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2.
Neuromuscul Disord ; 33(3): 241-249, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36753800

RESUMO

Pregnancy and birth in women with neuromuscular conditions has been associated with more rapid disease progression and obstetric complications. This study assessed the impact of functional status and specific diagnosis on patient reported pregnancy and birth outcomes in 26 genetic neuromuscular diseases. Pregnancy and birth outcomes were collected through electronic patient questionnaires and analysed by mobility group and diagnosis. Free text responses were grouped into themes. 721 pregnancies were reported by 305 women. Miscarriage (21% of pregnancies), caesarean delivery (38% of births) and instrumental vaginal delivery (19% of births) were all more frequent in respondents than in the general population (p<0.05), and were more common in those who were non-ambulant at conception than other mobility levels (p <0.05). Falls occurred during 42% of pregnancies and a deterioration in muscle strength during 43%. There was not an increased incidence of maternal complications, apart from maternal hypertension which was more common in limb girdle muscular dystrophy 2A/R1 (35%) and myotonic dystrophy (24%). Patients offered specific practical advice to prospective mothers. Women with neuromuscular conditions have a more complex antenatal and perinatal course than unaffected women. Prenatal counselling, specialist obstetric review and additional occupational therapy support should be considered.


Assuntos
Doenças Neuromusculares , Resultado da Gravidez , Gravidez , Humanos , Feminino , Estudos Prospectivos , Parto Obstétrico , Medidas de Resultados Relatados pelo Paciente
3.
Neuromuscul Disord ; 31(12): 1259-1265, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34702655

RESUMO

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in childhood. It is associated with progressive muscle function decline and premature death. Long-term oral glucocorticoid use slows muscle weakness but is associated with several side effects including delayed puberty. This study assessed the impact of a 2-year incremental intramuscular testosterone regimen on quality of life (QoL) in a cohort of 15 adolescents with DMD. The Pediatric Quality of Life Inventory (PedsQL) Neuromuscular module was used to assess QoL and was completed by parent-child dyads. Semi-structured interviews were carried out to understand patient views on testosterone therapy. QoL scores increased in 10 of the 15 participants during treatment, with a mean total PedsQL score of 74.6 pre-treatment v 80.2 post treatment (p = 0.04). This was supported by comments in the semi-structured interviews. Parent-reported PedsQL scores were lower than their child's post treatment (p = 0.007). Testosterone therapy for pubertal induction was associated with an improvement in QoL and the observed physical changes during puberty played an important role. Low self-esteem was also a prevailing theme. This data supports the inclusion of testosterone therapy for pubertal induction as a Standard of Care.


Assuntos
Androgênios/farmacologia , Nanismo/tratamento farmacológico , Distrofia Muscular de Duchenne/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Puberdade/efeitos dos fármacos , Qualidade de Vida , Testosterona/farmacologia , Adolescente , Androgênios/administração & dosagem , Criança , Nanismo/psicologia , Humanos , Masculino , Distrofia Muscular de Duchenne/psicologia , Pais , Autoimagem , Testosterona/administração & dosagem
4.
Eur J Neurol ; 28(2): 729-731, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33047465

RESUMO

α-methylacyl-CoA racemase (AMACR) deficiency is a rare disorder, affecting peroxisomal metabolism of pristanic acid, with ten published adult cases. We describe an AMACR deficiency case with a clinical presentation dominated by episodic hyperCKaemia, suggesting that myopathic features of AMACR should be considered.


Assuntos
Erros Inatos do Metabolismo Lipídico , Racemases e Epimerases , Adulto , Coenzima A , Humanos , Racemases e Epimerases/genética
5.
Eur J Neurol ; 27(12): 2604-2615, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32697863

RESUMO

BACKGROUND AND PURPOSE: The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and clinical/molecular data. METHODS: Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1-weighted and short-tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema. RESULTS: The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro-caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2. CONCLUSION: This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD-related disease spectrum.


