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Limb-girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra-rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty-one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.
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Distrofia Muscular de Cinturas , Mutación , Humanos , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/epidemiología , Distrofia Muscular de Cinturas/diagnóstico , Masculino , Brasil/epidemiología , Femenino , Adulto , Adolescente , Persona de Mediana Edad , Niño , Estudios de Cohortes , Adulto Joven , Linaje , Conectina/genética , Fenotipo , Predisposición Genética a la Enfermedad , PreescolarRESUMEN
BACKGROUND AND AIMS: The genetic epidemiology of inherited neuropathies in children remains largely unknown. In this study, we specifically investigated the genetic profile of a Brazilian cohort of pediatric patients with pure or complex axonal neuropathies, a crucial knowledge in the near future for establishing treatment priorities and perspectives for this group of patients. METHODS: Fifty-three pediatric patients who were assessed prior to reaching the age of 20, and who had clinical diagnoses of axonal hereditary neuropathy or presented with axonal neuropathy as the primary clinical feature, were included in the study. The recruitment of these cases took place from January 1, 2018, to December 31, 2020. The diagnosis was based on clinical and electrophysiological data. A molecular assessment was made using target-gene panel or whole-exome sequencing. Subsequently, segregation analysis was performed on available family members, and all candidate variants found were confirmed through Sanger. RESULTS: A molecular diagnosis was reached in 68% of the patients (n = 36/53), considering only pathogenic and probably pathogenic variants. Variants in MFN2 (n = 15) and GJB1 (n = 3) accounted for half of the genetically confirmed patients (50%; n = 18/36). The other 18 genetically diagnosed patients had variants in several less common genes. INTERPRETATION: Apart from MFN2 and GJB1 genes, universally recognized as a frequent cause of axonal neuropathies in most studied population, our Brazilian cohort of children with axonal neuropathies showed an important genetic heterogeneity, probably reflecting the multi ethnicity of the Brazilian population. Diagnostic, counseling, and future interventions should consider this characteristic.
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Enfermedad de Charcot-Marie-Tooth , Humanos , Niño , Enfermedad de Charcot-Marie-Tooth/genética , Brasil/epidemiología , Mutación , Proteína beta1 de Unión ComunicanteRESUMEN
INTRODUCTION/AIMS: Considering the heterogeneity of the clinical manifestations of Duchenne muscular dystrophy (DMD), it is important to describe their various clinical profiles. Thus, in this study we aimed to develop percentile curves for DMD using a battery of measures to define the patterns of functional abilities, timed tests, muscle strength, and range of motion (ROM). METHODS: This retrospective data analysis was based on the records of patients with DMD using the Motor Function Measure (MFM) scale, isometric muscle strength (IS), dorsiflexion ROM, 10-meter walk test (10 MWT), and 6-minute walk test (6 MWT). Percentile curves (25th, 50th, and 75th percentiles) with MFM, IS, ROM, 10 MWT, and 6 MWT on the y axis and patient age on the x axis were constructed using the generalized additive model for location, scale, and shape, with Box-Cox power exponential distribution. RESULTS: There were records of 329 assessments of patients between 4 and 18 years of age. The MFM percentiles showed a gradual reduction in all dimensions. Muscle strength and ROM percentiles showed that the knee extensors were the most affected from 4 years of age, and dorsiflexion ROM negative values were noted from the age of 8 years. The 10 MWT showed a gradual increase in performance time with age. For the 6 MWT, the distance curve remained stable until 8 years, with a subsequent progressive decline. DISCUSSION: In this study we generated percentile curves that can help health professionals and caregivers follow the trajectory of disease progression in DMD patients.
