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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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Background: Dysferlinopathies represent a group of limb girdle or distal muscular dystrophies with an autosomal-recessive inheritance pattern resulting from the presence of pathogenic variants in the dysferlin gene (DYSF). Objective: In this work, we describe a population from a small city in Brazil carrying the c.5979dupA pathogenic variant of DYSF responsible for limb girdle muscular dystrophy type 2R and distal muscular dystrophy. Methods: Genotyping analyses were performed by qPCR using customized probe complementary to the region with the duplication under analysis in the DYSF. Results: A total of 104 individuals were examined. c.5979dupA was identified in 48 (46.15%) individuals. Twenty-three (22%) were homozygotes, among whom 13 (56.5%) were female. A total of 91.3% (21) of homozygous individuals had a positive family history, and seven (30.4%) reported consanguineous marriages. Twenty-five (24%) individuals were heterozygous (25.8±16 years) for the same variant, among whom 15 (60%) were female. The mean CK level was 697 IU for homozygotes, 140.5 IU for heterozygotes and 176 IU for wild-type homo-zygotes. The weakness distribution pattern showed 17.3% of individuals with a proximal pattern, 13% with a distal pattern and 69.6% with a mixed pattern. Fatigue was present in 15 homozygotes and one heterozygote. Conclusion: The high prevalence of this variant in individuals from this small community can be explained by a possible founder effect associated with historical, geographical and cultural aspects.
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INTRODUCTION/AIM: The most common limb girdle muscular dystrophy (LGMD) worldwide is LGMD type R1 (LGMDR1). The aim of this study was to correlate the MRI findings with functional scores and to describe the whole-body MRI (WBMRI) pattern in a LGMDR1 Brazilian cohort. METHODS: LGMDR1 patients under follow-up in three centers were referred for the study. Clinical data were collected and a functional evaluation was performed, consisting of Gardner-Medwin and Walton (GMW) and Brooke scales. All patients underwent a WBMRI study (1.5T) with axial T1 and STIR images. Fifty-one muscles were semiquantitatively assessed regarding fatty infiltration and muscle edema. RESULTS: The study group consisted of 18 patients. The highest fatty infiltration scores involved the serratus anterior, biceps femoris long head, adductor magnus, and lumbar erector spinae. There was a latero-medial and caudo-cranial descending gradient of involvement of the paravertebral muscles, with erector spinae being significantly more affected than the transversospinalis muscles (p < 0.05). A striped appearance that has been dubbed the "pseudocollagen sign" was present in 72% of the patients. There was a positive correlation between the MRI score and GMW (Rho:0.83) and Brooke (Rho:0.53) scores. DISCUSSION: WBMRI in LGMDR1 allows a global patient evaluation including involvement of the paraspinal muscles, usually an underestimated feature in the clinical and imaging study of myopathies. Knowledge of the WBMRI pattern of LGMDR1 involvement can be useful in the diagnostic approach and in future studies to identify the best target muscles to serve as outcome measures in clinical trials.
