Single-centre experience with autosomal recessive limb-girdle muscular dystrophy: case series and literature review / Experiência de um único centro em distrofia muscular de cinturas do tipo autossômica recessiva: série de casos e revisão de literatura

Abstract Limb-girdle muscular dystrophy (LGMD) is a group of myopathies that lead to progressive muscle weakness, predominantly involving the shoulder and pelvic girdles; it has a heterogeneous genetic etiology, with variation in the prevalence of subtypes according to the ethnic backgrounds and geographic origins of the populations. The aim of the present study was to analyze a series of patients with autosomal recessive LGMD (LGMD-R) to contribute to a better characterization of the disease and to find the relative proportion of the different subtypes in a Southern Brazil cohort. The sample population consisted of 36 patients with LGMD-R. A 9-gene targeted next-generation sequencing panel revealed variants in 23 patients with LGMD (64%), and it identified calpainopathy (LGMD-R1) in 26%, dysferlinopathy (LGMD-R2) in 26%, sarcoglycanopathies (LGMD-R3-R5) in 13%, telethoninopathy (LGMD-R7) in 18%, dystroglicanopathy (LGMD-R9) in 13%, and anoctaminopathy (LGMD-R12) in 4% of the patients. In these 23 patients with LGMD, there were 27 different disease-related variants in the ANO5, CAPN3, DYSF, FKRP, SGCA, SGCB, SGCG, and TCAP genes. There were different causal variants in different exons of these genes, except for the TCAP gene, for which all patients carried the p.Gln53* variant, and the FKRP gene, which showed recurrence of the p.Leu276Ile variant. We analyzed the phenotypic, genotypic and muscle immunohistochemical features of this Southern Brazilian cohort.

Resumo A distrofia muscular de cinturas (DMC) é um grupo de miopatias que leva à fraqueza muscular progressiva, e envolvendo predominante as cinturas escapular e pélvica. A DMCtem uma etiologia genética heterogênea, com variação na prevalência de subtipos de acordo com as origens étnicas e geográficas das populações. O objetivo deste estudo foi analisar uma série de pacientes com DMC do tipo autossômico recessivo (DMC-R) para contribuir para uma melhor caracterização da doença e encontrar a proporção relativa dos diferentes subtipos em uma coorte do Sul do Brasil. A população amostral foi composta por 36 pacientes com DMC-R. O painel de sequenciamento de nova geração com 9 genes revelou variantes em 23 pacientes com DMC (64%), e identificou calpainopatia (DMC-R1) em 26%, disferlinopatia (DMC-R2) em 26%, sarcoglicanopatias (DMC-R3-R5) em 13%, teletoninopatia (D-MCR7) em 18%, distroglicanopatia (D-MCR9) em 13%, e anoctaminopatia (DMC-R12) em 4% dos pacientes. Nesses 23 pacientes com DMC, havia 27 variantes diferentes nos genes ANO5, CAPN3, DYSF, FKRP, SGCA, SGCB, SGCG e TCAP. Foram encontradas diferentes variantes em diferentes éxons desses genes, com exceção do gene TCAP, para o qual todos os pacientes eram portadores da variante p.Gln53*, e do gene FKRP, que apresentou recorrência da variante p.Leu276Ile. As características fenotípicas, genotípicas e imuno-histoquímicas musculares desta coorte do Sul do Brasil foram analisadas.

Fisioterapia aquática em paciente com distrofia muscular de cinturas do tipo 2b: relato de caso / Aquatic Physical therapy in a patient with Limb-Girdle Muscular Dystrophy, type 2b: a case report