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Distrofia Muscular de Duchenne , Masculino , Humanos , Niño , Distrofia Muscular de Duchenne/diagnóstico , Estudios Retrospectivos , Actividades Cotidianas , Caminata , Prueba de PasoRESUMEN
In the last few decades, there have been considerable improvements in the diagnosis and care of Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy. International guidelines have been published and recently reviewed. A group of Brazilian experts has developed a standard of care based on a literature review with evidence-based graded recommendations in a two-part publication. Implementing best practice management has helped change the natural history of this chronic progressive disorder, in which the life expectancy for children of the male sex in the past used to be very limited. Since the previous publication, diagnosis, steroid treatment, rehabilitation, and systemic care have gained more significant insights with new original work in certain fields. Furthermore, the development of new drugs is ongoing, and some interventions have been approved for use in certain countries. Therefore, we have identified the need to review the previous care recommendations for Brazilian patients with DMD. Our objective was to create an evidence-based document that is an update on our previous consensus on those topics.
Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.
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Distrofia Muscular de Duchenne , Niño , Humanos , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Brasil , ConsensoRESUMEN
It was argued that researchers and clinicians are not able to make judgments between most categories of the original Medical Research Council (MRC) scale and that a modified short version would reach higher agreement levels. We aimed to assess the inter-rater reliability for both the original and the Rasch-modified MRC scoring criteria of Manual Muscle Strength tests (MMSt) in patients with neuromuscular diseases. Two MRC scoring criteria were used to score muscle strength using MMSt in 40 muscle groups of the upper and lower limbs in patients with neuromuscular disorders. Three investigators performed the evaluations; the order of the MMSt and the use of the scales were performed according to the preferences of the investigators. The agreement coefficient (Gwet's AC2 ) was used to compute the reliability. Sixty patients (mean age of 39.3 years ± 15.2) with neuromuscular diseases were included. The mean AC2 for the muscle groups of the upper limbs ranged from 0.82 to 0.96 using the modified MRC scale and from 0.86 to 0.96 using the original MRC scale. The AC2 for the lower limb muscle groups ranged from 0.80 to 0.91 (modified MRC scale) and from 0.87 to 0.93 (original MRC scale). These values might be interpreted as "almost perfect agreement" with no significant differences between the scales. The results indicate that both MRC scoring criteria have significant reliability among trained observers. Moreover, the Rasch-modified MRC scale is as reliable as the original MRC scale and can be used in future clinical studies.
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Investigación Biomédica , Enfermedades Neuromusculares , Humanos , Adulto , Reproducibilidad de los Resultados , Músculo Esquelético , Fuerza Muscular/fisiología , Enfermedades Neuromusculares/diagnósticoRESUMEN
Abstract In the last few decades, there have been considerable improvements in the diagnosis and care of Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy. International guidelines have been published and recently reviewed. A group of Brazilian experts has developed a standard of care based on a literature review with evidence-based graded recommendations in a two-part publication. Implementing best practice management has helped change the natural history of this chronic progressive disorder, in which the life expectancy for children of the male sex in the past used to be very limited. Since the previous publication, diagnosis, steroid treatment, rehabilitation, and systemic care have gained more significant insights with new original work in certain fields. Furthermore, the development of new drugs is ongoing, and some interventions have been approved for use in certain countries. Therefore, we have identified the need to review the previous care recommendations for Brazilian patients with DMD. Our objective was to create an evidence-based document that is an update on our previous consensus on those topics.
Resumo Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.
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BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. The correct diagnosis at the onset of the disease is sometimes very difficult, due to the symptoms being very similar to those of other neurological syndromes. OBJECTIVE: This study aimed to analyze the initial manifestations, the specialty of the first physician visited due the initial complaint, the misdiagnoses, as well as the unnecessary surgical interventions in a new ALS Brazilian population. METHODS: The medical records of 173 patients with typical ALS were reviewed. RESULTS: The present study demonstrated that other symptoms, besides weakness, were very frequent as initial presentation of ALS, and orthopedics was the medical specialty most sought by patients at the onset of symptoms. Our frequency of misdiagnoses was 69.7%, and in 7.1% of them, an unnecessary surgical intervention was performed. CONCLUSIONS: Amyotrophic lateral sclerosis presents a very large pool of signs and symptoms; therefore, there is an urgent need of increasing the disease awareness to other specialties due to the high frequency of misdiagnoses observed in clinical practice.
