Analysis of clinical characteristics and genetic variants in two children with Limb-girdle muscular dystrophy autosomal recessive 9 FKRP-related / 中华医学遗传学杂志

OBJECTIVE@#To explore the correlation between clinical manifestations of Limb-girdle muscular dystrophy autosomal recessive 9 FKRP-related (R9 FKRP-related) and variants of the FKRP gene.@*METHODS@#Two children who had presented at the Children's Hospital of Nanjing Medical University respectively due to increased serum myocardial zymogram and hepatic dysfunction on September 30, 2018 and August 3, 2018 were selected as the study subjects. Clinical data of the children were collected. Both children were suspected for Duchenne or Becker muscular dystrophy for asymptomatic high creatine kinase (CK) levels. Peripheral blood samples of the children and their parents were collected for whole exome sequencing, and candidate variants were validated by Sanger sequencing.@*RESULTS@#Genetic testing revealed that both children have carried compound heterozygous variants of the FKRP gene. The c.545A>G and c.941C>T variants in child 1 have been reported previously, among which the c.545A>G is a hot spot mutation in the Chinese population. Child 2 has carried c.602T>C and c.961G>A variants, both of which were unreported previously.@*CONCLUSION@#Both children have met the diagnostic criteria for LGMD R9 FKRP-related. Carriers of the c.545A>G variant may present milder symptoms. Compared with patients carrying null variants, carriers of compound heterozygous missense variants may present with a milder phenotype, manifesting as asymptomatic high CK level.

Analysis of genetic variants in five pedigrees affected with Dysferlinopathy / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic variants in five Chinese pedigrees affected with Dysferlinopathy.@*METHODS@#Next generation sequencing (NGS) was carried out for the probands from the five pedigrees. Suspected variants were validated by Sanger sequencing. Pathogenicity of the variants was assessed based on the standards and guidelines by the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#Ten DYSF gene variants (including 5 frameshift variants, 3 splicing variants, 1 missense variant and 1 nonsense variant) were detected. Among these, c.1375dupA (p.Met459Asnfs*15), c.610C>T (p.Arg204X), c.1180+5G>A and c.1284+2T>C were known to be pathogenic, while c.4008_4010delCCTinsAC (p.Leu1337Argfs*8), c.1137_1169del (p.379_390del), c.754A>G(p.Thr252Ala), c.1175_1176insGCAGAGTG (p.Met394Serfs*7), c.3114_3115insCGGC (p.Arg1040Profs*74) and c.1053+3G>C were unreported previously. Of the six novel variants, c.1137_1169del, c.1175_1176insGCAGAGTG and c.3114_3115insCGGC were predicted as pathogenic (PVS1+PM2+PM3), c.4008_4010delCCTinsAC as likely pathogenic (PVS1+PM2), c.754A>G and c.1053+3G>C as variants of uncertain significance based on the ACMG standards and guidelines.@*CONCLUSION@#Variants of the DYSF gene probably underlay Dysferlinopathy in the patients among the five pedigrees. Above finding has enriched the spectrum of DYSF gene variants.

Motor learning through a non-immersive virtual task in people with limb-girdle muscular dystrophies / Aprendizagem motora por meio de tarefa virtual não imersiva em pessoas com distrofia muscular de cinturas

INTRODUCTION: Limb-girdle muscular dystrophies (LGMDs) are neuromuscular and genetic disorders that progress with weakness and damage of the proximal muscles, developing with loss of functionality. Virtual reality environments are suggested as an effective alternative for performance of daily life activities. However, there is no evidence in the literature on the use of virtual reality in this populationOBJECTIVE: Assess motor performance through a motor learning protocol in a coincident timing taskMETHODS: 10 participants with LGMD and 10 healthy individuals were selected and included in the study to perform a non-immersive virtual reality task divided into three phases: acquisition (20 attempts), retention (5 attempts), and transfer (5 attempts, with speed increaseRESULTS: It is observed that the accuracy of movement improves from the beginning to the end of the acquisition (p = 0.01); however, there is a marginal difference between the groups in block A1 (p = 0.089). Regarding the variability of touches, observed by the variable error, both groups improved performance in all phasesCONCLUSION: Even with lower performance than the control group at the beginning of the practice, individuals with LGMD showed the potential to optimize motor function during the practice of a non-immersive virtual reality activity and were able to match their performance with the control group after a few attempts