INTRODUÇÃO: A distrofia muscular de cinturas do tipo 2B (DMC2B) é uma doença neuromuscular, degenerativa, rara, hereditária, progressiva, com consequentes prejuízos progressivos na capacidade motora e funcional. OBJETIVO: descrever e analisar os efeitos da fisioterapia aquática sobre a funcionalidade, força muscular, amplitude de movimento e qualidade de vida de uma paciente com diagnóstico DMC2B atendida em projeto de extensão universitária. MÉTODOS: Paciente do sexo feminino, 32 anos, solteira, com diagnóstico genético de Distrofia Muscular de Cinturas do Tipo 2B, nível 3 da escala Vignos (modificada por Garder-Medwin e Walton). O relato de caso apresenta a reabilitação através da Fisioterapia Aquática (hidrocinesioterapia) e seus impactos sobre a força muscular, amplitude de movimento, capacidade funcional e qualidade de vida da paciente (CAAE No. 43505321.0.0000.0018). RESULTADOS: O protocolo de fisioterapia aquática, composto por 12 sessões, 60 min/2x/semana, resultou em melhoras na capacidade funcional global e aumento de 9,52% na avaliação da função motora distal, aumentos de 100% da força de preensão manual e aumento para o limite superior (grau 5) na escala MRC para várias das musculaturas testadas, além de ganho de ADM e melhora expressiva da Qualidade de Vida. CONCLUSÃO: A melhora funcional apresentada pela paciente sugere que a reabilitação funcional fundamentada na fisioterapia aquática, em intensidade leve a moderada, é uma opção terapêutica segura e eficaz para a melhora da força muscular, amplitude de movimento, capacidade funcional e qualidade de vida na DMC2B.

INTRODUCTION: Limb-Girdle Muscular Dystrophy, Type 2B (LGMD2B), is a rare, hereditary, progressive neuromuscular degenerative disease coursing with progressive impairments in motor and functional capacity. OBJECTIVE: To describe and analyze the effects of aquatic physical therapy on the functionality, muscle strength, range of motion, and quality of life of a patient diagnosed with LGMD2B attended on an outreach program. METHODS: A female patient, 32 years old, single, with genetic diagnosis of LGMD2B, level 5 at Vignos scale (modified by Garder-Medwin e Walton). The case reports the Aquatic Physical Therapy rehabilitation protocol (hydrokinesiotherapy) and its impacts on muscle strength, range of motion, functional capacity, and patient quality of life (CAAE No. 43505321.0.0000.0018). RESULTS: The aquatic physical therapy protocol, composed of 12 sessions, 60 minutes/2x/week, resulted in improvements in overall functional capacity and a 9.52% increase of distal motor function, 100% increase in handgrip strength, and increase up to the upper limit (grade 5) on the MRC scale for several of the muscles tested, in addition to increased range of motion and expressive improvement in Quality of Life. CONCLUSION: The patient' functional improvement suggests that water-based physical therapy rehabilitation, at mild to moderate exercise intensity, is a safe and effective therapeutic option for improvement muscle strength, range of motion, functional capacity, and quality of life in LGMD2B patients.

Qualidade de vida em crianças e adolescentes com doenças neuromusculares e validação de dois questionários para o português: Life Satisfaction Index for Adolescents - LSI-A e Pediatric Quality of Life Inventory Duchenne Muscular Dystrophy Module / Quality of life in children and adolescents with neuromuscular diseases and validation of two questionnaires into Portuguese: Life Satisfaction Index for Adolescents - LSI-A and Pediatric Quality of Life Inventory Duchenne Muscular Dystrophy Module - PedsQL DMD

As distrofias musculares progressivas e a amiotrofia espinhal progressiva (AEP) são doenças neuromusculares (DNM) caracterizadas pela degeneração irreversível das fibras musculares, a qual leva à fraqueza muscular e à incapacidade motora. Qualidade de Vida Relacionada à Saúde (QVRS) inclui subjetividade, multidimensionalidade, aspectos negativos e positivos diante da percepção e da expectativa individual de vida; sofre influência cultural. JUSTIFICATIVA: A avaliação da QVRS é essencial para definir a resposta ao tratamento multidisciplinar ou efetivo do paciente com DNM e para sinalizar medidas destinadas a incrementar o sucesso terapêutico. OBJETIVOS: Validar os questionários Life Satisfaction Índex for Adolescents (LSI-A) versão pais e versão paciente e Pediatric Quality of Life Inventory Duchenne (PedsQL DMD) versão pais e versão paciente para o português; avaliar a QVRS dos pacientes com distrofia muscular de Duchenne (DMD), amiotrofia espinhal progressiva (AEP) ou distrofia muscular de cinturas (DMC); avaliar a QV familiar e da mãe/cuidadora. METODOLOGIA: Os questionários LSI-A e PedsQL DMD foram validados obedecendo às etapas de adaptação cultural e validação. Após validação, o questionário LSI-A foi aplicado a pacientes com DMD, AEP ou DMC; o PedsQL Duchenne foi aplicado aos pacientes com DMD e o PedsQL NM a pacientes com AEP ou DMC. Os pais dos pacientes responderam ao FQoL e as mães/cuidadoras ao WHOQOL-Bref. Para cálculo estatístico utilizaram-se: testes alfa de Cronbach, CIC, Pearson, Curva ROC para a validação, e Mann Whitney, Friedman e Dunn para a aplicação. RESULTADOS: Quanto à validação: Probe final do LSI-A versão pais, 97% e versão paciente, 95%; PesdQL DMD versão pais, 99% e versão paciente, 97%, sinalizando compreensão excelente; o teste ? de Cronbach no LSI-A versão pais e paciente, respectivamente, obteve escore geral 0.87 e 0.89; no PesdsQL versão pais e versão paciente, respectivamente, escore geral 0.87 e...