ANTECEDENTES: A esclerose lateral amiotrófica (ELA) é uma doença neurodegenerativa que afeta os neurônios motores superior e inferior. O diagnóstico correto no início da doença é, às vezes, muito difícil, pois os sintomas de início são muito semelhantes aos de outras síndromes neurológicas. OBJETIVO: Este estudo teve como objetivo analisar as manifestações iniciais, a especialidade do primeiro médico visitado devido à queixa inicial, os diagnósticos errôneos, bem como as intervenções cirúrgicas desnecessárias em uma nova população brasileira acometida por ELA. MéTODOS: Os prontuários médicos de 173 pacientes com ELA típica foram revisados. RESULTADOS: O presente estudo demonstrou que outros sintomas, além da fraqueza, foram muito frequentes como apresentação inicial da ELA, sendo a ortopedia a especialidade médica mais procurada pelos pacientes no início dos sintomas. Nossa frequência de diagnósticos errôneos foi de 69,7%, e em 7,1% deles foi realizada intervenção cirúrgica desnecessária. CONCLUSõES: A ELA apresenta um conjunto amplo de sinais e sintomas; portanto, há necessidade urgente de uma melhor educação de outras especialidades devido à alta frequência de diagnósticos equivocados observada na prática clínica.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/diagnóstico , Brasil , Errores Diagnósticos , Humanos , Neuronas MotorasRESUMEN
Abstract Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. The correct diagnosis at the onset of the disease is sometimes very difficult, due to the symptoms being very similar to those of other neurological syndromes. Objective This study aimed to analyze the initial manifestations, the specialty of the first physician visited due the initial complaint, the misdiagnoses, as well as the unnecessary surgical interventions in a new ALS Brazilian population. Methods The medical records of 173 patients with typical ALS were reviewed. Results The present study demonstrated that other symptoms, besides weakness, were very frequent as initial presentation of ALS, and orthopedics was the medical specialty most sought by patients at the onset of symptoms. Our frequency of misdiagnoses was 69.7%, and in 7.1% of them, an unnecessary surgical intervention was performed. Conclusions Amyotrophic lateral sclerosis presents a very large pool of signs and symptoms; therefore, there is an urgent need of increasing the disease awareness to other specialties due to the high frequency of misdiagnoses observed in clinical practice.
Resumo Antecedentes A esclerose lateral amiotrófica (ELA) é uma doença neurodegenerativa que afeta os neurônios motores superior e inferior. O diagnóstico correto no início da doença é, às vezes, muito difícil, pois os sintomas de início são muito semelhantes aos de outras síndromes neurológicas. Objetivo Este estudo teve como objetivo analisar as manifestações iniciais, a especialidade do primeiro médico visitado devido à queixa inicial, os diagnósticos errôneos, bem como as intervenções cirúrgicas desnecessárias em uma nova população brasileira acometida por ELA. Métodos Os prontuários médicos de 173 pacientes com ELA típica foram revisados. Resultados O presente estudo demonstrou que outros sintomas, além da fraqueza, foram muito frequentes como apresentação inicial da ELA, sendo a ortopedia a especialidade médica mais procurada pelos pacientes no início dos sintomas. Nossa frequência de diagnósticos errôneos foi de 69,7%, e em 7,1% deles foi realizada intervenção cirúrgica desnecessária. Conclusões A ELA apresenta um conjunto amplo de sinais e sintomas; portanto, há necessidade urgente de uma melhor educação de outras especialidades devido à alta frequência de diagnósticos equivocados observada na prática clínica.