INTRODUÇÃO: As distrofias musculares de cinturas (DMC) são distúrbios neuromusculares e genéticos que progridem com fraqueza e dano dos músculos proximais, desenvolvendo-se com perda de funcionalidade. Sugere-se ambientes de realidade virtual como uma alternativa eficaz para o desempenho das atividades da vida diária. No entanto, não há evidências na literatura sobre o uso da realidade virtual nessa populaçãoOBJETIVO: Avaliar o desempenho motor através de um protocolo de aprendizagem motora em uma tarefa de timing coincidenteMÉTODO: 10 participantes com DMC e 10 indivíduos saudáveis foram selecionados e incluídos no estudo para realizar uma tarefa de realidade virtual não imersiva dividida em três fases: aquisição (20 tentativas), retenção (5 tentativas) e transferência (5 tentativas, com aumento de velocidadeRESULTADOS: Observou-se que a acurácia do movimento melhorou do início ao final da aquisição (p = 0,01); no entanto, existe uma diferença marginal entre os grupos no bloco A1 (p = 0,089). Em relação à variabilidade de toques, observada pelo erro variável, ambos os grupos melhoraram o desempenho em todas as fasesCONCLUSÃO: Mesmo com desempenho inferior ao grupo controle no início da prática, os indivíduos com DMC mostraram potencial para otimizar a função motora durante a prática de uma atividade de realidade virtual não imersiva e foram capazes de corresponder seu desempenho com o grupo controle após poucas tentativas

Distrofia muscular de cinturas 2J, revisión bibliográfi-ca y reporte de un caso pediátrico en Ecuador / 2J girdle muscular dystrophy, bibliographic review and report of a pediatric case in Ecuador

RESUMEN La distrofia muscular de cinturas de las extremidades (LGMD, por sus siglas en inglés) incluye varios trastornos con etiologías heterogéneas. Se heredan en patrón autosómico recesivo o autosómico dominante y constituyen la cuarta causa genética más común de debilidad muscular, reportando una prevalencia de 1 en 20,000. Las manifestaciones clínicas son inespecíficas, pueden presentarse desde la primera infancia hasta la edad adulta, dependiendo del subtipo de la enfermedad y de la proteína afectada. El diagnóstico inicial se realiza mediante pruebas genéticas antes de obtener una biopsia muscular. Hasta la actualidad no hay tratamientos que modifiquen la evolución de la enfermedad. El propósito de la terapia es conservar la independencia funcional y tratar las complicaciones asociadas, manteniendo al máximo la calidad de vida.A continuación se reporta el caso de un paciente pediátrico, residente en Quito, Ecuador sin antecedentes patológicos ni familiares previos, con alteración de la motricidad fina progresiva dado por trastorno motor en manos, dedos en flexión, hipotrofia de eminencias tenar e hipotenar y atrofia de interóseos de manos, se realizan estudios en relación a neuropatía periférica distal con afectación de sensibilidad bilateral y simétrica, encontrando como única variante, cambios electromiográficos: polineuropatía crónica, sensitiva y motora de predominio axonal, (desmielinizante en menor grado), de grado marcado presumi-blemente de etiología hereditaria. El diagnostico final lo determinó estudio genético con mutación del gen TTN en relación con: Distrofia muscular de cinturas, tipo 2J (CINTURA ESCAPULAR DE PREDOMINIO DISTAL).

