RESUMO
OBJECTIVES: We describe the public health response to an outbreak of acute rheumatic fever (ARF) in a remote Aboriginal community. METHODS: In August 2021, the Northern Territory Rheumatic Heart Disease Control Program identified an outbreak of acute rheumatic fever in a remote Aboriginal community. A public health response was developed using a modified acute poststreptococcal glomerulonephritis protocol and the National Acute Rheumatic Fever Guideline for Public Health Units. RESULTS: 12 cases were diagnosed during the outbreak; six-times the average number of cases in the same period in the five years prior (n=1.8). Half (n=6) of the outbreak cases were classified as recurrent episodes with overdue secondary prophylaxis. Contact tracing and screening of 11 households identified 86 close contacts. CONCLUSIONS: This outbreak represented an increase in both first episodes and recurrences of acute rheumatic fever and highlights the critical need for strengthened delivery of acute rheumatic fever secondary prophylaxis, and for improvements to the social determinants of health in the region. IMPLICATIONS FOR PUBLIC HEALTH: Outbreaks of acute rheumatic fever are rare despite continuing high rates of acute rheumatic fever experienced by remote Aboriginal communities. Nevertheless, there can be improvements in the current national public health guidance relating to acute rheumatic fever cluster and outbreak management.
RESUMO
OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.
Assuntos
Cefaleia Histamínica , Transtornos de Enxaqueca , Masculino , Humanos , Feminino , Cefaleia Histamínica/epidemiologia , Cefaleia Histamínica/genética , Fatores de Risco , Estudo de Associação Genômica Ampla , Fumar/efeitos adversos , Fumar/genética , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/genéticaRESUMO
OBJECTIVE: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies. METHODS: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp. RESULTS: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of KV 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV 1.6 or KV 1.1 subunits. SIGNIFICANCE: This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.
Assuntos
Epilepsia , Transtornos do Neurodesenvolvimento , Humanos , Epilepsia/genética , Mutação/genética , Convulsões/genética , Canal de Potássio Kv1.6/genéticaRESUMO
BACKGROUND: A positive family history predisposes to the development of cluster headache. The distinct characteristics of familial cluster headache have yet to be confirmed, however, evidence suggests a younger age of onset and higher proportion of females in this subgroup. OBJECTIVES: To assess the rate and mode of inheritance of familial cluster headache in a tertiary referral centre for headache. To describe the clinical features of familial cluster headache. METHODS: A retrospective study conducted between 2007 and 2017. Cluster headache was confirmed in probands and affected relatives. Differences in demographics, clinical characteristics, and response-to-treatment in familial cluster headache were delineated through multivariate analysis using a control cohort of 597 patients with sporadic cluster headache. RESULTS: Familial cluster headache was confirmed in 48 (7.44%) patients and predominantly reflected an autosomal dominant mode of inheritance with reduced penetrance. Familial cases were more likely to report nasal blockage (OR 4.06, 95% CI; 2.600-6.494, p < 0.001) during an attack and a higher rate of concurrent short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (OR 3.76, 95% CI; 1.572-9.953, p = 0.004). CONCLUSION: These findings add to evidence suggesting a genetic component to cluster headache. Here, we demonstrated prominent nasal blockage, and a higher occurrence of concomitant short-lasting unilateral neuralgiform headache with conjunctival injection and tearing in this subgroup, further delineating the phenotype.
Assuntos
Cefaleia Histamínica , Obstrução Nasal , Neuralgia , Cefaleia Histamínica/complicações , Cefaleia Histamínica/epidemiologia , Cefaleia Histamínica/genética , Feminino , Cefaleia/complicações , Humanos , Obstrução Nasal/complicações , Estudos RetrospectivosRESUMO
OBJECTIVE: Identifying common genetic variants that confer genetic risk for cluster headache. METHODS: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. RESULTS: An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10-8 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2 = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. INTERPRETATION: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216.
Assuntos
Cefaleia Histamínica/epidemiologia , Cefaleia Histamínica/genética , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de RNA/métodosRESUMO
OBJECTIVE: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.
Assuntos
Cefaleia Histamínica/epidemiologia , Cefaleia Histamínica/genética , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Cefaleia Histamínica/diagnóstico , Estudos de Coortes , Feminino , Humanos , Masculino , Suécia/epidemiologia , Reino Unido/epidemiologiaRESUMO
Mutations in the CACNA1A gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the CACNA1A gene (c.4055G>A, p.R1352Q). The R1352Q CACNA1A variant shares the phenotype with other described CACNA1A mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.