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BACKGROUND: The commonly used dynamometers can be ineffective in evaluating handgrip in patients with Duchenne muscular dystrophy (DMD), especially children with generalized muscle weakness. The aim of this study was to analyze whether the modified sphygmomanometer is an effective instrument for handgrip strength evaluation in patients with DMD, during different stages of the disease. METHOD: The handgrip strength of 33 patients was evaluated by the Jamar dynamometer and the modified sphygmomanometer. Motor function was evaluated by the Motor Function Measurement (MFM) scale. Four evaluations, with a six-month interval between each, were performed: Evaluation 1 (N = 33), Evaluation 2 (N = 24), Evaluation 3 (N = 15), and Evaluation 4 (N = 8). A linear regression model with mixed effects was used for the longitudinal data and descriptive analysis of strength for all four evaluations. RESULT: The first evaluation data presented very high correlations between the dynamometer and the modified sphygmomanometer (r = 0.977; p < 0.001). The longitudinal analysis showed a significant difference between Evaluation 1 and the other handgrip strength evaluations obtained using the dynamometer (p < 0.05) but not the modified sphygmomanometer (p > 0.05). Null values were obtained only when using the dynamometer device. CONCLUSION: The modified sphygmomanometer seems to be more suitable than the dynamometer for measuring handgrip strength in all stages of DMD.
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Fuerza de la Mano , Distrofia Muscular de Duchenne , Niño , Fuerza de la Mano/fisiología , Humanos , Fuerza Muscular/fisiología , Debilidad Muscular , Distrofia Muscular de Duchenne/diagnósticoRESUMEN
PURPOSE: The purpose of this study was to perform a cross-cultural adaptation of the Functional Mobility Scale (FMS) to Brazilian Portuguese and analyse its construct validity and intra-rater reliability in a sample of caregivers of children and adolescents with spina bifida (SB). MATERIAL AND METHODS: The cross-cultural adaptation followed five stages: two forward translations, synthesis, back-translation, committee review and pre-testing (n = 20). Construct validity was assessed by comparing the FMS with the classifications of Hoffer and Schoenmakers (n = 40). Intra-rater reliability was assessed by comparing the ratings of 14 caregivers, on two occasions. Kendall's tau correlation coefficient was used to test the construct validity of the FMS, while the kappa coefficient was used to test intra-rater reliability. RESULTS: Caregivers reported no difficulties with completing the FMS in Brazilian Portuguese. Construct validity tests showed positive correlations between the distances of 5 m (house), 50 m (school) and 500 m (community) in the FMS and the classifications of Hoffer (τ = 0.84; τ = 0.90; τ = 0.68; p < 0.01) and Schoenmakers (τ = 0.83; τ = 0.89; τ = 0.76; p < 0.01), respectively. Excellent intra-rater reliability (kappa = 0.9-1.0) was found for all three distances in the FMS. CONCLUSIONS: The FMS in Brazilian Portuguese showed acceptable intra-rater reliability and construct validity when used to measure the mobility level of patients with SB. We recommend its use in clinical practice and research.Implications for RehabilitationA valid and reliable instrument for assessing the mobility of patients with SB;A cross-cultural and adapted FMS in Brazilian Portuguese;An instrument for therapeutic and functional approaches outside the clinicalsetting;The FMS in the Brazilian Portuguese online version shows mistranslations.