ABSTRACT Limb girdle muscular dystrophy (LGMD) includes several disorders with heterogeneous etiologies. They are inherited in an autosomal recessive or autosomal dominant pattern and constitute the fourth most common genetic cause of muscle weakness, reporting a prevalence of 1 in 20,000. The clinical manifestations are nonspecific, can begin from early childhood to adulthood depending on the subtype of the disease and the protein affected. The initial diagnosis is made by genetic testing before obtaining a muscle biopsy. To date there are no treatments that modify the evolution of the disease. The purpose of therapy is to preserve functional independence and treat associated complications, maintaining quality of life as much as possible.The following is the case of a pediatric patient, resident in Quito, Ecuador with no prior family or pathological history, with progressive fine motor disorder due to motor disorder in the hands, flexed fingers, hypotrophy of tenar and hypothenar eminences, and atrophy of interosseous hands, studies are performed in relation to distal peripheral neuropathy with bilateral and symmetrical sensitivity involvement, finding electromyographic changes as the only variant: chronic, sensitive and motor polyneuropathy with axonal predominance (demyelinating to a lesser degree), of marked degree presumably of hereditary etiology. The final diagnosis was determined by a genetic study with a mutation of the TTN gene in relation to: Girdle Muscular dystrophy, type 2J (DISTAL PREDOMINANT SCAPULAR GIRDLE).

Deficiency of Anoctamin 5/TMEM16E causes nuclear positioning defect and impairs Ca²⁺ signaling of differentiated C2C12 myotubes

Anoctamin 5 (ANO5)/TMEM16E belongs to a member of the ANO/TMEM16 family member of anion channels. However, it is a matter of debate whether ANO5 functions as a genuine plasma membrane chloride channel. It has been recognized that mutations in the ANO5 gene cause many skeletal muscle diseases such as limb girdle muscular dystrophy type 2L (LGMD2L) and Miyoshi muscular dystrophy type 3 (MMD3) in human. However, the molecular mechanisms of the skeletal myopathies caused by ANO5 defects are poorly understood. To understand the role of ANO5 in skeletal muscle development and function, we silenced the ANO5 gene in C2C12 myoblasts and evaluated whether it impairs myogenesis and myotube function. ANO5 knockdown (ANO5-KD) by shRNA resulted in clustered or aggregated nuclei at the body of myotubes without affecting differentiation or myotube formation. Nuclear positioning defect of ANO5-KD myotubes was accompanied with reduced expression of Kif5b protein, a kinesin-related motor protein that controls nuclear transport during myogenesis. ANO5-KD impaired depolarization-induced [Ca²⁺]i transient and reduced sarcoplasmic reticulum (SR) Ca²⁺ storage. ANO5-KD resulted in reduced protein expression of the dihydropyridine receptor (DHPR) and SR Ca²⁺-ATPase subtype 1. In addition, ANO5-KD compromised co-localization between DHPR and ryanodine receptor subtype 1. It is concluded that ANO5-KD causes nuclear positioning defect by reduction of Kif5b expression, and compromises Ca²⁺ signaling by downregulating the expression of DHPR and SERCA proteins.

Research advances in limb-girdle muscular dystrophy type 2Q / 中国当代儿科杂志

Limb-girdle muscular dystrophy (LGMD) is a group of muscular dystrophies with predominantly proximal muscular weakness, and some genes associated with this disease have been identified at present. LGMD type 2Q (LGMD2Q) is a subtype of LGMD and is associated with PLEC gene mutation. Major phenotypes of PLEC gene mutation include epidermolysis bullosa with late-onset muscular dystrophy and epidermolysis bullosa with other lesions. LGMD2Q without skin lesions is rarely reported. This article reviews the pathogenic gene PLEC and clinical manifestations of LGMD2Q, so as to deepen the understanding of the pathogenic gene and phenotype of LGMD2Q.

Progression of GNE Myopathy Based on the Patient-Reported Outcome

BACKGROUND AND PURPOSE: GNE myopathy is a rare progressive myopathy caused by biallelic mutations in the GNE gene, and frequently accompanied by rimmed vacuoles in muscle pathology. The initial symptom of foot drop or hip-girdle weakness eventually spreads to all limbs over a period of decades. Recent advances in pathophysiologic research have facilitated therapeutic trials aimed at resolving the core biochemical defect. However, there remains unsettled heterogeneity in its natural course, which confounds the analysis of therapeutic outcomes. We performed the first large-scale study of Korean patients with GNE myopathy. METHODS: We gathered the genetic and clinical profiles of 44 Korean patients with genetically confirmed GNE myopathy. The clinical progression was estimated retrospectively based on a patient-reported questionnaire on the status of the functional joint sets and daily activities. RESULTS: The wrist and neck were the last joints to lose antigravity functionality irrespective of whether the weakness started from the ankle or hip. Two-thirds of the patients could walk either independently or with an aid. The order of losing daily activities could be sorted from standing to eating. Patients with limb-girdle phenotype showed an earlier age at onset than those with foot-drop onset. Patients with biallelic kinase domain mutations tended to progress more rapidly than those with epimerase and kinase domain mutations. CONCLUSIONS: The reported data can guide the clinical management of GNE myopathy, as well as provide perspective to help the development of clinical trials.