RESUMO
OBJECTIVE: To determine the prevalence and clinical predictors of pituitary adenomas in cluster headache patients, in order to determine the necessity of performing dedicated pituitary magnetic resonance imaging in patients with cluster headache. METHODS: A retrospective study was conducted of all consecutive patients diagnosed with cluster headache and with available brain magnetic resonance imaging between 2007 and 2017 in a tertiary headache center. Data including demographics, attack characteristics, response to treatments, results of neuroimaging, and routine pituitary function tests were recorded. RESULTS: Seven hundred and eighteen cluster headache patients attended the headache clinic; 643 underwent a standard magnetic resonance imaging scan, of whom 376 also underwent dedicated pituitary magnetic resonance imaging. Pituitary adenomas occurred in 17 of 376 patients (4.52%). Non-functioning microadenomas (n = 14) were the most common abnormality reported. Two patients, one of whom lacked the symptoms of pituitary disease, required treatment for their pituitary lesion. No clinical predictors of those adenomas were identified after multivariate analysis using random forests. Systematic pituitary magnetic resonance imaging scanning did not benefit even a single patient in the entire cohort. CONCLUSION: The prevalence of pituitary adenomas in cluster headache is similar to that reported in the general population, thereby precluding an over-representation of pituitary lesions in cluster headache. We conclude that the diagnostic assessment of cluster headache patients should not include specific pituitary screening. Only patients with standard brain magnetic resonance imaging findings or symptoms suggestive of a pituitary disorder require brain magnetic resonance imaging with dedicated pituitary views.
Assuntos
Adenoma/complicações , Adenoma/diagnóstico por imagem , Doenças do Sistema Nervoso Autônomo/complicações , Cefaleia Histamínica/etiologia , Imageamento por Ressonância Magnética/métodos , Hipófise/diagnóstico por imagem , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico por imagem , Cefalalgias Autonômicas do Trigêmeo/diagnóstico , Adenoma/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefaleia Histamínica/diagnóstico por imagem , Cefaleia Histamínica/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Neoplasias Hipofisárias/epidemiologia , Estudos RetrospectivosRESUMO
PURPOSE: To understand the role of the angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IAs), we investigated its role in a large cohort of familial IAs. METHODS: Individuals with family history of IA were recruited to the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study. The ANGPTL6 gene was sequenced using Sanger sequencing. Identified genetic variants were compared to a control population. RESULTS: We found 6 rare ANGPTL6 genetic variants in 9/275 individuals with a family history of IA (3.3%) (5 missense mutations and 1 nonsense mutation leading to a premature stop codon), none present in controls. One of these had been previously reported: c.392A>T (p.Glu131Val) on exon 2; another was very close: c.332G>A (p.Arg111His). Two further genetic variants lie within the fibrinogen-like domain of the ANGPTL6 gene, which may influence function or level of the ANGPTL6 protein. The last 2 missense mutations lie within the coiled-coil domain of the ANGPTL6 protein. All genetic variants were well conserved across species. CONCLUSION: ANGPTL6 genetic variants are an important cause of IA. Defective or lack of ANGPTL6 protein is therefore an important factor in blood vessel proliferation leading to IA; dysfunction of this protein is likely to cause abnormal proliferation or weakness of vessel walls. With these data, not only do we emphasize the importance of screening familial IA cases for ANGPTL6 and other genes involved in IA, but also highlight the ANGPTL6 pathway as a potential therapeutic target. CLASSIFICATION OF EVIDENCE: This is a Class III study showing some specificity of presence of the ANGPTL6 gene variant as a marker of familial intracranial aneurysms in a small subset of individuals with familial aneurysms.
Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Predisposição Genética para Doença , Aneurisma Intracraniano/genética , Hemorragia Subaracnóidea/genética , Adulto , Idoso , Proteína 6 Semelhante a Angiopoietina , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Bancos de TecidosRESUMO
Emerging data-points towards a possible aetiological and therapeutic relevance of trigeminal neurovascular contact in short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and perhaps in short lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). We aimed to assess the prevalence and significance of trigeminal neurovascular contact in a large cohort of consecutive SUNCT and SUNA patients and evaluate the radiological differences between them. The standard imaging protocol included high spatial and nerve-cistern contrast resolution imaging acquisitions of the cisternal segments of the trigeminal nerves and vessels. MRI studies were evaluated blindly by two expert evaluators and graded according to the presence, location and degree of neurovascular contact. The degree of contact was graded as with or without morphological changes. Neurovascular contact with morphological changes was defined as contact with distortion and/or atrophy. A total of 159 patients (SUNCT = 80; SUNA = 79) were included. A total of 165 symptomatic and 153 asymptomatic trigeminal nerves were analysed. The proportion of neurovascular contact on the symptomatic trigeminal nerves was higher (80.0%) compared to the asymptomatic trigeminal nerves (56.9%). The odds on having neurovascular contact over the symptomatic nerves was significantly higher than on the asymptomatic nerves [odds ratio (OR): 3.03, 95% confidence interval (CI) 1.84-4.99; P < 0.0001]. Neurovascular contact with morphological changes were considerably more prevalent on the symptomatic side (61.4%), compared to the asymptomatic side (31.0%) (OR 4.16, 95% CI 2.46-7.05; P < 0.0001). On symptomatic nerves, neurovascular contact with morphological changes was caused by an artery in 95.0% (n = 77/81). Moreover, the site of contact and the point of contact around the trigeminal root were respectively proximal in 82.7% (67/81) and superior in 59.3% (48/81). No significant radiological differences emerged between SUNCT and SUNA. The multivariate analysis of radiological predictors associated with the symptomatic side, indicated that the presence of neurovascular contact with morphological changes was strongly associated with the side of the pain (OR: 2.80, 95% CI 1.44-5.44; P = 0.002) even when adjusted for diagnoses. Our findings suggest that neurovascular contact with morphological changes is involved in the aetiology of SUNCT and SUNA. Along with a similar clinical phenotype, SUNCT and SUNA also display a similar structural neuroimaging profile, providing further support for the concept that the separation between them should be abandoned. Furthermore, these findings suggest that vascular compression of the trigeminal sensory root, may be a common aetiological factor between SUNCT, SUNA and trigeminal neuralgia thereby further expanding the overlap between these disorders.
Assuntos
Transtornos da Cefaleia/diagnóstico por imagem , Síndrome SUNCT/diagnóstico por imagem , Nervo Trigêmeo/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anatomia Transversal , Atrofia , Estudos de Coortes , Feminino , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Dor/diagnóstico por imagem , Prevalência , Neuralgia do Trigêmeo , Adulto JovemRESUMO
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
Assuntos
Aspartato-tRNA Ligase/genética , Mutação com Ganho de Função/genética , Mutação com Perda de Função/genética , Transtornos do Neurodesenvolvimento/genética , Aminoacil-RNA de Transferência/genética , Alelos , Aminoacil-tRNA Sintetases/genética , Linhagem Celular , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Linhagem , RNA de Transferência/genética , Células-Tronco/fisiologiaRESUMO
Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.
Assuntos
Agenesia do Corpo Caloso/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Mutação , Simportadores/genética , Adolescente , Adulto , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Feminino , Células HEK293 , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Domínios Proteicos , Simportadores/química , Simportadores/metabolismo , SíndromeRESUMO
OBJECTIVES: To define the characteristics of post-traumatic headache with cluster headache phenotype (PTH-CH) and to compare these characteristics with primary CH. METHODS: A retrospective study was conducted of patients seen between 2007 and 2017 in a headache centre and diagnosed with PTH-CH that developed within 7 days of head trauma. A control cohort included 553 patients with primary CH without any history of trauma who attended the headache clinic during the same period. Data including demographics, attack characteristics and response to treatments were recorded. RESULTS: Twenty-six patients with PTH-CH were identified. Multivariate analysis revealed significant associations between PTH-CH and family history of CH (OR 3.32, 95% CI 1.31 to 8.63), chronic form (OR 3.29, 95% CI 1.70 to 6.49), parietal (OR 14.82, 95% CI 6.32 to 37.39) or temporal (OR 2.04, 95% CI 1.10 to 3.84) location of pain, and presence of prominent cranial autonomic features during attacks (miosis OR 11.24, 95% CI 3.21 to 41.34; eyelid oedema OR 5.79, 95% CI 2.57 to 13.82; rhinorrhoea OR 2.65, 95% CI 1.26 to 5.86; facial sweating OR 2.53, 95% CI 1.33 to 4.93). Patients with PTH-CH were at a higher risk of being intractable to acute (OR 12.34, 95% CI 2.51 to 64.73) and preventive (OR 16.98, 95% CI 6.88 to 45.52) treatments and of suffering from associated chronic migraine (OR 10.35, 95% CI 3.96 to 28.82). CONCLUSION: This largest series of PTH-CH defines it as a unique entity with specific evolutive profile. Patients with PTH-CH are more likely to suffer from the chronic variant, have marked autonomic features, be intractable to treatment and have associated chronic migraine compared with primary CH.