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Comparación Transcultural , Disrafia Espinal , Adolescente , Brasil , Niño , Humanos , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , TraduccionesRESUMEN
BACKGROUND: Freezing human biopsies is common in clinical practice for storage. However, this technique disrupts mitochondrial membranes, hampering further analyses of respiratory function. To contribute to laboratorial diagnosis of mitochondrial diseases, this study sought to develop a respirometry approach using O2k (Oroboros Ins.) to measure the whole electron transport chain (ETC) activity in homogenates of frozen skeletal muscle biopsies. PATIENTS AND METHODS: We enrolled 16 patients submitted to muscle biopsy in the process of routine diagnostic investigation: four with mitochondrial disease and severe mitochondrial dysfunction; seven with exercise intolerance and multiple deletions of mitochondrial DNA, presenting mild to moderate mitochondrial dysfunction; five without mitochondrial disease, as controls. Whole homogenates of muscle fragments were prepared using grinder-type equipment. O2 consumption rates were normalized using citrate synthase activity. RESULTS: Transmission electron microscopy confirmed mitochondrial membrane discontinuation, indicating increased permeability of mitochondrial membranes in homogenates from frozen biopsies. O2 consumption rates in the presence of acetyl-CoA lead to maximum respiratory rates sensitive to rotenone, malonate and antimycin. This protocol of acetyl-CoA-driven respiration (ACoAR), applied in whole homogenates of frozen muscle, was sensitive enough to identify ETC abnormality, even in patients with mild to moderate mitochondrial dysfunction. We demonstrated adequate repeatability of ACoAR and found significant correlation between O2 consumption rates and enzyme activity assays of individual ETC complexes. CONCLUSIONS: We present preliminary data on a simple, low cost and reliable procedure to measure respiratory function in whole homogenates of frozen skeletal muscle biopsies, contributing to diagnosis of mitochondrial diseases in humans.
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Acetilcoenzima A/metabolismo , Mitocondrias Musculares/metabolismo , Enfermedades Mitocondriales/diagnóstico , Músculo Esquelético/metabolismo , Consumo de Oxígeno , Adolescente , Adulto , Biopsia , Respiración de la Célula , Niño , Técnicas de Laboratorio Clínico/métodos , Criopreservación , Transporte de Electrón , Femenino , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/metabolismo , Masculino , Potencial de la Membrana Mitocondrial , Enfermedades Mitocondriales/metabolismo , Membranas Mitocondriales/metabolismo , Músculo Esquelético/patología , Oftalmoplejía Externa Progresiva Crónica/diagnóstico , Oftalmoplejía Externa Progresiva Crónica/metabolismo , Fosforilación Oxidativa , Permeabilidad , Manejo de Especímenes , Adulto JovenRESUMEN
A avaliação de sintomas na distrofia muscular de Duchenne (DMD) permite o adequado manejo terapêutico e o Edmonton Symptom Assessment System (ESAS) possui esta função: avaliar simultaneamente múltiplos sintomas de pacientes em cuidados paliativos (dor, cansaço, sonolência, náusea, apetite, falta de ar, depressão, ansiedade e bem-estar). Objetivo: Verificar se pacientes com DMD entendem os termos do ESAS e são capazes de graduar seus sintomas por este instrumento. Métodos: 10 pacientes com DMD foram avaliados transversalmente em relação à: compreensão dos itens do ESAS, caracterização dos sintomas (pelo ESAS e Escala de Faces) e medida da função motora. A graduação de sintomas do paciente, pelo ESAS, foi realizada também pelo avaliador. Os dados foram analisados descritivamente e por meio do coeficiente de correlação de Spearman. Resultados: Todos os pacientes compreenderam os sintomas dor, cansaço, sonolência, depressão (tristeza) e bem-estar, já os sintomas náusea, apetite, falta de ar e ansiedade não foram