RESUMEN
PURPOSE: To evaluate differences in diffusion parameters in thigh muscles in patients with glycogen storage disease type V (McArdle disease) using muscle diffusion tensor imaging (mDTI) compared to healthy controls METHODS: In this prospective study, we evaluated thigh muscles from hip to knee of 10 McArdle patients (5 female, mean age 33.7 ± 14.4 years) and 10 healthy age- and gender-matched volunteers. MRI scans were performed at 3 T and comprised mDTI, T1-weighted and T2-weighted imaging between May 2015 and May 2017. Needle biopsy of the vastus lateralis muscle was performed in three McArdle patients. The muscle tissue was analyzed by using histochemical and enzyme-histochemical techniques for glycogen content and histopathological changes. Mean values of the eigenvalues (λ1-λ3), fractional anisotropy (FA), and mean diffusivity (MD) were obtained for the vastus lateralis, vastus medialis, rectus femoris, biceps femoris, semitendinosus, and semimembranosus and compared between groups using Student's t tests, as well as ANCOVA; significance level was set at p < 0.05. RESULTS: Needle biopsy showed intracellular glycogen accumulation in skeletal muscle fibers of three McArdle patients. Extracellular histopathological changes were not found. Muscle DTI analysis did not show statistically significant differences between patients and controls for any of the muscles. CONCLUSION: Despite intracellular glycogen accumulation in the three biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. We conclude that the currently used mDTI acquisition and processing lack the sensitivity to detect intracellular changes due to accumulated glycogen in this cohort of McArdle patients. KEY POINTS: ⢠Despite intracellular glycogen accumulation in three examined biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. ⢠In its current form, diffusion MR does not provide additional information in quantifying intracellular glycogen accumulations within skeletal muscle fibers in McArdle patients.
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Imagen de Difusión Tensora , Enfermedad del Almacenamiento de Glucógeno Tipo V/diagnóstico por imagen , Músculo Esquelético/diagnóstico por imagen , Muslo/diagnóstico por imagen , Adulto , Anisotropía , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo V/patología , Músculos Isquiosurales/diagnóstico por imagen , Músculos Isquiosurales/patología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Estudios Prospectivos , Músculo Cuádriceps/diagnóstico por imagen , Músculo Cuádriceps/patología , Muslo/patología , Adulto JovenRESUMEN
Here we present the generation of HIMRi006-A and HIMRi007-A Pompe disease (PD) patient derived human induced pluripotent stem cell (hiPSC) lines. HIMRi006-A represents an infantile onset disease (IOPD) phenotype caused by a homozygous c.307 T > G mutation in the GAA gene. HIMRi007-A is characterized by heterozygous mutations c.-32-13 T > G/c.1716C > G and is associated with an adult onset of disease symptoms (LOPD). Both lines are generated via lentiviral expression of OCT4, SOX2, KLF4, and c-MYC. The lines display a typical embryonic stem cell morphology, express pluripotency markers, retain a normal karyotype (46, XX/XY) and have the differentiation capacity in all three germ layers. Altogether, both lines provide a resource tool to the community for future in depth molecular studies of PD pathomechanism.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Células Madre Pluripotentes Inducidas , Factor 4 Similar a Kruppel , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Enfermedad del Almacenamiento de Glucógeno Tipo II/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación Celular , Línea Celular , Masculino , Lactante , Mutación , FemeninoRESUMEN
Here we introduce the human induced pluripotent stem cell lines (hiPSCs), HIMRi004-A and HIMRi005-A from dermal fibroblasts of a 48-year-old female (HIMRi004-A) carrying missense mutation that translate to the first described filamin C isoform p.W2710X and from a 56-year-old female (HIMRi005-A) carrying a recently described mutation in the same domain p.Y2704X. Both lines are generated via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. The lines display a typical embryonic stem cell-like morphology, express pluripotency markers, retain a normal karyotype (46, XX) and have the differentiation capacity in all three germ layers. The two lines can be used to elucidate the pathomechanisms of FLNC myofibrillar myopathies and to develop novel therapeutic options.
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Células Madre Pluripotentes Inducidas , Femenino , Humanos , Persona de Mediana Edad , Diferenciación Celular/genética , Línea Celular , Dimerización , Fibroblastos/metabolismo , Filaminas/genética , Filaminas/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Mutación/genéticaRESUMEN
Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.