Variant analysis for a pedigree affected with limb-girdle muscular dystrophy type 2D / 中华医学遗传学杂志

OBJECTIVE@#To analyze variant of SGCA gene in a Chinese pedigree affected with limb-girdle muscular dystrophy type 2D with whole exome sequencing (WGS).@*METHODS@#Multiplex ligation-dependent probe amplification (MLPA) was employed to detect large fragment deletion or duplication of the DMD gene. FastTarget next generation sequencing was used to detect variants of the DMD gene, and the result was verified by Sanger sequencing. After excluding the diagnosis of DMD for the proband, WGS was applied to test the proband and his parents. Suspected pathogenic variants were validated by Sanger sequencing.@*RESULTS@#No variant, deletion or duplication of the DMD gene was detected. Whole exome sequencing showed that the proband has carried compound heterozygous missense variants c.409G>A (p.Glu137Lys) and c.409G>C (p.Glu137Gln) in exon 5 of the SGCA gene, which were respectively inherited from his mother and father. Neither variant was found in DNA derived from the cord blood sample.@*CONCLUSION@#The c.409G>A (p.Glu137Lys) and c.409G>C (p.Glu137Gln) compound heterozygous missense variants probably underlie the disease in the proband. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.

Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation? / Doença de Pompe de início tardio: qual é a prevalência na apresentação de fraqueza muscular de cinturas?

ABSTRACT Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

RESUMO A doença de Pompe é uma doença hereditária causada pela deficiência da enzima alfa-glicosidase ácida (GAA). Estudo observacional foi realizado, em um único centro, para determinar a prevalência da doença de Pompe de início tardio (LOPD) em uma população brasileira de alto risco, usando teste em gota seca (DBS) como ferramenta principal de triagem para detectar a deficiência da GAA. DBS foi coletado para avaliar a atividade da GAA em 24 pacientes com fraqueza muscular de cinturas "não explicada" sem miopatia vacuolar na biópsia muscular. As amostras com atividade enzimática reduzida foram também submetidas a análise de mutações no gene GAA. Dos 24 pacientes com DBS, baixa atividade da enzima GAA (NaG/AaGIA: 40.42; %INH: 87.22%) foi encontrada em um paciente (4.2%). Nessa paciente, a análise genética confirmou duas mutações em heterozigose composta no gene GAA (c.-32-13T > G/p.Arg854Ter). Nossos resultados confirmam que LOPD deve ser investigada quando a manifestação clínica é uma fraqueza muscular de cinturas "não explicada", mesmo na ausência de miopatia vacuolar na biópsia muscular.

Two Korean Families with Limb-Girdle Muscular Dystrophy Type 1D Associated with DNAJB6 Mutations

Limb-girdle muscular dystrophies (LGMD) are heterogeneous disorders with autosomal inheritance. Autosomal dominant LGMD mapped to 7q36.3 has been classified as LGMD type 1D (LGMD1D) in the Human Gene Nomenclature Committee Database. LGMD1D is characterized predominantly by limb-girdle weakness and may also show a bulbar symptom in some cases. In the past, the frequency of this disease was uncommon, and this disorder was mainly found in Europe and the United States. However, recently, this disorder has been reported in Asia, including Japan, Korea, and Taiwan. Here, we report on three LGMD1D patients, including one with a novel mutation in DNAJB6, c.298T>A. While two patients complained of limb-girdle weakness, as would be expected, one patient had distal weakness. They had various serum creatine kinase levels. Radiologic findings in one patient showed fatty degeneration and atrophy in the posterior part of distal muscles. Pathologic findings in one of the patients showed rimmed vacuoles. Although LGMD1D is still uncommon in Korea, we discovered three Korean patients with LGMD1D, including one novel mutation in DNAJB6, p.Phe100Ile (c.298T>A).