Progressive muscular dystrophies and spinal muscular atrophy (SMA) are neuromuscular diseases (NMD) characterized by irreversible degeneration of muscle fibers which leads to muscle weakness and motor disability. Health-related quality of life (HRQoL) includes subjectivity, multidimensionality, negative and positive aspects on the perception and individual life expectancy; in addition, it suffers cultural influences. BACKGROUND: The assessment of HRQoL is essential to define the response to the multidisciplinary or effective treatment of patients with NMD and to indicate measures to increase the therapeutic success. OBJECTIVES: to validate to the Portuguese the following HRQoL instruments for patients with NMD: Life Satisfaction Index for Adolescents (LSI-A) and Pediatric Quality of Life Inventory Duchenne (PedsQL Duchenne); to evaluate the HRQoL of patients with Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) or limb girdle muscular dystrophy (LGMD), and to assess the family and caregiver QoL. METHODOLOGY: The LSI-A and PedsQL Duchenne questionnaires were validated obeying the stages of cultural adaptation and validation. After validation, the LSI-A questionnaire was administered to patients with DMD, SMA or LGMD, the PedsQL Duchenne to patients with DMD, and the PedsQL NM to patients with SMA or LGMD. Parents of patients responded to FQoL and mothers/caregiver to WHOQOL-Bref. For statistical calculations were used: ? test Cronbach, CIC, Pearson, ROC curve for validation, and Mann Whitney, Friedman and Dunn for the application. RESULTS: Validation: the final "Probe" of the LSI-A parents version was 97% and patient version, 95%; PesdQL DMD parents version, 99% and patient version, 97%, indicating excellent comprehension; Cronbach's alfa test at LSI-A parents and patients version, respectively, achieved overall score 0.87 and 0.89; at PesdsQL parents and patient version, respectively, were obtained overall score 0.87 and 0.84. At...

Muscle magnetic resonance imaging changes and relationship with clinical symptoms in patients with dysferlinopathy / 中华神经科杂志

Objective To investigate the characteristics of muscle edema and fatty infiltration in thighs and relationship with clinical symptoms in Chinese patients with different phenotypes of dysferlinopathy.Methods A total of 32 patients were enrolled , including 13 limb-girdle muscular dystrophy 2B (LGMD2B), 13 Miyoshi myopathy (MM), 4 proximodistal myopathy and 2 hyper-creatine-kinase-emia.Clinical symptoms were evaluated using modified Gardner-Medwin and Walton ( GM-W) score.Muscle MRI was performed in thighs to observe fatty infiltration and edema.We then compared the age of onset , disease duration, GM-W score, muscle edema and muscle fatty infiltration between LGMD 2B and MM groups,and the relationship of muscle edema score and fatty infiltration score with disease duration and GM-W score in all patients.Results The median GM-W score was 4.00 (2.00,5.00) in all patients, 4.00 (3.00,4.50)in LGMD2B and 4.00(2.00,5.00)in MM, respectively.Muscle fatty infiltration appeared in 30 cases (93.75%), with the same pattern in LGMD2B and MM.The mean fatty infiltration score was 28.20 ±12.86 in all patients, 28.50 ±13.03 in LGMD2B and 29.00 ±12.63 in MM, respectively.Muscle edema appeared in 26 cases (81.25%) with same pattern in LGMB2B and MM.The mean edema score was 18.36 ±13.60 in all patients, 22.88 ±11.59 in LGMD2B and 16.77 ±13.80 in MM.The age of onset , disease duration, GM-W score, muscle fatty infiltration and edema score were not significantly different between LGMD2B and MM patients.Muscle fatty infiltration score significantly correlated with GM-W score (rs=0.737,P=0.000) and disease duration (rs=0.637,P=0.000).Conclusions Fatty infiltration and edema in thigh muscles are very common in patients with dysferlinopathy , with similar radiological changes in main subtypes.The muscle fatty infiltration can be used as a predictor of disease progression.