compreendidos por todos. A média geral de todos os sintomas avaliados pela escala ESAS foi abaixo de 5 pontos. Entre os resultados da escala ESAS e Escala de faces, houve correlação forte para os sintomas "depressão" (r= 0,64) e "ansiedade" (r= 0,65). Houve correlação perfeita (r= 1,0) entre ESAS preenchida pelo paciente e pelo avaliador para os itens "depressão" e "ansiedade" e correlação forte (r= 0,82) para "sonolência". Conclusão: Pacientes com DMD entenderam os termos do ESAS e graduaram seus sintomas por este instrumento, portanto, não há necessidade de alteração dos termos do ESAS para avaliação de pacientes com DMD
Symptom assessment, in Duchenne Muscular Dystrophy (DMD), allows an adequate treatment, and the Edmonton Symptom Assessment System (ESAS) assess it: evaluating clinical problems of patients in palliative care (pain, tiredness, drowsiness, nausea, appetite, shortness of breath, depression, anxiety, and well-being). Objective: To verify if patients with DMD understand the terms of the ESAS and if their symptoms could be assessed using this instrument. Methods: Ten patients with DMD were cross-sectional evaluated in relation to the understanding of the ESAS items, capacity to describe symptom (using the ESAS and the Faces Scale) and the Motor Function Measure. The patient's symptom by ESAS was also classified by evaluator. A descriptive and correlation (Spearman's correlation coefficient) analysis of data was performed. Results: All patients understood the symptoms of pain, tiredness, drowsiness, depression (sadness), and well-being. However, some patients did not understand the symptoms of nausea, appetite, shortness of breath. The general mean of all symptoms assessed by the ESAS was below 5 points. For the symptom 'depression' and 'anxiety', a strong correlation was found between the results of the ESAS and the Face scale (r= 0.64, and r= 0.65, respectively). Additionally, a perfect and strong correlation, respectively, was found between the ESAS completed by the patient and the evaluator for the items ''depression'," and 'anxiety' (r= 1.0)" and a 'drowsiness' (r= 0.82). Conclusion: DMD patients understood the ESAS terms and graded their symptoms using this instrument. Therefore, it is not necessary to change the ESAS terms to assess patients with DMD
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Limb-girdle muscular dystrophies (LGMD) are a group of genetically heterogeneous disorders characterized by predominantly proximal muscle weakness. We aimed to characterize epidemiological, clinical and molecular data of patients with autosomal recessive LGMD2/LGMD-R in Brazil. A multicenter historical cohort study was performed at 13 centers, in which index cases and their affected relatives' data from consecutive families with genetic or pathological diagnosis of LGMD2/LGMD-R were reviewed from July 2017 to August 2018. Survival curves to major handicap for LGMD2A/LGMD-R1-calpain3-related, LGMD2B/LGMD-R2-dysferlin-related and sarcoglycanopathies were built and progressions according to sex and genotype were estimated. In 370 patients (305 families) with LGMD2/LGMD-R, most frequent subtypes were LGMD2A/LGMD-R1-calpain3-related and LGMD2B/LGMD-R2-dysferlin-related, each representing around 30% of families. Sarcoglycanopathies were the most frequent childhood-onset subtype, representing 21% of families. Five percent of families had LGMD2G/LGMD-R7-telethonin-related, an ultra-rare subtype worldwide. Females with LGMD2B/LGMD-R2-dysferlin-related had less severe progression to handicap than males and LGMD2A/LGMD-R1-calpain3-related patients with truncating variants had earlier disease onset and more severe progression to handicap than patients without truncating variants. We have provided paramount epidemiological data of LGMD2/LGMD-R in Brazil that might help on differential diagnosis, better patient care and guiding future collaborative clinical trials and natural history studies in the field.