Muscle Magnetic Resonance Imaging in Patients with Various Clinical Subtypes of -Related Muscular Dystrophy / 中华医学杂志(英文版)

<p><b>Background</b>LMNA-related muscular dystrophy can manifest in a wide variety of disorders, including Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), and LMNA-associated congenital muscular dystrophy (L-CMD). Muscle magnetic resonance imaging (MRI) has become a useful tool in the diagnostic workup of patients with muscle dystrophies. This study aimed to investigate whether there is a consistent pattern of MRI changes in patients with LMNA mutations in various muscle subtypes.</p><p><b>Methods</b>Twenty-two patients with LMNA-related muscular dystrophies were enrolled in this study. MRI of the thigh and/or calf muscles was performed in them. The muscle MRI features of the three subtypes were compared by the Mann-Whitney U-test. The relationship between the clinical and MRI findings was also investigated by Spearman's rank analyses.</p><p><b>Results</b>The present study included five EDMD, nine LGMD, and eight L-CMD patients. The thigh muscle MRI revealed that the fatty infiltration of the adductor magnus, semimembranosus, long and short heads of the biceps femoris, and vasti muscles, with relative sparing of the rectus femoris, was the predominant change observed in the EDMD, LGMD, and advanced-stage L-CMD phenotypes, although the involvement of the vasti muscles was not prominent in the early stage of L-CMD. At the level of the calf, six patients (one EDMD, four LGMD, and one L-CMD) also showed a similar pattern, in which the soleus and the medial and lateral gastrocnemius muscles were most frequently observed to have fatty infiltration. The fatty infiltration severity demonstrated higher scores associated with disease progression, with a corresponding rate of 1.483 + 0.075 × disease duration (X) (r = 0.444, P = 0.026). It was noteworthy that in six L-CMD patients with massive inflammatory cell infiltration in muscle pathology, no remarkable edema-like signals were observed in muscle MRI.</p><p><b>Conclusions</b>EDMD, LGMD and advanced-staged L-CMD subtypes showed similar pattern of muscle MRI changes, while early-staged L-CMD showed somewhat different changes. Muscle MRI of L-CMD with a muscular dystrophy pattern in MRI provided important clues for differentiating it from childhood inflammatory myopathy. The fatty infiltration score could be used as a reliable biomarker for outcome measure of disease progression.</p>

A Family of Bethlem Myopathy Caused by a Heterozygous COL6A1 Mutation

Collagen-VI-related myopathies are caused by mutations in the COL6A1, COL6A2, and COL6A3 and are known to have a wide phenotypic spectrum, including Bethlem myopathy, Ullrich congenital muscular dystrophy, intermediate phenotype, and limb-girdle muscular dystrophy. These patients present with joint hyperextensibility and/or contractures as well as skin changes and muscle weakness, and so clinicians need to notice those extramuscular symptoms in order to achieve a correct diagnosis. We describe the clinical, pathological, and radiological features in a family with Bethlem myopathy caused by a COL6A1 mutation.

Clinical and genetic features of limb-girdle muscular dystrophy type 1B: a case report / 中国当代儿科杂志

This article reports a case of limb-girdle muscular dystrophy type 1B (LGMD1B) caused by a novel splicing heterozygous mutation in the LMNA gene. The proband presented with progressive aggravation of weakness in walking. There was no atrophy of the scapular muscles and the lower-extremity proximal muscles, with normal muscle tension of the extremities, grade 4 muscle strength in the upper and lower extremities, and positive Gower sign. The level of creatine kinase was 779 U/L. Muscle hematoxylin-eosin staining showed muscular dystrophy, and there was no significant reduction in the expression of Lamin A protein. Second-generation sequencing revealed a novel splicing heterozygous mutation, c.810+2T>C, in the LMNA gene, while this locus was normal in his parents. GERP++RS software predicted that the mutation site was highly conservative. Human Splice Finder and Spliceman software predicted that the mutation might be a pathogenic mutation. ExPASy software predicted that the new amino acid sequence became shorter. There were two sequences of mRNA in the patient's muscle: one was the normal sequence, which accounted for 92.2%; the other was partial intron 4 retention, which was the abnormal splice variant accounting for 7.8%. LGMD1B is a type of autosomal dominant inherited myopathy caused by a mutation in the LMNA gene located on the autosomal 1q22. This study extends the mutation spectrum of the LMNA gene and provides help to the diagnosis of LGMD1B.

Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture

BACKGROUND AND PURPOSE: The early diagnosis of LMNA-associated muscular dystrophy is important for preventing sudden arrest related to cardiac conduction block. However, diagnosing early-onset Emery-Dreifuss muscular dystrophy (EDMD) with later involvement of contracture and limb-girdle muscular dystrophy type 1B is often delayed due to heterogeneous clinical presentations. We aimed to determine the clinical features that contribute to a delayed diagnosis. METHODS: We reviewed four patients who were recently diagnosed with LMNA-associated muscular dystrophy by targeted exome sequencing and who were initially diagnosed with nonspecific or other types of muscular dystrophy. RESULTS: Certain clinical features such as delayed contracture involvement and calf hypertrophy were found to contribute to a delayed diagnosis. Muscle biopsies were not informative for the diagnosis in these patients. CONCLUSIONS: Genetic testing of single or multiple genes is useful for confirming a diagnosis of LMNA-associated muscular dystrophy. Even EDMD patients could experience the later involvement of contracture, so clinicians should consider early genetic testing for patients with undiagnosed muscular dystrophy or laminopathy.

Dysferlin Gene Mutation Spectrum in a Large Cohort of Chinese Patients with Dysferlinopathy / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Dysferlinopathy is caused by mutations in the dysferlin (DYSF) gene. Here, we described the genetic features of a large cohort of Chinese patients with this disease.</p><p><b>METHODS</b>Eighty-nine index patients were included in the study. DYSF gene analysis was performed by Sanger sequencing in 41 patients and targeted next generation sequencing (NGS) in 48 patients. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect exon duplication/deletion in patients with only one pathogenic mutation.</p><p><b>RESULTS</b>Among the 89 index patients, 79 patients were demonstrated to carry two disease-causing (73 cases) or possibly disease-causing mutations (6 cases), including 26 patients with homozygous mutations. We identified 105 different mutations, including 59 novel ones. Notably, in 13 patients in whom only one pathogenic mutation was initially found by Sanger sequencing or NGS, 3 were further identified to carry exon deletions by MLPA. The mutations identified in this study appeared to cluster in the N-terminal region. Mutation types included missense mutations (30.06%), nonsense mutations (17.18%), frameshift mutations (30.67%), in-frame deletions (2.45%), intronic mutations (17.79%), and exonic rearrangement (1.84%). No genotype-phenotype correlation was identified.</p><p><b>CONCLUSIONS</b>DYSF mutations in Chinese patients clustered in the N-terminal region of the gene. Exonic rearrangements were found in 23% of patients with only one pathogenic mutation identified by Sanger sequencing or NGS. The novel mutations found in this study greatly expanded the mutational spectrum of dysferlinopathy.</p>

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...

Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations

PURPOSE: This study was designed to investigate the characteristics of Korean patients with calpainopathy. MATERIALS AND METHODS: Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed. RESULTS: Nine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology. CONCLUSION: We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.

First Identification of Compound Heterozygous FKRP Mutations in a Korean Patient with Limb-Girdle Muscular Dystrophy

No abstract available.