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Caveolinas/genética , Contracción Muscular , Músculo Esquelético , Enfermedades Musculares/genética , Mutación Missense , Caveolina 3 , Creatina Quinasa/sangre , Proteínas del Citoesqueleto/genética , Humanos , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Estimulación FísicaRESUMEN
Metabolic myopathies include a broad group of diseases involving inherited enzyme defects in the various metabolic pathways and skeletal musculature. They show an extensive phenotypic variability of symptoms and different ages of manifestation. Symptoms often included intolerance to duress or permanent paresis. Some forms of metabolic myopathy, in particular mitochondriopathy, are associated with multsystemic organ participation. The diagnostics must be adjusted to individual cases and carried out in stages. Primary investigations should include blood parameters (e.g. creatine kinase measurement, muscle load tests and determination of the acylcarnitine spectrum) and a second step includes muscle biopsy for histological and enzyme investigations and special molecular genetic tests although the causative enzyme defect cannot be clarified in every case. On the other hand by means of a thorough investigation it is particularly important in patients with load intolerance to differentiate between other causes, in particular psychosomatic diseases. If this is not done there is a danger of classifying the symptoms of a metabolic myopathy as a somatoform disorder. Therapy is mostly symptom-oriented as Pompe disease is the only one which can be treated with enzyme replacement therapy.
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Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/terapia , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/terapia , HumanosRESUMEN
As Pompe disease glycogen storage disease type 2 with a severely reduced life expectancy is now a treatable disorder, accurate diagnostic procedures and evidence-based indications for therapy are mandatory. We screened the literature for consensus reports and published trial data of late-onset Pompe disease. These data were summarized in a Delphi consensus method approach. The clinical suspicion of late-onset Pompe disease should be substantiated by the validated dry blood spot test measurement for acid α-glucosidase activity. Alternatively, enzyme activity analysis in lymphocytes is also feasible. Glucosidase α gene sequencing for verifying the diagnosis is recommended. A muscle biopsy including measurements of acid α-glucosidase activity and glycogen concentration is warranted for differential diagnosis in selected cases. The confirmed diagnosis should lead to a multidisciplinary treatment approach, possibly including enzyme replacement therapy.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Adulto , Factores de Edad , Biopsia , Conducta Cooperativa , Estudios Transversales , Técnica Delphi , Diagnóstico Diferencial , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Adhesión a Directriz , Humanos , Comunicación Interdisciplinaria , Imagen por Resonancia Magnética , Músculo Esquelético/patología , Examen Neurológico , Ensayos Clínicos Controlados Aleatorios como Asunto , alfa-Glucosidasas/uso terapéuticoRESUMEN
Here we introduce the human induced pluripotent stem cell (hiPSC) line HIMRi001-A generated from cultured dermal fibroblasts of a 60-year-old male patient with a myofibrillar myopathy, carrying a heterozygous c.4984C > T [p.Q1662X] mutation in the filamin C (FLNC)-gene, via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. HIMRi001-A displays typical embryonic stem cell-like morphology, carries the c.4984C > T FLNC gene mutation, expressed several pluripotent stem cell makers, retained normal karyotype (46, XY) and holds the potential to differentiate in all three germ layers. We postulate that HIMRi001-A can be used for the elucidation of FLNC-associated pathomechanisms and for developing new therapeutic options.
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Células Madre Pluripotentes Inducidas , Células Madre Pluripotentes , Masculino , Humanos , Persona de Mediana Edad , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Fibroblastos/metabolismo , Mutación , Diferenciación Celular/genéticaRESUMEN
Here we introduce the human induced pluripotent stem cell lines (hiPSCs), HIMRi002-A and HIMRi003-A, generated from cultured dermal fibroblasts of 61-year-old (HIMRi002-A) and 38-year-old (HIMRi003-A) female patients, carrying a known heterozygous pathogenic variant (p.A46T) in the Caveolin 3 (CAV3) gene, via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. HIMRi002-A and HIMRi003-A display typical embryonic stem cell-like morphology, carry the p.A46T CAV3 gene mutation, express several pluripotent stem cell markers, retain normal karyotype (46, XX) and can differentiate in all three germ layers. We postulate that the HIMRi002-A and HIMRi003-A iPSC lines can be used for the characterization of CAV3-associated pathomechanisms and for developing new therapeutic options.
