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1.
Biochimie ; 199: 36-45, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35398442

RESUMO

UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) is a bifunctional enzyme (N-terminal epimerase and C-terminal Kinase domain) that catalyses the rate limiting step in sialic acid biosynthesis. More than 200 homozygous missense or compound heterozygous mutations in GNE have been reported worldwide to cause a rare neuromuscular disorder, GNE myopathy. It is characterized by a slowly progressive defect in proximal and distal skeletal muscles with patients becoming wheel-chair-bound. There are no current approved therapies available for GNE myopathy. ManNAc therapy is currently in advanced clinical trials and has shown signs of slowing the disease progression in a phase 2 trial. The present study aims to understand the effect of GNE mutation on its enzymatic activity and identification of potential small effector molecules. We characterized different GNE mutations (p.Asp207Val, p.Val603Leu, p.Val727Met, p.Ile618Thr and p.Arg193Cys) prevalent in Asian population that were cloned, expressed and purified from Escherichia coli as full-length recombinant proteins. Our study demonstrates that full length GNE can be expressed in E. coli in its active form and analysed for the functional activity. Each mutation showed variation in epimerase and kinase activity and responded to the small effector molecules (metformin, BGP-15 kaempferol, catechin, quercetin) in a differential manner. Our study opens an area for futuristic structural determination of full length GNE and identification of potential therapeutic molecules.


Assuntos
Miopatias Distais/genética , Doenças Neuromusculares/genética , Doenças Raras/genética , Povo Asiático , Carboidratos Epimerases/genética , Miopatias Distais/tratamento farmacológico , Miopatias Distais/epidemiologia , Homozigoto , Humanos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Mutação
2.
Clin Neurol Neurosurg ; 212: 107057, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34871992

RESUMO

OBJECTIVE: GNE myopathy is a rare autosomal recessive adult-onset distal myopathy caused by biallelic pathogenic variants in GNE. Although some extra-muscular manifestations associated with GNE myopathy have been reported, little is known about whether they are disease-specific and how often they present. This study aimed to characterize extra-muscular manifestations of GNE myopathy. METHODS: We conducted a questionnaire survey of GNE myopathy patients registered in a national registry in Japan. The questionnaire requested information regarding idiopathic thrombocytopenia, cardiac involvement, respiratory involvement, sleep apnea syndrome (SAS), and psychiatric diseases. RESULTS: The response rate was 62.4% (126/198), yielding a total of 51 male and 75 female participants. Of the participants, 4.1% (5/123) had a diagnosis of idiopathic thrombocytopenia, and 16.3% (8/49) of males and 6.6% of females (5/76) had a diagnosis of SAS. In total, 0.8% (1/126) of participants had pervasive developmental disabilities and 14.7% (16/109) had a psychiatric disease. CONCLUSION: The frequencies of idiopathic thrombocytopenia and SAS among Japanese GNE myopathy patients were higher than those observed in the general Japanese population. Routine blood tests and evaluation of sleep-disordered breathing should be considered in order to better manage GNE myopathy patients.


Assuntos
Miopatias Distais/complicações , Sistema de Registros , Síndromes da Apneia do Sono/etiologia , Trombocitopenia/etiologia , Adulto , Idoso , Miopatias Distais/epidemiologia , Feminino , Inquéritos Epidemiológicos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos , Síndromes da Apneia do Sono/epidemiologia , Inquéritos e Questionários , Trombocitopenia/epidemiologia
3.
J Med Genet ; 58(4): 284-288, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32376792

RESUMO

Charcot-Marie-Tooth disease (CMT) is one of the most common Mendelian disorders characterised by genetic heterogeneity, progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. In this report, we describe genetic testing data including comprehensive sequencing and copy number analysis of 34 CMT-related genes in a Canadian cohort of patients with suspected CMT. We have demonstrated a notable gender testing bias, with an overall diagnostic yield of 15% in males and 21% in females. We have identified a large number of novel pathogenic variants as well as variants of unknown clinical significance in CMT-related genes. In this largest to date analysis of gene CNVs in CMT, in addition to the common PMP22 deletion/duplication, we have described a significant contribution of pathogenic CNVs in several CMT-related genes. This study significantly expand the mutational spectrum of CMT genes, while demonstrating the clinical utility of a comprehensive sequence and copy number next-generation sequencing-based clinical genetic testing in patients with suspected diagnosis of CMT.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Variações do Número de Cópias de DNA/genética , Miopatias Distais/genética , Testes Genéticos , Adulto , Idoso , Canadá/epidemiologia , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/patologia , Estudos de Coortes , Miopatias Distais/diagnóstico , Miopatias Distais/epidemiologia , Miopatias Distais/patologia , Feminino , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fenótipo
4.
J Hum Genet ; 64(1): 11-16, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30390020

