charged arginines by neutral glutamines. The missense mutation in this family is similar and is also located in the S4-transmembrane segment but of protein domain III. Functional studies performed in channels with the two previously Clin Genet 2004: 65: 70–72 Copyright # Blackwell Munksgaard 2004 Printed inDenmark. All rights reserved CLINICALGENETICS
A retrospective chart review of all patients with cerebrovascular diseases attending the outpatie... more A retrospective chart review of all patients with cerebrovascular diseases attending the outpatients' clinic during a 5-year period was performed to identify patients with seizures secondary to cerebrovascular diseases, in order to evaluate the routine clinical management of these patients. We found 57 epileptic patients out of 985 cases regularly followed for cerebrovascular diseases. The clinical characteristics of these 57
Background SCN1A is the most relevant gene in epilepsy. Only seven SCN1A mutations have been iden... more Background SCN1A is the most relevant gene in epilepsy. Only seven SCN1A mutations have been identified in 10 familial hemiplegic migraine (FHM) kindreds worldwide. Cases and kindreds In 2009, we presented a kindred with FHM due to the L263V SCN1A mutation. In the current study, we report a novel FHM3 kindred from the same village. The first family exhibited the co-occurrence of FHM and epilepsy. No case of epilepsy was observed in the new kindred. An L263V mutation was found in all patients, and the haplotype analysis supports a unique mutational event. Comments Despite its bioelectric activity, the SCN1A L263V mutation most likely requires a combination of several endogenous or environmental induction stimuli to attain an epileptogenic threshold.
Objectives: Migraine pathophysiology involves several pathways. Our aims were to explore a possib... more Objectives: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene ( BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene-related peptide gene ( CGRP); and a possible interaction between the two. Methods: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP—rs1553005—of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable-logistic regression and confirmed by a multifactor dimensionality reduction analysis. Results: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT-genotype of rs2049046 and the GC-genoty...
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Papers by Jose Barros