Assuntos
Distrofia Muscular Facioescapuloumeral , Humanos , Extremidade Inferior , Imageamento por Ressonância Magnética , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular Facioescapuloumeral/diagnóstico por imagem , Distrofia Muscular Facioescapuloumeral/genética
6.
Eur J Neurol ; 27(11): 2257-2266, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32558070

RESUMO

BACKGROUND AND PURPOSE: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations, including exercise intolerance, cardiomyopathy and liver disease. The aim of this study was to describe the clinical and genetic manifestations of six patients with adult-onset VLCADD. METHODS: In this study, the clinical, pathological and genetic findings of six adult patients (four from Iran and two from Serbia) with VLCADD and their response to treatment are described. RESULTS: The median (range) age of patients at first visit was 31 (27-38) years, and the median (range) age of onset was 26.5 (19-33) years. Parental consanguinity was present for four patients. Four patients had a history of rhabdomyolysis, and the recorded CK level ranged between 67 and 90 000 IU/l. Three patients had a history of exertional myalgia, and one patient had a non-fluctuating weakness. Through next-generation sequencing analysis, we identified six cases with variants in the ACADVL gene and a confirmed diagnosis of VLCADD. Of the total six variants identified, five were missense, and one was a novel frameshift mutation identified in two unrelated individuals. Two variants were novel, and three were previously reported. We treated the patients with a combination of L-carnitine, Coenzyme Q10 and riboflavin. Three patients responded favorably to the treatment. CONCLUSION: Adult-onset VLCADD is a rare entity with various presentations. Patients may respond favorably to a cocktail of L-carnitine, Coenzyme Q10, and riboflavin.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adulto , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Humanos , Masculino , Doenças Mitocondriais , Doenças Musculares , Adulto Jovem
7.
Acta Neuropathol ; 139(3): 565-582, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31897643

RESUMO

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.


Assuntos
Distroglicanas/metabolismo , Glucosiltransferases/genética , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Animais , Animais Geneticamente Modificados , Drosophila melanogaster , Feminino , Estudos de Associação Genética , Glicosilação , Humanos , Masculino , Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Mutação , Linhagem , Células Satélites de Músculo Esquelético/patologia
8.
Acta Neuropathol ; 138(6): 1013-1031, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31463572

RESUMO

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.


Assuntos
Proteínas de Ciclo Celular/genética , Doenças Cerebelares/genética , Proteínas do Citoesqueleto/genética , DNA Mitocondrial , Doenças Mitocondriais/genética , Distrofias Musculares/genética , Mutação , Adolescente , Adulto , Atrofia , Células Cultivadas , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/patologia , Doenças Cerebelares/fisiopatologia , Criança , Variações do Número de Cópias de DNA , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/patologia , Doenças Mitocondriais/fisiopatologia , Músculos/patologia , Distrofias Musculares/diagnóstico por imagem , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Fenótipo , Adulto Jovem
9.
BMC Pediatr ; 19(1): 131, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023296

RESUMO

BACKGROUND: Adolescents with DMD treated with chronic high dose GC therapy typically have profound pubertal delay. Testosterone, the main circulating androgen in men, promotes virilisation and growth with associated accrual of fat-free muscle mass and bone mineral content. Testosterone therapy is routinely used to mimic the normal stages of pubertal development in patients with hypogonadotrophic hypogonadism, androgen deficiency secondary to testicular disease and in constitutional delay of growth and puberty (CDGP). Improved life expectancy in DMD has meant that more adolescents are eligible for testosterone supplementation but there is little objective data regarding the impact of this treatment on muscle structure and function, bone integrity and overall well-being. METHODS: This is a single centre observational clinical trial (NCT02571205) that aims to follow the progress of 15 adolescents with Duchenne muscular dystrophy and delayed puberty as they are managed with incremental testosterone therapy to induce puberty. Subjects will all be treated with a steadily increasing dose of testosterone administered by injection every 4 weeks and data will be collected to help us determine the effectiveness and tolerability of the described treatment regimen. We will use the data to explore the effects of testosterone on pubertal development, growth, muscle strength and function, bone mineral density, body composition with a detailed record of any adverse events. We will also carry out interviews to explore the boys' views on the tolerability of the regimen. The study will last for 27 months in total for each participant. DISCUSSION: Our experience has indicated that testosterone treatment in adolescents with DMD is liked and well tolerated but we have not collected objective data on a specific treatment regimen and there is no current consensus. Testosterone supplementation is not part of the standard of care of pubertal delay in DMD but inclusion in future protocols may be appropriate depending on the results of this trial. TRIAL REGISTRATION: EudraCT Number: 2015-003195-68. Research Registry & References: Clinical trials.gov- NCT02571205 (registered 8/10/15).