RESUMO

GNE myopathy is a rare autosomal recessive distal myopathy caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the bi-functional enzyme critical for sialic acid biosynthesis. In this study, we summarized the clinical features, pathological characteristics, and genetic profiles of 46 GNE patients. The clinical and mutational profile of 54 previously reported Chinese patients were also reviewed. A total of 21 novel mutations, including a gross deletion spanning exon 1-2 and a retrotransposon insertion were found in our cohort, enlarging the spectrum of GNE mutations. The most frequent mutation in Chinese population was D207V, which accounts for 25.5% of total alleles (51/200). The age of onset was much later in the patients carrying D207V compared to other patients, indicated the less deleterious effect of D207V on enzyme activity. GNE myopathy may be overlooked in China with a relatively milder phenotype due to the common mutation D207V.


Assuntos
Povo Asiático/genética , Miopatias Distais/genética , Miopatias Distais/patologia , Complexos Multienzimáticos/genética , Mutação , Adolescente , Adulto , China/epidemiologia , Estudos de Coortes , Miopatias Distais/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Neuromuscul Disord ; 28(2): 158-168, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29305133

RESUMO

GNE myopathy is a rare distal myopathy, caused by mutations in the GNE gene, affecting sialic acid synthesis. Clinical presentation varies from asymptomatic early stage patients to severely debilitating forms. This first report describes clinical presentations and severity of the disease, using data of 150 patients collected via the on-line, patient-reported registry component of the GNE Myopathy Disease Monitoring Program (GNEM-DMP). Disease progression was prospectively analysed, over a 2-year period, using the GNE myopathy functional activity scale (GNEM-FAS). The average annual rates of decline in function were estimated at -9.6% and -3.2% in ambulant and non-ambulant patients respectively. 4.3% of participants became non-ambulant within one year. The mean time from onset to required use of a wheelchair was 11.9 years. Mean delay of genetic diagnosis from symptom onset was 5.2 years. Mutation specific analysis demonstrated genotype-phenotype relationships; i.e. p.Ala662Val may be associated with a more severe phenotype, compared to p.Val727Met. Patients with compound heterozygous mutation in epimerase and kinase domain appeared to have a more severe phenotype compared to patients with both mutations located within one domain. Acknowledging the limitations of the study, these findings suggest that the severity of the GNE mutations affects disease severity. The GNEM-DMP is a useful data collection tool, prospectively measuring the progression of GNE myopathy, which could play an important role in translational and clinical research and further understanding of genotype-phenotype correlations.


Assuntos
Miopatias Distais/epidemiologia , Miopatias Distais/genética , Adulto , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Estudos de Associação Genética , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/genética , Fenótipo , Sistema de Registros , Índice de Gravidade de Doença , Adulto Jovem
6.
Clin Calcium ; 27(3): 429-434, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28232658

RESUMO

GNE myopathy is rare muscle disease which affect distal muscles. GNE gene, which encodes for a key enzyme in the sialic acid biosynthesis pathway, is mutated in the homozygote or compound heterozygote in the disease. The lack of sialic acid in skeletal muscle is the critical pathological process in GNE myopathy. GNE myopathy model mouse was established and supplementation of sialic acid improves the phenotype of model mouse. Phase Ⅰ clinical trial was conducted at Tohoku University Hospital using aceneuramic acid, followed by the trials using slow release product of sialic acid. Phase Ⅱ/Ⅲ study is ongoing.


Assuntos
Miopatias Distais/tratamento farmacológico , Ensaios Clínicos como Assunto , Miopatias Distais/diagnóstico , Miopatias Distais/epidemiologia , Miopatias Distais/patologia , Humanos , Ácido N-Acetilneuramínico/uso terapêutico , Prognóstico
8.
Duodecim ; 132(18): 1635-44, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-29188941

RESUMO

Distal myopathies are a group of rare muscular dystrophies comprising more than 20 different genetic entities. The first distal myopathy in Finland, tibial muscular dystrophy, was identified more than 20 years ago. Muscle weakness predominantly affects the feet and hands, although variable weakness can be detected clinically and on muscle MRI in the proximal muscles in the later stages of the disease. Advanced molecular genetic techniques have enabled identification of several distinct distal myopathies in Finland. The clinical findings of different distal myopathies overlap, but there are also distinguishable differences that might help final genetic diagnostics.