Clinical and pathological analysis of seven patients with limb-girdle muscular dystrophy 2B / 中国医师进修杂志

Objective To analyze the clinical and pathological features of limb-girdle muscular dystrophy2B(LGMD2B).Methods The clinical and pathological features of 7 patients with LGMD2B were analyzed retrospectively.Results Seven patients had a slow onset,and progressive proximal muscle weakness,muscle atrophy,progressive,and incresed serum creatine phosphokinase; muscle biopsy showed different degree of muscle fiber degeneration,necrosis; stromal and inflammatory cell infiltration in muscle fiber; monoclonal antibody immunohistoehemical staining:showed expression of Dysferlin protein was not found in muscle cell membrane,Dystrophin,Sarcoglycans protein expression was normal.Monoclonal antibody immunohistochemical staining the proteins were expressed in normal cell membrane.Conclusions LGMD2B is a slow onset,progressive proximal muscle weakness,muscle atrophy.Histochemical staining on the basis of further immunohistochemical staining,to detect the membrane protein and Dysferlin protein expression,that is a necessary means to diagnose LGMD2B and inflammatory myopathies.

An analysis of clinical features and pathology in 40 patients with dysferlinopathy / 中华神经科杂志

Objective To analyze retrospectively the clinical manifestations,features of the biopsy of skeletal muscle with histochemistry and immunohistochemistry staining of 40 patients with dysferlinopathy and investigate its clinical,pathological diagnostic value.Methods The clinical data,features of the biopsy of skeletal muscle with histochemistry,immunohistochemistry staining of 40 patients with dysferlinopathy were analyzed.Results Chronic progressive weakness and wasting were the general clinical manifestations.In our study,it was divided into three phenotypes according to the involved muscles of dysferlinopathy:27 cases with proximal muscle,12 cases with the gastrocenemius,1 case with the tibialis anterior muscle.The serum creatine kinase levels all had a rise in different degree (134-19 795 U/L).All the patients showed myogenic lesions in electrophysiologic study.12 patients underwent skeletal muscle MRI.Proximal muscle was involved in 4 cases ; gastrocnemius muscle was mainly involved in 7 cases ; and anterior tibial muscle initially was involved in 1 case.All 40 cases showed active muscle fiber degeneration,necrosis and regeneration on muscle pathology.Connective tissues were proliferated and inflammatory cells infiltrated in endomysium,perimysium and perivascular sites of 16 patients.Immunohistochemical staining with anti-dysferlin monoclonal antibody identified the deficiency of dvsferlin in the sarcolemma of 30 cases with dysferlinopathy,and dysferlin was severely reduced in 10 cases.Conclusion Progressive weakness and wasting of skeletal muscle are the clinical manifestations of dysferlinopathy.The early involved muscles determine the clinical phenotype of dysferlinopathy.High serum creatine kinase levels show that dysferlinopathy is a membrane protein null disease.Muscle MRI of lower limbs may reflect the involved muscles,which is essential for clinical phenotypes and selecting muscle biopsy.The pathological characters of dysferlinopathy are changes of muscular dystrophy.Inflammatory cellular infiltration is relatively common in biopsied muscles of many dysferlinopathy patients,and dysferlinopathy needs to be differentiated from inflammatory myopathies.The deficiency or severely decreased dysferlin on the sarcolemma in immunohistochemical staining with anti-dysferlin monoclonal antibody is an important information for diagnosing dysferlinoapthy.