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Enfermedades Musculares , Distrofia Muscular de Cinturas , Humanos , Imagen por Resonancia Magnética/métodos , Músculo Esquelético/diagnóstico por imagenRESUMEN
INTRODUCTION: Down syndrome individuals have different gait patterns, which include specific characteristics such as foot rotation asymmetryOBJECTIVE: The aim of this study was to analyze the relationship between this asymmetry and the hands-and-knees crawling pattern before gait acquisition in Down syndrome children, as well as the possible association of this gait to gender, ethnicity, comorbidities, physiotherapy, and occupational therapy interventionsMETHODS: In this cross-sectional study, 361 children with or without foot rotation asymmetry were selected. An online questionnaire was administered to the parents or guardians of those childrenRESULTS: Hands-and-knees crawling decreased the prevalence of foot rotation asymmetry in Down syndrome children. The longer it took for walking onset, the higher the prevalence of this asymmetry. Indeed, for each month of delay, there was a 7% increase in prevalence. There was a significant relationship between orthopedic alterations in knees or flat feet and foot rotation asymmetry. There was no significance related to gender, ethnicity, other comorbidities, physiotherapy, or occupational therapy interventionsCONCLUSION: The findings in this study revealed that foot rotation asymmetry might be related to the acquisition of motor skills, hands-and-knees crawling and the walking onset
INTRODUÇÃO: As pessoas com síndrome de Down (SD) apresentam diferentes padrões de marcha, incluindo algumas características específicas como a marcha de base alargadaOBJETIVO: O objetivo deste estudo foi analisar a relação entre a marcha de base alargada e a aquisição motora engatinhar em quatro apoios adquiridas antes da marcha em crianças com SD, bem como a provável associação desta marcha com gênero, etnia, comorbidades e tratamentos de fisioterapia e terapia ocupacionalMÉTODO: Neste estudo transversal, foram selecionados 361 indivíduos que apresentaram ou não marcha de base alargada. Um questionário on-line foi administrado para pais / responsáveis destas criançasRESULTADOS: O engatinhar em quatro apoios diminuiu a prevalência da marcha de base alargada em crianças com SD. Quanto maior o tempo em meses para os primeiros-passos, maior a prevalência de base alargada, sendo que, a cada mês de atraso, a prevalência aumenta em 7%. Foi observada significância entre as alterações ortopédicas em joelhos e pés planos e a marcha de base alargada. Não foi encontrada significância relacionada a gênero, etnia, outras comorbidades, fisioterapia ou terapia ocupacionalCONCLUSÃO: Os achados deste estudo mostraram que o aparecimento da base alargada pode estar relacionado às aquisições motoras, engatinhar em quatro apoios, e aos primeiros passos
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Humanos , Masculino , Femenino , Postura , Estudios Transversales , Síndrome de Down , Locomoción , Destreza MotoraRESUMEN
INTRODUCTION: McArdle disease presents clinical and genetic heterogeneity. There is no obvious association between genotype and phenotype. PYGM (muscle glycogen phosphorylase gene) mRNA expression and its association with clinical, morphological, and genetic aspects of the disease as a set have not been studied previously. METHODS: We investigated genetic variation in PYGM considering the number of PTCs (premature termination codon) per sample and compared mRNA expression in skeletal muscle samples from 15 patients with McArdle disease and 16 controls to PTCs number and different aspects of the disease. RESULTS: The main variant found was c.148C>T (PTC-premature termination codon). Patients with two PTCs showed 42% mRNA expression compared to the control group. Most cases showed an inversely proportional relation among PTCs and mRNA expression. Association between mRNA expression and other aspects of the disease showed no statistically significant difference (p> 0.05). DISCUSSION: mRNA expression is not useful as a predictor factor for the prognosis and severity of the disease. Different mechanisms as post-transcriptional events, epigenetics factors or protein function may be involved.
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Demografía , Regulación Enzimológica de la Expresión Génica , Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Adulto , Codón sin Sentido/genética , Estudios Transversales , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo V/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo V/patología , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Adulto JovenRESUMEN
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
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
We examined nerve biopsies from 24 patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and proven 17p11.2-12 duplication. There were seven males and 17 females with a mean age of 27.85 +/- 18.95 years at the time of nerve biopsy. A family history consistent with dominant inheritance was present in 17 patients. Clinical features were classical in 16 patients and were atypical in the other eight: one had calf hypertrophy; two had Roussy-Levy syndrome; one had had a subacute inflammatory demyelinating polyneuropathy 11 years earlier and presented a relapse on the form of a chronic inflammatory demyelinating polyneuropathy; one had carpal tunnel syndrome; one had a recent painful neuropathy in both legs; and two had chronic inflammatory demyelinating polyneuropathy. Onion bulb formations (OMFs) were present in every case and most of them were characteristic, whereas burnt-out or cluster-associated OMFs were less common. Depletion of myelinated fibers was severe in 20 cases (169-2927/mm2) and varied from 5187 to 3725/mm2 in three children (4-9 years old). In addition, features of macrophage-associated demyelination were observed in the last four atypical cases. Known for more than 20 years, inflammatory demyelination superimposed in the course of CMT1A has been reported in a few cases in the past few years, mainly concerning asymptomatic or atypical patients. Such an association deserves to be better known because corticotherapy improves weakness in most of these patients.