Assuntos
Miopatias Distais/epidemiologia , Miopatias Distais/genética , Finlândia/epidemiologia , Humanos
9.
Brain Nerve ; 67(9): 1115-23, 2015 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-26329152

RESUMO

Distal myopathy with rimmed vacuoles or GNE myopathy, is an early adult-onset myopathy with slow progression that preferentially affects the tibialis anterior muscle. Severely affected patients show marked limb muscle atrophy together with respiratory dysfunction. The disease is caused by a mutation in the GNE gene that catalyzes two rate-limiting reactions in cytosolic sialic acid synthesis. Oral treatment with sialic acid metabolite prevents muscle atrophy and weakness in a mouse GNE myopathy model and a global Phase III study is currently underway. In addition, a global patient registry of neuromuscular cases is widely accepted as a useful tool to obtain epidemiological data and bolster patient recruitment for further development of this treatment strategy.


Assuntos
Miopatias Distais/tratamento farmacológico , Músculo Esquelético/patologia , Ácido N-Acetilneuramínico/uso terapêutico , Vacúolos/genética , Animais , Modelos Animais de Doenças , Miopatias Distais/diagnóstico , Miopatias Distais/epidemiologia , Miopatias Distais/genética , Humanos , Resultado do Tratamento , Vacúolos/metabolismo
10.
J Neurol Sci ; 354(1-2): 21-6, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25986339

RESUMO

GNE myopathy is an autosomal recessive distal myopathy caused by biallelic mutation in the GNE gene. It shows great genetic heterogeneity among different ethnic groups. In this study, we summarized the mutational spectrum and clinical profiles in 35 unrelated GNE myopathy patients from mainland China. Molecular analysis revealed 16 novel (p.G47D, p.F66Y, p.E173A, p.Y186H, p.R246L, p.R263*, p.R306*, p.A366D, p.V512M, p.C520Y, p.G545R, p.G548S, p.V622G, p.A638P, IVS2+1G>A and c.2112delC) and 13 reported mutations. Notably, the p.D176V mutation was detected in 65.7% (23/35) of this patient cohort, giving an allele frequency of 34.3% (24/70). We estimated the carrier frequency of p.D176V to be 0.19% (1/520) in the normal population, although haplotype analysis indicated no founder effect in the patients carrying p.D176V mutation. Clinically, 29 patients presented with the classic phenotype of predominant distal weakness, while six patients presented with atypical phenotype. However, muscle magnetic resonance imaging showed that the vastus lateralis was spared in both subgroups. In conclusion, p.D176V mutation in the GNE gene, which was the second most common mutation in Japanese patients, was the most common mutation in this cohort of Chinese patients. Novel GNE mutations found in this study expanded the mutational spectrum associated with GNE myopathy. There is phenotypic heterogeneity among patients with GNE myopathy, but muscle magnetic resonance imaging can be useful for differential diagnosis.


Assuntos
Povo Asiático/genética , Miopatias Distais/epidemiologia , Miopatias Distais/genética , Complexos Multienzimáticos/genética , Mutação/genética , Adulto , China/epidemiologia , Estudos de Coortes , Miopatias Distais/diagnóstico , Feminino , Humanos , Masculino , Adulto Jovem
11.
J Neurol Neurosurg Psychiatry ; 86(4): 385-92, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25002140

RESUMO

GNE myopathy is an autosomal recessive muscle disease caused by biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities, UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities' muscles, with marked sparing of the quadriceps. Characteristic findings on biopsies of affected muscles include 'rimmed' (autophagic) vacuoles, aggregation of various proteins and fibre size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based on the longest transcript (GenBank: NM_001128227), which encodes a 31-amino acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Based upon the pathophysiology of the disease, recent clinical trials as well as early gene therapy trials have evaluated the use of sialic acid or N-acetylmannosamine (a precursor of sialic acid) in patients with GNE myopathy. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.