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Células Madre Pluripotentes Inducidas , Enfermedades Musculares , Células Madre Pluripotentes , Humanos , Femenino , Persona de Mediana Edad , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Fibroblastos/metabolismo , Mutación , Diferenciación Celular/genéticaRESUMEN
We summarize the current therapeutic strategies and options in inflammatory myositis and the muscular dystrophies. In myositis, the therapeutic options include basic therapy with glucocorticosteroids and other standard immunosuppressive agents, and in individual cases escalating treatment with chemotherapy or monoclonal antibodies. The exact therapeutic sequence should be performed depending on the type of myositis and the response to immunosuppression.At present, there are still no effective causative interventions to significantly alter the progression of the muscular dystrophies. However, first gene therapy clinical studies have been started in some forms of muscular dystrophy which may open a new field of therapeutic options. Most patients with myositis or muscular dystrophy need symptom-oriented therapies which include physical therapy, adequate cardiorespiratory treatment and orthopedic interventions. In the future novel immunosuppressive options may be available in patients with myositis and possibly causative strategies in the muscular dystrophies.
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Anticuerpos Monoclonales/uso terapéutico , Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Distrofias Musculares/tratamiento farmacológico , Miositis/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: Myotonic Dystrophies type 1 and type 2 are hereditary myopathies with dystrophic muscle degeneration in varying degrees. Differences in muscle diffusion between both diseases have not been evaluated yet. OBJECTIVE: To evaluate the ability of muscle diffusion tensor imaging (mDTI) and Dixon fat-quantification to distinguish between Myotonic Dystrophy (DM) type 1 and type 2 and if both diseases show distinct muscle involvement patterns. METHODS: We evaluated 6 thigh and 7 calf muscles (both legs) of 10 DM 1, 13 DM 2 and 28 healthy controls (HC) with diffusion tensor imaging, T1w and mDixonquant sequences in a 3T MRI scanner. The quantitative mDTI-values axial diffusivity (λ1), mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA) as well as fat-fraction were analysed. CTG-triplet repeat-length of DM 1 patients was correlated with diffusion metrics and fat-fraction. RESULTS: mDTI showed significant differences between DM 1 and DM 2 vs. healthy controls in diffusion parameters of the thigh (all pâ<â0.001) except for FA (pâ=â0.0521 / 0.8337). In calf muscles mDTI showed significant differences between DM 1 and DM 2 patients (all pâ<â0.0001) as well as between DM 1 patients and controls (all pâ=â0.0001). Thigh muscles had a significant higher fat-fraction in both groups vs. controls (pâ<â0.05). There was no correlation of CTG triplet length with mDTI values and fat-fraction. DISCUSSION: mDTI reveals specific changes of the diffusion parameters and fat-fraction in muscles of DM 1 and DM 2 patients. Thus, the quantitative MRI methods presented in this study provide a powerful tool in differential diagnosis and follow-up of DM 1 and DM 2, however, the data must be validated in larger studies.
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Imagen de Difusión Tensora/métodos , Distrofia Miotónica/diagnóstico por imagen , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Pierna/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Músculo Esquelético , Estudios Prospectivos , Adulto JovenRESUMEN
UNLABELLED: In patients with late-onset glycogen storage disease type II, one mutation, c.-32-13T>G, in the α-glucosidase (GAA) gene is identified frequently in European populations from different regions along with many rarer mutations. We have performed molecular genetic investigations in 18 German index patients with late-onset disease. The c.-32-13T>G, c.525delT (p.Glu176fsX45), and c.2481+102_2646+31del mutations were detected by PCR/restriction enzyme digest. Other mutations were detected by sequencing. All patients were compound heterozygous and 17 patients harboured the c.-32-13T>G mutation. Seven other previously described mutations (including the c.-32-13T>G) were identified, of which the p.C103G (c.307T>G) and the c.2481+102_2646+31del mutations were present each in three unrelated patients. Sequencing revealed five novel mutations. CONCLUSIONS: Genetic testing was able to identify the genetic defects in all patients and screening of the c.-32-13T>G mutation identified 94% of the cases. This is important for quick and reliable diagnosis, especially in view of enzyme replacement. Among the rarer mutations, c.2481+102_2646+31del and p.C103G are rather frequent in Germany.