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Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , Edad de Inicio , Alelos , Biomarcadores , Brasil , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética/métodos , Genotipo , Geografía Médica , Humanos , Masculino , Debilidad Muscular , Distrofia Muscular de Cinturas/epidemiología , Fenotipo , Factores SexualesRESUMEN
OBJECTIVE: ANO5-related myopathy is an important cause of limb-girdle muscular dystrophy (LGMD) and hyperCKemia. The main descriptions have emerged from European cohorts, and the burden of the disease worldwide is unclear. We provide a detailed characterization of a large Brazilian cohort of ANO5 patients. METHODS: A national cross-sectional study was conducted to describe clinical, histopathological, radiological, and molecular features of patients carrying recessive variants in ANO5. Correlation of clinical and genetic characteristics with different phenotypes was studied. RESULTS: Thirty-seven patients from 34 nonrelated families with recessive mutations of ANO5 were identified. The most common phenotype was LGMD, observed in 25 (67.5%) patients, followed by pseudometabolic presentation in 7 (18.9%) patients, isolated asymptomatic hyperCKemia in 4 (10.8%) patients, and distal myopathy in a single patient. Nine patients presented axial involvement, including one patient with isolated axial weakness. The most affected muscles according to MRI were the semimembranosus and gastrocnemius, but paraspinal and abdominal muscles, when studied, were involved in most patients. Fourteen variants in ANO5 were identified, and the c.191dupA was present in 19 (56%) families. Sex, years of disease, and the presence of loss-of-function variants were not associated with specific phenotypes. INTERPRETATION: We present the largest series of anoctaminopathy outside Europe. The most common European founder mutation c.191dupA was very frequent in our population. Gender, disease duration, and genotype did not determine the phenotype.
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Anoctaminas/genética , Enfermedades Musculares/patología , Adolescente , Adulto , Anciano , Brasil , Niño , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Enfermedades Musculares/diagnóstico por imagen , Distrofia Muscular de Cinturas , Mutación , Fenotipo , Adulto JovenRESUMEN
Abstract Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. It is genetically heterogeneous, causative mutations have been disclosed in mitochondrial DNA and nuclear genes involved in the process of energy production in the mitochondria .We investigated the whole mitochondrial DNA in three Brazilian patients with LS, based on their clinical and biochemical data, with the aim to identify the disease-causing mutations. In two of the patients, with complex I deficiency, a novel heteroplasmic variant m.4142G>T (p.R279L) in MT-ND1 and a recurrent homoplasmic mutation m.10197G>A (p.A47T) in MT-ND3 were identified. In the remaining patient, with complex IV deficiency, a de novo heteroplasmic variant in MT-CO1 m.6547T>C (p.L215P) was found. The molecular investigation in mitochondrial diseases have shifted their focus from mitochondrial DNA to nuclear DNA, however, mtDNA protein-coding genes are one of the important genetic causes of mitochondrial disorders for Leigh syndrome. This study expands the molecular and clinical spectrum associated with this disease.
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The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.
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Mutación , Síndromes Miasténicos Congénitos/genética , Receptores Nicotínicos/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Brasil/epidemiología , Niño , Preescolar , Estudios de Cohortes , Exones , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Miasténicos Congénitos/tratamiento farmacológico , Síndromes Miasténicos Congénitos/epidemiología , Síndromes Miasténicos Congénitos/patología , Fenotipo , Prevalencia , Adulto JovenRESUMEN
PURPOSE: HyperCKemia is a persistent rise in serum creatine kinase (CK) levels of at least 1.5 times the normal value, as evidenced by a minimum of two measurements at 30-day intervals. One of the neuromuscular diseases associated with hyperCKemia is malignant hyperthermia (MH). This study investigated the susceptibility to MH in patients with hyperCKemia via in vitro contracture testing (IVCT) and a search of mutations in the RYR1 gene. METHODS: Patients in an MH centre were followed from 1997-2012, and their epidemiologic, clinical, and laboratory data were analyzed, including IVCT, muscle histochemical analysis, and next-generation sequencing molecular analysis. RESULTS: There were nine patients (eight male) in our study with a mean (SD) age of 33 (12) yr. Four patients were Caucasian and five were African Brazilian. Most complained about myalgia or cramps, but all had a normal neurological examination. They persistently presented with hyperCKemia from three months to ten years, with a mean (SD) CK value of 788 (507) IU·L-1 ranging from 210-1,667 IU·L-1. These values corresponded to a 1.5- to nine-fold increase in the normal value (mean increase, 3.7-fold). Six patients were MH susceptible (MHS) after a positive IVCT. Histopathological muscular analysis disclosed unspecified changes in four of the MHS patients. Mitochondrial proliferation was observed in the other two MHS patients and in three MH negative patients. No pathogenic mutations were identified in the RYR1 gene in the five patients evaluated. CONCLUSION: When investigating patients with idiopathic hyperCKemia, susceptibility to MH should be taken into account, and guidance should be offered to prevent anesthetic complications in the family.