Assuntos
Miopatias Distais/genética , Complexos Multienzimáticos/genética , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Miopatias Distais/diagnóstico , Miopatias Distais/epidemiologia , Miopatias Distais/patologia , Miopatias Distais/terapia , Humanos , Camundongos
12.
Orphanet J Rare Dis ; 9: 150, 2014 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-25303967

RESUMO

BACKGROUND: GNE myopathy is a slowly progressive autosomal recessive myopathy caused by mutations in the GNE (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) gene. This study aimed to (1) develop a nationwide patient registry for GNE myopathy in order to facilitate the planning of clinical trials and recruitment of candidates, and (2) gain further insight into the disease for the purpose of improving therapy and care. METHODS: Medical records of genetically-confirmed patients with GNE myopathy at the National Center Hospital of the National Center of Neurology and Psychiatry (NCNP) were retrospectively reviewed in order to obtain data reflecting the severity and progression of the disease. We also referred to items in the datasheet of the nationwide registry of dystrophinopathy patients in the Registry of Muscular Dystrophies (Remudy). Items selected for the registration sheet included age, sex, age at onset, past history and complications, family history, body weight and height, pathological findings of muscle biopsy, grip power, walking ability, respiratory function, cardiac function, willingness to join upcoming clinical trials, and participation in patient associations. A copy of the original genetic analysis report was required of each patient. RESULTS: We successfully established the Remudy-GNE myopathy. Currently, 121 patients are registered nationwide, and 93 physicians from 73 hospitals collaborated to establish the registry. The mean age at onset was 27.7 ± 9.6 years, and 19.8% (24/121) of patients could walk without assistance. Mean presumed durations from onset to use of assistive devices (cane and/or braces) and a wheelchair, and loss of ambulation were 12.4, 15.2, and 21.1 years, respectively. Three patients had a past history and/or complication of idiopathic thrombocytopenia. To share the progress of this study with the community, newsletters were published on a regular basis, and included information regarding new phase I clinical trials for GNE myopathy. The newsletters also served as a medium to bring attention to the importance of respiratory evaluation and care for respiratory insufficiency. CONCLUSION: The Japanese Remudy-GNE myopathy is useful for clarifying the natural history of the disease and recruiting patients with genetically-confirmed GNE myopathy for clinical trials.


Assuntos
Miopatias Distais/epidemiologia , Complexos Multienzimáticos/genética , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , Miopatias Distais/genética , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem
13.
Neurol Clin ; 32(3): 817-42, x, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25037092

RESUMO

In this article, distal myopathy syndromes are discussed. A discussion of the more traditional distal myopathies is followed by discussion of the myofibrillar myopathies. Other clinically and genetically distinctive distal myopathy syndromes usually based on single or smaller family cohorts are reviewed. Other neuromuscular disorders that are important to recognize are also considered, because they show prominent distal limb weakness.


Assuntos
Miopatias Distais/diagnóstico , Idade de Início , Progressão da Doença , Miopatias Distais/epidemiologia , Miopatias Distais/genética , Humanos , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação
14.
J Neurol Neurosurg Psychiatry ; 85(12): 1359-65, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24695763

RESUMO

OBJECTIVE: GNE myopathy is a rare recessive myopathy associated with inclusion bodies on muscle biopsy. The clinical phenotype is associated with distal muscle weakness with quadriceps sparing. Most of the current information on GNE myopathy has been obtained through studies of Jewish and Japanese patient cohorts carrying founder mutations in the GNE gene. However, little is known about GNE myopathy in Europe where the prevalence is thought to be very low. METHODS: Patients were referred through the National Specialist Commissioning Team service for limb-girdle muscular dystrophies at Newcastle (UK). All patients harbouring mutations in the GNE gene were recruited for our study. Detailed clinical and genetic data as well as muscle MRIs and muscle biopsies were reviewed. RESULTS: We identified 26 patients harbouring mutations in the GNE gene. Two previously reported mutations (c.1985C>T, p.Ala662Val and c.1225G>T, p.Asp409Tyr) were prevalent in the Scottish, Northern Irish and Northern English populations; with 90% of these patients carrying at least one of the two mutations. Clinically, we confirmed the homogenous pattern of selective quadriceps sparing but noted additional features like asymmetry of weakness at disease onset. CONCLUSIONS: GNE myopathy is an important diagnosis to consider in patients presenting with distal leg muscle weakness. We report, for the first time, two common mutations in the north of Britain and highlight the broader spectrum of clinical phenotypes. We also propose that the prevalence of GNE myopathy may be underestimated due to the frequent absence of rimmed vacuoles in the muscle biopsy.