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Pruebas Genéticas , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Mutación , alfa-Glucosidasas/genética , Adulto , Edad de Inicio , Anciano , Estudios de Casos y Controles , Análisis Mutacional de ADN , Exones , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Alemania/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo II/etnología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Heterocigoto , Humanos , Intrones , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Adulto JovenRESUMEN
In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named 'scapuloperoneal syndrome type Kaeser' (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absent.
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Desmina/genética , Miopatías Distales/genética , Mutación Missense , Adulto , Anciano de 80 o más Años , Biopsia , Análisis Mutacional de ADN/métodos , Miopatías Distales/patología , Femenino , Haplotipos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Linaje , Fenotipo , Factores Sexuales , SíndromeRESUMEN
Non-insulin-dependent diabetes mellitus (NIDDM) is caused by peripheral insulin resistance and impaired beta cell function. Phosphofructo-1-kinase (PFK1) is a rate-limiting enzyme in glycolysis, and its muscle subtype (PFK1-M) deficiency leads to the autosomal recessively inherited glycogenosis type VII Tarui's disease. It was evaluated whether PFK1-M deficiency leads to alterations in insulin action or secretion in humans. A core family of four members was evaluated for PFK1-M deficiency by DNA and enzyme-activity analyses. All members underwent oral and intravenous glucose tolerance tests (oGTT and ivGTT) and an insulin-sensitivity test (IST) using octreotide. Enzyme activity determinations in red blood cells showed that the father (46 yr, body mass index [BMI] 22. 4 kg/m2) and older son (19 yr, BMI 17.8 kg/m2) had a homozygous, while the mother (47 yr, BMI 28.4 kg/m2) and younger son (13 yr, BMI 16.5 kg/m2) had a heterozygous PFK1-M deficiency. DNA analyses revealed an exon 5 missense mutation causing missplicing of one allele in all four family members, and an exon 22 frameshift mutation of the other allele of the two homozygously affected individuals. The father showed impaired glucose tolerance, and the mother showed NIDDM. By ivGTT, both parents and the older son had decreased first-phase insulin secretion and a diminished glucose disappearance rate. The IST showed marked insulin resistance in both parents and the older, homozygous son, and moderate resistance in the younger son. PFK1-M deficiency causes impaired insulin secretion in response to glucose, demonstrating its participation in islet glucose metabolism, and peripheral insulin resistance. These combined metabolic sequelae of PFK-1 deficiency identify it as a candidate gene predisposing to NIDDM.
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Resistencia a la Insulina/genética , Insulina/metabolismo , Isoenzimas/deficiencia , Fosfofructoquinasa-1/deficiencia , Adulto , Niño , Femenino , Prueba de Tolerancia a la Glucosa , Glutamato Descarboxilasa/metabolismo , Hemoglobina Glucada/metabolismo , Humanos , Secreción de Insulina , Isoenzimas/genética , Masculino , Persona de Mediana Edad , Fosfofructoquinasa-1/genética , Mutación Puntual , Proinsulina/metabolismoRESUMEN
BACKGROUND: McArdle disease, a common metabolic myopathy with autosomal recessive inheritance, is caused by a frequent R50X mutation and many rare mutations in the myophosphorylase gene. OBJECTIVES: To identify spectrum and frequencies of myophosphorylase gene mutations in a large cohort of patients with McArdle disease, to discuss diagnostic implications, and to analyse genotype-phenotype relationship. METHODS: Molecular genetic analysis of 56 index patients with muscle biopsy-proven myophosphorylase deficiency from Germany (n = 35), UK (n = 13), and several other countries (n = 8) was performed using direct sequencing. RESULTS: Allele frequency of the R50X mutation was 58%, and 71% of the patients carried this mutation at least on one allele. We detected 26 other less common mutations, 13 of which are novel: G157V, R161C, Q337R, E384K, S450L, G486D, R570W, K575E, IVS6-2A>T, IVS10+1G>A, R650X, c.1354insC, c.1155_1156delGG. There was no genotype-phenotype correlation with respect to age of onset and severity. R270X was the most frequent mutation among the less common mutations reaching an allele frequency of 5% followed by R94W and G686R representing a frequency of 4% each. CONCLUSIONS: The study further extends the genetic heterogeneity of myophosphorylase gene mutations showing no mutational hotspot and no genotype-phenotype correlation. Most novel missense mutations were located in secondary structures or active sites of the enzyme. Some of the less common mutations are recurrent with different frequencies within Europe. Ethnic origin and frequency of less common mutations must be considered to establish efficient strategies in molecular genetic testing. Performing molecular testing can avoid muscle biopsy.