Assuntos
Glucocorticoides/efeitos adversos , Força Muscular/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Puberdade Tardia/tratamento farmacológico , Testosterona/administração & dosagem , Adolescente , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Criança , Relação Dose-Resposta a Droga , Esquema de Medicação , Seguimentos , Glucocorticoides/administração & dosagem , Humanos , Injeções Intramusculares , Masculino , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/diagnóstico , Satisfação do Paciente , Estudos Prospectivos , Resultado do Tratamento , Reino Unido
10.
Neuromuscul Disord ; 29(4): 261-268, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30852071

RESUMO

The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5-18 years) and functional abilities, from ambulant (n = 60) to non-ambulant (n = 29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI [-7.44,-0.72], p = 0.02 in ambulant; 4.81, 95% CI [-6.79,-2.82], p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI [-6.48,-4.45], p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI [-4.79,3.47], p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force -5.51%, 95% CI [-6.54,-4.48], p < 0.001 in ambulant and a slower decline -2.86%; 95% CI -3.29,-2.43, p < 0.001, in non-ambulant; pinch force: -2.66%, 95% CI [-3.82,-1.51], p < 0.001 in ambulant and -2.23%, 95% CI [-2.92,-1.53], p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.


Assuntos
Limitação da Mobilidade , Atividade Motora/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Transtornos Respiratórios/fisiopatologia , Extremidade Superior/fisiopatologia , Adolescente , Criança , Pré-Escolar , Europa (Continente) , Humanos , Masculino , Distrofia Muscular de Duchenne/complicações , Estudos Prospectivos , Respiração , Transtornos Respiratórios/etiologia , Testes de Função Respiratória
12.
Neuromuscul Disord ; 27(11): 1043-1046, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28803818

RESUMO

Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy.


Assuntos
Manosiltransferases/genética , Proteínas de Membrana/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Distroglicanas/metabolismo , Feminino , Homozigoto , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Fenótipo
13.
Eur J Paediatr Neurol ; 20(6): 904-909, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27524390

RESUMO

INTRODUCTION: Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in children. Recent years have seen an increase in age of survival into adulthood following the introduction of proactive standards of care. We reviewed mortality in DMD in our population in order to identify potential underlying risk factors for premature death and improve clinical care. METHOD: A retrospective case note review of all deaths in the DMD population over the last 10 years in North East England. We identified 2 groups of patients: patients who died from underlying cardiac and/or respiratory failure (group 1) and patients who died unexpectedly in the absence of underlying cardio-respiratory failure (group 2). RESULTS: Detailed information was available on 21 patients. Mean age of death in group 1 (17 patients) was 23.9 (14.4-39.5) years, in group 2 (4 patients) 14 (12.7-14.9) years. Causes of death in group 2 were acute pneumonia, cardiac arrest, acute respiratory distress and multi-organ failure. Across both groups we identified concerns regarding respiratory failure, inadequate nutrition, non-attendance at appointments, suboptimal coordination of care and decreased psychological wellbeing. In group 2, fat embolism, cardiac arrhythmia and adrenal insufficiency were also potential contributing factors. CONCLUSIONS: The main cause of death in DMD in our population remains cardio-respiratory failure. Four patients (19%) died in their teenage years in the absence of severe cardiorespiratory failure. A more thorough understanding of the impact of DMD and its treatment on all organs systems is required to minimise the risk of an untimely death.