Assuntos
Miopatias Distais/genética , Complexos Multienzimáticos/genética , Mutação/genética , Adolescente , Adulto , Criança , Miopatias Distais/epidemiologia , Miopatias Distais/patologia , Feminino , Mutação da Fase de Leitura/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Debilidade Muscular/genética , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Mutação de Sentido Incorreto/genética , Reino Unido/epidemiologia , Adulto Jovem
15.
Rev Neurol (Paris) ; 169(8-9): 534-45, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24008050

RESUMO

The distal myopathies are a heterogeneous group of genetic disorders defined by a predominant distal weakness at onset or throughout the evolution of the disease and by pathological data supporting a myopathic process. The number of genes associated with distal myopathies continues to increase. Fourteen distinct distal myopathies are currently defined by their gene and causative mutations, compared to just five entities delineated on clinical grounds two decades ago. The known proteins affected in the distal myopathies are of many types and include a significant number of sarcomeric proteins. The useful indicators for clinicians to direct towards a correct molecular diagnosis are the mode of inheritance, the age at onset, the pattern of muscle involvement, the serum creatine kinase level and the muscle pathology findings. This review gives an overview of the clinical and genetic characteristics of the currently identified distal myopathies with emphasis on some recent findings.


Assuntos
Miopatias Distais/genética , Adulto , Idade de Início , Criança , Miopatias Distais/classificação , Miopatias Distais/epidemiologia , Genes Dominantes , Genes Recessivos , Humanos , Padrões de Herança , Distrofia Muscular Oculofaríngea/diagnóstico , Distrofia Muscular Oculofaríngea/epidemiologia , Distrofia Muscular Oculofaríngea/genética
16.
Neurol India ; 61(4): 371-4, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24005727

RESUMO

BACKGROUND: GNE myopathy is a clinicopathologically distinct distal myopathy with autosomal-recessive inheritance. The GNE gene mutations are known to cause this form of distal myopathy MATERIALS AND METHODS: Over the last 6 years, a total of 54 patients from 48 families were diagnosed to have GNE myopathy based on the clinical and histopathological findings. We have reported on 23 cases earlier and from this cohort 12 patients from 11 families underwent genetic testing for GNE mutation. RESULTS: Nine patients belonging to eight families were confirmed as GNE myopathy by genetic analysis. There were six women and three men. Mean age of onset was 26.7 ± 5.47 years (20-36 years) and mean age at clinical examination was 32.3 ± 4.2 years (28-39 years). Mean duration of the illness was 5.7 ± 4.7 years (1-14 years). All had characteristic clinical features of progressive weakness and wasting of the anterior part of leg muscles, adductors of thighs and hamstrings with relative sparing of the quadriceps muscles. Biopsy from the tibialis anterior muscles revealed the presence of rimmed vacuoles. Mutation analysis of the GNE gene revealed that c. 2086G > A (p.Val696Met) change was common in our series like Thailand and six of eight families carried this mutation, heterozygously. CONCLUSION: These results show the presence of a common mutation in GNE gene in Southeast Asia.


Assuntos
Miopatias Distais/epidemiologia , Miopatias Distais/genética , Complexos Multienzimáticos/genética , Mutação/genética , Adulto , Biópsia , Estudos de Coortes , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Índia , Masculino , Músculo Esquelético/patologia , Adulto Jovem
17.
Clin Genet ; 84(6): 589-92, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23278550

RESUMO

GNE myopathy or hereditary inclusion body myopathy (HIBM) is an ultra-rare severely disabling autosomal recessive adult onset muscle disease which affects roughly one to three individuals per million worldwide. Genetically, HIBM is caused by mutations in the glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase gene (GNE), resulting in diminished enzyme function and reduced sialic acid biosynthesis. A founder variant GNE p.M712T was first described in patients of Iranian and Middle-Eastern descent living outside of Iran. Asymptomatic heterozygote or carrier frequency has been reported as high as 1 in 11 within the Persian-Jewish community residing in Los Angeles, CA. To investigate the prevalence of the p.M712T variant in Iran, we studied 792 samples collected from random individuals in Sangesar (Mahdishahr) in Northern Iran. DNA samples were obtained by buccal swab, and genotyping was performed by melting curve analysis. The results included 31 of 792 (3.91%) heterozygous carriers and 5 (0.31%) homozygotes for GNE p.M712T. All five homozygous individuals, age 30-64 years, were already symptomatic at the start of the study. Our findings suggest that the prevalence of GNE p.M712T is higher in the Sangesar population, comprised mostly of Muslim and Bahai descendants, compared with the general world population. Additional HIBM distribution studies are warranted within various subpopulations of Iran.