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Creatina Quinasa/sangre , Hipertermia Maligna/epidemiología , Canal Liberador de Calcio Receptor de Rianodina/genética , Adolescente , Adulto , Susceptibilidad a Enfermedades , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Hipertermia Maligna/etiología , Hipertermia Maligna/genética , Persona de Mediana Edad , Mutación , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents.
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Medicina Basada en la Evidencia , Glucocorticoides/uso terapéutico , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Brasil , Ensayos Clínicos como Asunto , Técnica Delphi , Estudios de Seguimiento , Pruebas Genéticas , Humanos , Distrofia Muscular de Duchenne/genética , Grupo de Atención al Paciente , Literatura de Revisión como Asunto , Resultado del TratamientoRESUMEN
ABSTRACT Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents.
RESUMO Avanços na compreensão e no manejo da distrofia muscular de Duchenne (DMD) ocorreram desde a publicação de diretrizes internacionais em 2010. Nosso objetivo foi elaborar um consenso nacional baseado em evidências de cuidado multidisciplinar dos pacientes com DMD no Brasil. Utilizamos a técnica de Delphi combinada com revisão sistemática da literatura de 2010 a 2016 classificando níveis de evidência e graus de recomendação. Nossas recomendações foram divididas em duas partes. Apresentamos aqui a parte 1, descrevendo a metodologia utilizada e conceitos gerais da doença, e fornecemos recomendações sobre diagnóstico, tratamento com corticosteroides e novas perspectivas de tratamentos medicamentosos. As principais recomendações: 1) testes genéticos deveriam ser a primeira linha para confirmação de casos suspeitos; 2) pacientes com diagnóstico de DMD devem receber corticosteroides; 3) por enquanto, a falta de publicações de resultados dos ensaios clínicos de fase 3, dificulta recomendações de uso medicamentos que "saltam exons" ou "passam" por código de parada prematura.
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Humanos , Medicina Basada en la Evidencia , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Grupo de Atención al Paciente , Brasil , Literatura de Revisión como Asunto , Pruebas Genéticas , Ensayos Clínicos como Asunto , Estudios de Seguimiento , Técnica Delphi , Resultado del Tratamiento , Distrofia Muscular de Duchenne/genéticaRESUMEN
The North Star Ambulatory Assessment measures motor performance in ambulatory boys with Duchenne muscular dystrophy, a hereditary and degenerative muscle disorder. To use the North Star Ambulatory Assessment in Brazilian boys, we performed the cross-cultural adaptation to the Portuguese language spoken in Brazil and evaluated the reliability and validity of the instrument. Cross-cultural adaptation included: independent translations, synthesis, committee review, pre-testing in 12 boys, back-translation and comparison with the original instrument. Thirty-five boys with Duchenne muscular dystrophy and 38 healthy age-matched controls were recruited for further analyses. Reliability was assessed by internal consistency and reproducibility. Validity studies included face, content, construct and known-groups analyses. Cross-cultural adaptation resulted in an adequate instrument. Reliability studies demonstrated high internal consistency (Cronbach's alpha = 0.935) and adequate intra and inter-rater reproducibility (intraclass correlation coefficient = 0.988 and 0.962). Validation analyses indicated satisfactory content, face and convergent construct validities, with positive correlations with the Motor Function Measure total score (r = 0.863) and the 6-minute walk test (r = 0.433). The known group validity was demonstrated by higher scores in younger boys with Duchenne muscular dystrophy (p = 0.005). North Star Ambulatory Assessment in Brazilian Portuguese is a reliable and valid instrument to measure functional capacity in boys with Duchenne muscular dystrophy.