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Predisposición Genética a la Enfermedad/genética , Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Músculo Esquelético/enzimología , Mutación Missense/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Estudios de Cohortes , Análisis Mutacional de ADN , Progresión de la Enfermedad , Europa (Continente) , Femenino , Frecuencia de los Genes , Heterogeneidad Genética , Predisposición Genética a la Enfermedad/etnología , Pruebas Genéticas , Genotipo , Enfermedad del Almacenamiento de Glucógeno Tipo V/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo V/etnología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Fenotipo , Polimorfismo GenéticoRESUMEN
BACKGROUND: Progressive muscle weakness is a main symptom of most hereditary muscle diseases. Creatine is a popular nutritional supplement among athletes. It improves muscle performance in healthy individuals and might be helpful for treating myopathies. OBJECTIVES: To evaluate the efficacy of oral creatine supplementation in muscle diseases. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register in May 2004 for randomised trials using the search term 'creatine'. We also searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2005) using the same search term. We adapted this strategy to search MEDLINE (PubMed, from January 1966 to September 2005) and EMBASE (from January 1980 to May 2004). We reviewed the bibliographies of the randomised trials identified, contacted the authors and known experts in the field and approached pharmaceutical companies to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: randomised or quasi-randomised controlled trials. TYPES OF PARTICIPANTS: people of all ages with hereditary muscle disease. Types of intervention: any creatine supplementation of at least 0.03 g/kg body weight/day. PRIMARY OUTCOME MEASURE: change in muscle strength measured by quantitative muscle testing. SECONDARY OUTCOME MEASURES: change in muscle strength measured by manual muscle testing, change in energy parameters assessed by 31 phosphorous spectroscopy, change in muscle mass or a surrogate for muscle mass, adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria, assessed trial quality and extracted data. Some missing data were obtained from investigators. MAIN RESULTS: Twelve trials, including 266 participants, met the selection criteria. One trial compared creatine and glutamine treatment with placebo. In trials with 138 participants with muscular dystrophies treated with creatine, there was a significant increase in maximum voluntary contraction in the creatine group compared to placebo, with a weighted mean difference of 8.47% (95% confidence intervals 3.55 to 13.38). There was also an increase in lean body mass during creatine treatment compared to placebo (weighted mean difference 0.63 kg, 95% confidence intervals 0.02 to 1.25). No trial reported any clinically relevant adverse event. In trials with 33 participants with metabolic myopathies treated with creatine, there was no significant difference in maximum voluntary contraction between the creatine and placebo group (weighted mean difference -2.26%, confidence intervals -6.29 to 1.78). One trial reported a significant increase in muscle pain during high-dose creatine treatment (150 mg/kg body weight) in glycogen storage disease type V. AUTHORS' CONCLUSIONS: Evidence from randomised controlled trials shows that short- and medium-term creatine treatment improves muscle strength in people with muscular dystrophies, and is well-tolerated. Evidence from randomised controlled trials does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine in glycogenosis type V increased muscle pain.
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Creatina/uso terapéutico , Suplementos Dietéticos , Fuerza Muscular/efectos de los fármacos , Enfermedades Musculares/tratamiento farmacológico , Humanos , Contracción Muscular/efectos de los fármacos , Fuerza Muscular/fisiología , Distrofias Musculares/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
McArdle's disease is caused by genetic defects of the muscle-specific isozyme of glycogen phosphorylase, which block ATP formation from glycogen in skeletal muscle. Creatine supplementation and ketogenic diet have been tested as potential supplements for muscle energy metabolism which may improve muscle symptomatic. Outcome measures were clinical scores describing muscle symptomatic and parameters derived from 31P-MRS examinations on working muscle. In two placebo controlled cross-over studies low dose creatine showed beneficial effects on muscle symptoms and performance whereas high dose creatine distinctly worsened muscle symptomatic in patients. In both studies, however, the absence of an elevation in phosphocreatine indicated the absence of a creatine uptake by the muscle fibre. The effects of creatine on muscle symptomatic may be independent from energy metabolism in muscle. In a case study, ketogenic diet improved muscle symptomatic and performance. However, these effects again did not result in 31P-MRS visible changes in muscle energy metabolism.