Assuntos
Miopatias Distais/epidemiologia , Miopatias Distais/genética , Complexos Multienzimáticos/genética , Mutação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Miopatias Distais/diagnóstico , Feminino , Genótipo , Geografia , Humanos , Lactente , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Adulto Jovem
18.
Neuromuscul Disord ; 23(1): 84-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23127962

RESUMO

GNE myopathy is a rare and mildly progressive autosomal recessive myopathy caused by GNE mutations. Respiratory dysfunction has not been reported in GNE myopathy patients. In this study, we retrospectively reviewed the respiratory function of 39 severely affected GNE myopathy patients (13 men, 26 women) from medical records, and compared these parameters with various other patient characteristics (e.g., GNE mutations, age at onset, creatine kinase levels, and being wheelchair-bound) for correlations. The mean % forced vital capacity [FVC] was 92 (26) (range, 16-128). In 12/39 (31%) patients, %FVC was <80%. Of these 12 patients, 11 (92%) were entirely wheelchair-dependent. These patients exhibited significantly earlier onset (20 [4] vs. 30 [8] years, p<0.001) and lower creatine kinase levels (56 [71] vs. 279 [185] IU/L) than patients with normal respiratory function. Two patients exhibited severe respiratory failure and required non-invasive positive pressure ventilation. Patients with a homozygous mutation in the N-acetylmannosamine kinase domain exhibited lower %FVC, while only one compound heterozygous patient with separate mutations in the uridinediphosphate-N-acetylglucosamine 2-epimerase and the N-acetylmannosamine kinase domains had respiratory dysfunction. Our results collectively suggest that GNE myopathy can cause severe respiratory failure. Respiratory dysfunction should be carefully monitored in patients with advanced GNE myopathy characterized by early onset and homozygous homozygous mutations in the N-acetylmannosamine kinase domain.


Assuntos
Miopatias Distais/genética , Miopatias Distais/fisiopatologia , Mutação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Sistema Respiratório/fisiopatologia , Adulto , Idade de Início , Creatina Quinase/metabolismo , Miopatias Distais/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Estudos Retrospectivos , Capacidade Vital/fisiologia
19.
Neuromuscul Disord ; 22(1): 5-12, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22197426

RESUMO

Distal myopathies are a group of muscle diseases which share the clinical pattern of predominant weakness in the feet and/or hands. Rapid advance in the understanding of underlying gene defects have to date separated more than 20 distinct disorders and many are yet without genetic characterisation. No definite diagnosis can be made on other grounds than identification of the final molecular genetic defect. Besides usual investigations including EMG and muscle biopsy, muscle imaging is very important in defining the precise pattern of muscle involvement. Based on the combination of age at onset, mode of inheritance, pathology and muscle imaging, the number of underlying candidate genes for a certain disease can be significantly reduced, which is of help for the molecular genetic approach.


Assuntos
Miopatias Distais/diagnóstico , Miopatias Distais/genética , Idade de Início , Biópsia , Miopatias Distais/epidemiologia , Mãos , Humanos
20.
Clin Neurol Neurosurg ; 111(7): 613-8, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19493611

RESUMO

Dysferlinopathy refers to a variety of autosomal recessive, skeletal muscle disorders due to the mutations of dysferlin-encoding gene, DYSF. It encompasses limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), distal myopathy with anterior tibial onset (DMAT), isolated hyperCKemia, rigid spine syndrome and congenital muscular dystrophy. Herein, we report five Thai patients with distal myopathy due to dysferlinopathy including four MM and one DMAT patients. Muscle biopsy from one MM patient depicted numerous ring fibers which is an atypical finding in dysferlinopathy. Mutation analysis of DYSF revealed novel compound heterozygous mutations of p.Tyr309X and c.236+1G>T in two related MM patients, known homozygous mutations, p.Arg89X and p.Gln176X, in two MM patients and a heterozygous missense mutation, p.Arg555Trp, in a DMAT patient. Most of the previously reported DMAT patients were Hispanic. To the best of our knowledge, this is the first report of genetically confirmed patients with dysferlinopathy in Thailand.


Assuntos
Miopatias Distais/genética , Proteínas de Membrana/genética , Proteínas Musculares/genética , Adulto , Western Blotting , Creatina Quinase/sangue , Miopatias Distais/epidemiologia , Miopatias Distais/patologia , Disferlina , Éxons/genética , Família , Feminino , Humanos , Imuno-Histoquímica , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Força Muscular , Músculo Esquelético/patologia , Mutação/fisiologia , Polimorfismo Genético/genética , Polimorfismo Genético/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tailândia/epidemiologia , Adulto Jovem
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