Assuntos
Distrofia Muscular de Duchenne/mortalidade , Adolescente , Corticosteroides/uso terapêutico , Adulto , Ansiedade/etiologia , Ansiedade/psicologia , Causas de Morte , Criança , Depressão/etiologia , Depressão/psicologia , Inglaterra/epidemiologia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/tratamento farmacológico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Fatores de Risco , Capacidade Vital , Adulto Jovem
14.
Clin Genet ; 90(2): 166-70, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27409453

RESUMO

Four and a half LIM protein 1 (FHL1/SLIM1) has recently been identified as the causative gene mutated in four distinct diseases affecting skeletal muscle that have overlapping features, including reducing body myopathy, X-linked myopathy, X-linked dominant scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. FHL1 localises to the sarcomere and the sarcolemma and is believed to participate in muscle growth and differentiation as well as in sarcomere assembly. We describe in this case report a boy with a deletion of the entire FHL1 gene who is now 15 years of age and presented with muscle hypertrophy, reduced subcutaneous fat, rigid spine and short stature. This case is the first, to our knowledge, with a complete loss of the FHL1 protein and MAP7D3 in combination. It supports the theory that dominant negative effects (accumulation of cytotoxic-mutated FHL1 protein) worsen the pathogenesis. It extends the phenotype of FHL1-related myopathies and should prompt future testing in undiagnosed patients who present with unexplained muscle hypertrophy, contractures and rigid spine, particularly if male.


Assuntos
Deleção de Genes , Hipertrofia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Musculares/genética , Doenças Musculares/genética , Coluna Vertebral/patologia , Gordura Subcutânea/patologia , Adolescente , Expressão Gênica , Humanos , Hipertrofia/patologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Proteínas com Domínio LIM/deficiência , Masculino , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Musculares/deficiência , Doenças Musculares/patologia , Fenótipo , Coluna Vertebral/metabolismo , Gordura Subcutânea/metabolismo
16.
Neuromuscul Disord ; 24(11): 990-2, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25088310

RESUMO

We report two siblings of Croatian consanguineous healthy parents with a novel homozygous missense mutation in the POMT1 gene, presenting with intellectual disability and psychotic, in particular hallucinatory symptoms and abnormal brain MRIs, preceding classical symptoms of limb-girdle muscular dystrophy by several years. Weakness became apparent in early adulthood and both siblings remained ambulant into the 3rd and 4th decade of life. The muscle biopsy showed reduced α-dystroglycan compatible with the POMT1 defect. This case report extends the phenotypic spectrum of POMT1 associated muscular dystrophies to the adult onset limb girdle muscular dystrophies with psycho-organic deficits.


Assuntos
Transtornos Cognitivos/etiologia , Manosiltransferases/genética , Transtornos Mentais/etiologia , Distrofia Muscular do Cíngulo dos Membros/complicações , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação/genética , Adulto , Encéfalo/patologia , Transtornos Cognitivos/genética , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Imageamento por Ressonância Magnética , Transtornos Mentais/genética , Irmãos
17.
Neuromuscul Disord ; 23(7): 540-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23628358

RESUMO

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.


Assuntos
Hipertermia Maligna/genética , Mutação/genética , Rabdomiólise/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Exercício Físico/fisiologia , Feminino , Heterozigoto , Humanos , Masculino , Hipertermia Maligna/complicações , Fenótipo , Rabdomiólise/complicações , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
18.
Neuromuscul Disord ; 21(8): 569-78, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21724396

RESUMO

To identify serum biomarkers that allow monitoring of disease progression and treatment effects in Duchenne muscular dystrophy (DMD) patients, levels of matrix metalloproteinase-9 (MMP-9), tissue inhibitors of metalloproteinase-1 (TIMP-1) and osteopontin (OPN) were determined in 63 DMD patients on corticosteroid therapy. These proteins were selected for their role in the pathogenesis of muscular dystrophy. Levels of MMP-9 and TIMP-1 were significantly higher in sera of DMD patients compared to healthy controls, whereas the OPN levels showed no significant difference. MMP-9 levels were also observed to be significantly higher in older, nonambulant patients, compared to ambulant patients. Longitudinal data from a smaller cohort of DMD patients followed up for over 4years showed that MMP-9, but not TIMP-1 increased significantly with age. Hence, MMP-9 is a potential DMD biomarker for disease progression. Future studies have to confirm whether serum MMP-9 levels can be used to monitor therapeutic response.