Clinical features and molecular genetic analysis of a pedigree of limb girdle muscular dystrophy / 中华神经科杂志

Objective To investigate the clinical features and analyze the molecular genetics of a pedigree of limb girdle muscular dystrophy (LGMD).Methods Pedigree analysis and clinical examination were performed in one four-generation family with LGMD.Electrophysiology and muscle biopsy were done in the affected members.With an informed consent, gene mutation, genome screening and linkage analysis were conducted in 26 members of this pedigree.Results Seven patients were identified.Pedigree analysis was consistent with autosomal dominant inheritance.Affected members had early presentation.Main features included proximal muscle weakness without dysarthria nor spasticity; electrophysiology and muscle biopsy revealed myopathic changes.LGMD1 A, 1B, 1C and facioscapulohumeral dystrophy genes were not detected by gene mutation analysis.Genome screening and linkage analysis did not reveal any linkage with the disease-causing gene and the reported loci of LGMD1D and LGMD1F genes.Conclusions The clinical manifestations of this LGMD family are highly heterogeneous, and the disease-causing gene of this family is not linked to any of the reported sites, suggesting this may be a new disease-causing locus, or a new genetic type of LGMD.

Diagnosing limb-girdle muscular dystrophy type 2A by Western blot analysis / 中华神经科杂志

Objective To evaluate Western blot analysis in diagnosing limb-girdle muscular dystrophy type 2A (LGMD2A). Methods The clinical records including their pathological and biochemical results of 4 patients with LGMD type 2 were reviewed. Histochemical and immunohistochemical staining were performed on muscle biopsy specimens from the four patients. The expressions of dysferlin and calpain-3 in muscles were analyzed by Western biol. Results All 4 LGMD patients shared some common clinical features, such as dorsal muscular atrophy of lower limbs and remarkably elevated CK. The immunohistochemical results showed partial or complete deficiency of dysferlin staining in all 4 LGMD patients. However, Western blot revealed that the calpain-3 protein in the muscle of patient 1 was completely absent, who was later diagnosed with LGMD2A. The other 3 patients had complete dysferlin deficiency with reduced calpain-3 expression and they were confirmed to be LGMD2B. Conclusions Western blot analysis of calpain-3 and dysfcrlin can be used to differentiate LGMD2A which shows absence of calpain-3 from other LGMD types which show dysferlin deficiency. Western blot is an invaluable method in clinical diagnosis of LGMD2A.

Diagnosis of limb-girdle muscular dystrophy type 2A using Western blot with micro-sample / 中华神经科杂志

Objective To diagnose limb-girdle muscular dystrophy type 2A(LGMD2A)using Western blot with micro-sample.nethods Skeletal muscle specimens of 73 cases of progressive muscular dystrophy with prominent proximal muscle involvement were obtained by open biopsy,and underwent histochemical,immunohistochemical stains with anti-dystrophin-N,C,R,α,β,γ,δ-sarcoglycan,dysferlin,caveolin-3 monoclonal antibodies.Twenty-nine cases were excluded with deficiency of dystrophin,sarcoglycans,dysferlin and caveolin-3,then Western blot and immunoreaction were performed with anti-calpain-3,caveolin-3 monoclonal antibodies.Results Ten cases with LGMD2A were diagnosed,all presenting muscle weakness of the proximal limb and elevated creatine kinase in vacant levels.and electromyography showed myogenic change.Histochemical stains showed variation in fiber size,different extent of degeneration,regeneration and necrosis,increased connective tissue elements,while lobulated fibers presented in 6 cases.Immunohistochemical stains identified dystrophin,sarcoglycans,dysferlin and caveolin-3 expressed normal in muscle fibers.Western blot,compared with the control,confirmed that the bands at 94 000 were absent(8 cases)or partly(2 cases)deficient:The additional bands at 30 000expressed weakly;The bands at 22 000 were normal.Conclusion Western blot analysis with microspecimen of skeletal muscle is an effective modality to diagnose LGMD2A,and is suitable to diagnose the sub-type of LGMD in clinic.