Evolução funcional da distrofia muscular do tipo Cinturas em indivíduos de uma mesma família / Functional evolution of Girdle Muscular Dystrophy in individuals of the same family

A Distrofia Muscular de Cinturas (DMC) possui herança autossômica dominante ou recessiva e caracteriza-se por paresia progressiva que induz à deterioração funcional e dificuldades no desempenho de atividades cotidianas. O objetivo do presente estudo foi analisar a evolução funcional de indivíduos com diagnóstico de DMC de uma mesma família. Nove indivíduos foram avaliados por um questionário para identificação do parentesco, idade de inicio dos primeiros sintomas e queixas principais, e pelas Escalas de Vignos (EV) e Hammersmith (EMFH). O projeto foi aprovado pelo CEP/UFVJM, protocolo nº061/12. A idade média foi de 33 ± 8.1 anos, com seis indivíduos sendo do sexo masculino, a idade de aparecimento dos primeiros sintomas foi aos 9± 2,83 anos e os sintomas iniciais mais frequentes foram dificuldade de correr, quedas e marcha equina. Os sujeitos pontuaram 4, 6 e 7 na EV e no exame físico verificou-se acometimento principalmente dos membros inferiores. Foi encontrado correlação negativa entre idade dos sujeitos e escore na EMFH (r2=-0,839) e entre pontuação na EV e EMFH (r2 =-0,819), e correlação positiva entre EV e uso de dispositivos (r2=0,866). Nossos achados sugerem que a mesma patologia diagnosticada em indivíduos de uma mesma família apresenta repercussões funcionais diferentes. O aspecto ambiente deve ser levado em consideração ao avaliar a funcionalidade desses indivíduos uma vez que, independente do diagnóstico em comum, da idade, e limitações físicas, os indivíduos apresentaram adaptações particulares com objetivo de manutenção do seu deslocamento de acordo com as características do ambiente em que vive.(AU)

Limb Girdle Muscular Dystrophy (LGMD) is an autosomal-dominant or recessive hereditary disease. Progressive muscular weakness leads to functional damage and difficulty to perform activities of daily life. The present study aimed to analyze the functional evolution of LGMD individuals of the same family. Nine individuals were assessed using a questionnaire (to identify their relationship, age of onset of the first signs of the disease and main complaints) and by Vignos and Hammersmith Scales. Projetct was aproved by Ethics Committee of UFVJM, protocol nº061/12. Mean age was 33±8.1 years old, six male, mean age of onset of the first signs was 9± 2,83 years old and the most frequent signs were difficulty to run, falls and gait with ankle on plantar flexion. Subjects scored 4, 6 and 7 on Vignos Scale and on physical exam, lower limbs were the most affected. Negative correlation between age and Hammermith scale (r 2=-0,839), Vignos and Hammersmith Scale (r2=-0,819) were found. Positive correlation between Vignos Scale and use of assistive devices (r2=0,866). Our finds suggest that the same disease in individuals of the same family leads to different functional impairment. The environmental aspect should be considered when assessing functionality of individuals with LGMD once although they present the same diagnosis, they present particular adaptations with the aim of maintain displacement according to characteristics of the environment where they live.(AU)

Limb-girdle muscular dystrophy type 2A in Brazilian children / Distrofia muscular cinturas tipo 2A em crianças brasileiras

ABSTRACT Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A) caused by mutations in CAPN3 gene. Objective To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results All patients were female (three to 12 years). The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.

RESUMO Calpainopatia é uma distrofia muscular de cinturas autossômica recessiva (LGMD2A) causada por mutações no gene CAPN3. Objetivo Apresentar os aspectos clínicos e histológicos em seis crianças com diagnostico molecular de LGMD2A e adicionalmente os achados na RNM de músculo em duas delas. Método Nos retrospectivamente analisamos os dados de prontuário de seis crianças com mutações no gene CAPN3. Resultados Todos os pacientes eram do sexo feminino (3 a 12 anos). A média de idade de inicio da doença foi de nove anos. Todos mostraram uma fraqueza progressiva com predomínio nos membros inferiores. Outros achados incluíam escapula alada, contratura de tendão de Aquiles e hipertrofia de panturrilhas. Uma menina apresentou um fenótipo mais severo quando comparado a sua irmã gêmea dizigótica o que foi confirmado pelos achados encontrados na RNM de músculo. Em todos os pacientes a biópsia muscular mostrou um padrão distrófico. Conclusão Nesta coorte de crianças com LGMD2A, os aspectos clínicos foram bastante similares a pacientes adultos com a mesma doença.