Assuntos
Cefaleia Histamínica/diagnóstico , Fenótipo , Cefaleia Pós-Traumática/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: The population rate of familial cluster headache (CH) has been reported to be as high as 20% however this varies considerably across studies. To obtain a true estimate of family history in CH, we conducted a systematic review and meta-analysis of previously published data. METHODS: Our systematic review involved a search of electronic databases (Medline, EMBASE, PubMed, CINAHL) to identify and appraise studies of interest utilising the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. To further ameliorate the accuracy of our analysis we included an additional unpublished cohort of CH patients recruited at a tertiary referral centre for headache, who underwent detailed family history with diagnostic verification in relatives. Data was extracted and meta-analysis conducted to provide a true estimation of family history. RESULTS: In total, we identified 7 studies which fulfilled our inclusion criteria. The estimated true prevalence of CH patients with a positive family history was 6.27% (95% CI:4.65-8.40%) with an overall I2 of 73%. Fitted models for gender subgroups showed higher estimates 9.26% (95% CI: 6.29-13.43%) in females. However the I2 for the female model was 58.42% and significant (p = 0.047). CONCLUSION: Our findings estimate a rate of family history in CH to be approximately 6.27% (95% CI: 4.65-8.40%). While estimates were larger for female probands, we demonstrated high heterogeneity in this subgroup. These findings further support a genetic role in the aetiology of CH.
Assuntos
Cefaleia Histamínica/diagnóstico , Cefaleia Histamínica/epidemiologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , PrevalênciaRESUMO
Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.
Assuntos
Acetiltransferases/genética , Flavoproteínas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Doenças do Sistema Nervoso/genética , Proteínas Nucleares/genética , Monoéster Fosfórico Hidrolases/genética , Fatores de Transcrição/genética , Acetiltransferases/química , Acetiltransferases/ultraestrutura , Idade de Início , Antígenos de Superfície/genética , Núcleo Celular/genética , Criança , Pré-Escolar , Exodesoxirribonucleases/genética , Feminino , Regulação da Expressão Gênica/genética , Glicoproteínas/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Íntrons/genética , Masculino , Doenças do Sistema Nervoso/patologia , Proteínas Nucleares/ultraestrutura , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Fenótipo , Fosfoproteínas/genética , Conformação Proteica , Transporte de RNA/genética , RNA Mensageiro/genéticaRESUMO
INTRODUCTION: Adenocarcinoma is the commonest histologic subtype of lung cancer and is often identified by immunohistochemical staining for thyroid transcription factor-1 (TTF-1). However, up to 20% of lung adenocarcinomas do not express TTF-1, and there is uncertainty regarding the significance of this. We aimed to evaluate the prognostic effect of TTF-1 expression status on survival in patients treated with pemetrexed-based chemotherapy for advanced adenocarcinoma of the lung. METHODS: This retrospective study included patients treated with pemetrexed-based chemotherapy for stage IIIB/IV lung adenocarcinoma, who had known TTF-1 expression status. Clinical and demographic data were obtained from medical records. Overall survival (OS) was estimated using the Kaplan-Meier method, and differences in survival between groups assessed using the Cox proportional hazards model. RESULTS: Forty-four patients were identified with documented TTF-1 expression: 35 with TTF-1-positive and 9 with TTF-1-negative disease. Patients in the TTF-1-negative group had poorer performance scores than those in the TTF-1-positive group (ECOG 2: 67 vs 20%, p = 0.008), and received less chemotherapy (median cycles 2 vs 4, p = 0.009), and were fewer in treatment with doublet regimens (22 vs 69%, p = 0.013). OS was significantly shorter in the TTF-1-negative group than in the TTF-1-positive group (2.4 vs 11.5 months, HR 8.38, p < 0.0001). CONCLUSIONS: In this group of patients treated with pemetrexed-based chemotherapy for advanced pulmonary adenocarcinoma, absence of TTF-1 expression was associated with an aggressive tumor phenotype, poorer performance status, and poor survival. This subgroup of patients should be recognized as having a distinct clinical course, with limited benefit from standard chemotherapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fator Nuclear 1 de Tireoide/metabolismo , Adenocarcinoma/secundário , Adulto , Idoso , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Pemetrexede/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative ataxic disorders with autosomal dominant inheritance. We aim to provide an update on the recent clinical and scientific progresses in SCA where numerous novel genes have been identified with next-generation sequencing techniques. The main disease mechanisms of these SCAs include toxic RNA gain-of-function, mitochondrial dysfunction, channelopathies, autophagy and transcription dysregulation. Recent studies have also demonstrated the importance of DNA repair pathways in modifying SCA with CAG expansions. In addition, we summarise the latest technological advances in detecting known and novel repeat expansion in SCA. Finally, we discuss the roles of antisense oligonucleotides and RNA-based therapy as potential treatments.