Assuntos
Progressão da Doença , Metaloproteinase 9 da Matriz/sangue , Distrofia Muscular de Duchenne/sangue , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Estudos Longitudinais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/tratamento farmacológico , Osteopontina/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Resultado do Tratamento , Adulto Jovem
19.
Neurology ; 76(4): 346-53, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21263136

RESUMO

OBJECTIVE: There are currently no effective treatments to halt the muscle breakdown in Duchenne muscular dystrophy (DMD), although genetic-based clinical trials are being piloted. Most of these trials have as an endpoint the restoration of dystrophin in muscle fibers, hence requiring sufficiently well-preserved muscle of recruited patients. The choice of the muscles to be studied and the role of noninvasive methods to assess muscle preservation therefore require further evaluation. METHODS: We studied the degree of muscle involvement in the lower leg muscles of 34 patients with DMD >8 years, using muscle MRI. In a subgroup of 15 patients we correlated the muscle MRI findings with the histology of open extensor digitorum brevis (EDB) muscle biopsies. Muscle MRI involvement was assigned using a scale 0-4 (normal-severe). RESULTS: In all patients we documented a gradient of involvement of the lower leg muscles: the posterior compartment (gastrocnemius > soleus) was most severely affected; the anterior compartment (tibialis anterior/posterior, popliteus, extensor digitorum longus) least affected. Muscle MRI showed EDB involvement that correlated with the patient's age (p = 0.055). We show a correlation between the MRI and EDB histopathologic changes, with MRI 3-4 grades associated with a more severe fibro-adipose tissue replacement. The EDB was sufficiently preserved for bulk and signal intensity in 18/22 wheelchair users aged 10-16.6 years. CONCLUSION: This study provides a detailed correlation between muscle histology and MRI changes in DMD and demonstrates the value of this imaging technique as a reliable tool for the selection of muscles in patients recruited into clinical trials.


Assuntos
Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/patologia , Adolescente , Criança , , Humanos , Perna (Membro) , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia
20.
Neurology ; 76(3): 227-35, 2011 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-21242490

RESUMO

BACKGROUND: Oculopharyngodistal myopathy (OPDM) has been reported as a rare, adult-onset hereditary muscle disease with putative autosomal dominant and autosomal recessive inheritance. Patients with OPDM present with progressive ocular, pharyngeal, and distal limb muscle involvement. The genetic defect causing OPDM has not been elucidated. METHODS: Clinical and genetic findings of 47 patients from 9 unrelated Turkish families diagnosed with OPDM at the Department of Neurology, Istanbul Faculty of Medicine, between 1982 and 2009 were evaluated. RESULTS: The mean age at onset was around 22 years. Both autosomal dominant and autosomal recessive traits were observed, without any clear difference in clinical phenotype or severity. The most common initial symptom was ptosis, followed by oropharyngeal symptoms and distal weakness, which started after the fifth disease year. Intrafamilial variability of disease phenotype and severity was notable in the largest autosomal dominant family. Atypical presentations, such as absence of limb weakness in long-term follow-up in 9, proximal predominant weakness in 4, and asymmetric ptosis in 3 patients, were observed. Swallowing difficulty was due to oropharyngeal dysphagia with myopathic origin. Serum creatine kinase levels were slightly increased and EMG revealed myopathic pattern with occasional myotonic discharges. Myopathologic findings included rimmed and autophagic vacuoles and chronic myopathic changes. Importantly, a considerable proportion of patients developed respiratory muscle weakness while still ambulant. Linkage to the genetic loci for all known muscular dystrophies, and for distal and myofibrillar myopathies, was excluded in the largest autosomal dominant and autosomal recessive OPDM families. CONCLUSIONS: We suggest that OPDM is a clinically and genetically distinct myopathy.


Assuntos
Blefaroptose/etiologia , Deglutição , Genes Dominantes , Genes Recessivos , Distrofia Muscular Oculofaríngea/diagnóstico , Distrofia Muscular Oculofaríngea/genética , Prega Vocal/fisiopatologia , Adolescente , Adulto , Idade de Início , Idoso , Atrofia , Criança , Progressão da Doença , Eletromiografia , Músculos Faciais/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular , Distrofia Muscular Oculofaríngea/complicações , Distrofia Muscular Oculofaríngea/patologia , Distrofia Muscular Oculofaríngea/fisiopatologia , Fenótipo , Índice de Gravidade de Doença , Espirometria , Fatores de Tempo , Turquia , Prega Vocal/patologia
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