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Creatina/uso terapéutico , Enfermedad del Almacenamiento de Glucógeno Tipo V/dietoterapia , Enfermedad del Almacenamiento de Glucógeno Tipo V/tratamiento farmacológico , Músculo Esquelético/fisiopatología , Suplementos Dietéticos , Enfermedad del Almacenamiento de Glucógeno Tipo V/fisiopatología , Humanos , Resultado del TratamientoRESUMEN
The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes.
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Heterogeneidad Genética , Técnicas de Diagnóstico Molecular/métodos , Proteínas Musculares/genética , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/genética , Análisis Mutacional de ADN/métodos , Bases de Datos Genéticas/estadística & datos numéricos , Diagnóstico Diferencial , Salud de la Familia , Genotipo , Humanos , Técnicas de Diagnóstico Molecular/economía , Enfermedades Neuromusculares/clasificaciónRESUMEN
INTRODUCTION: Myofibrillar myopathies are characterized by progressive muscle weakness and impressive abnormal protein aggregation in muscle fibers. In about 10 % of patients, the disease is caused by mutations in the MYOT gene encoding myotilin. The aim of our study was to decipher the composition of protein deposits in myotilinopathy to get new information about aggregate pathology. RESULTS: Skeletal muscle samples from 15 myotilinopathy patients were included in the study. Aggregate and control samples were collected from muscle sections by laser microdissection and subsequently analyzed by a highly sensitive proteomic approach that enables a relative protein quantification. In total 1002 different proteins were detected. Seventy-six proteins showed a significant over-representation in aggregate samples including 66 newly identified aggregate proteins. Z-disc-associated proteins were the most abundant aggregate components, followed by sarcolemmal and extracellular matrix proteins, proteins involved in protein quality control and degradation, and proteins with a function in actin dynamics or cytoskeletal transport. Forty over-represented proteins were evaluated by immunolocalization studies. These analyses validated our mass spectrometric data and revealed different regions of protein accumulation in abnormal muscle fibers. Comparison of data from our proteomic analysis in myotilinopathy with findings in other myofibrillar myopathy subtypes indicates a characteristic basic pattern of aggregate composition and resulted in identification of a highly sensitive and specific diagnostic marker for myotilinopathy. CONCLUSIONS: Our findings i) indicate that main protein components of aggregates belong to a network of interacting proteins, ii) provide new insights into the complex regulation of protein degradation in myotilinopathy that may be relevant for new treatment strategies, iii) imply a combination of a toxic gain-of-function leading to myotilin-positive protein aggregates and a loss-of-function caused by a shift in subcellular distribution with a deficiency of myotilin at Z-discs that impairs the integrity of myofibrils, and iv) demonstrate that proteomic analysis can be helpful in differential diagnosis of protein aggregate myopathies.
Asunto(s)
Inmunohistoquímica , Proteínas Musculares/metabolismo , Miopatías Estructurales Congénitas , Agregación Patológica de Proteínas/etiología , Proteómica , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Espectrometría de Masas , Microscopía Confocal , Persona de Mediana Edad , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mutación/genética , Miopatías Estructurales Congénitas/complicaciones , Miopatías Estructurales Congénitas/metabolismo , Miopatías Estructurales Congénitas/patología , Agregación Patológica de Proteínas/patologíaRESUMEN
Friedreich's ataxia (FA) is an autosomal recessive disease that has been attributed to a GAA triplet repeat expansion in the first intron of the X25/frataxin gene. Impaired glucose tolerance is present in up to 39% of FA patients, and clinically apparent diabetes is seen in approximately 18% of the affected individuals. Subjects carrying the X25/frataxin GAA repeat in a heterozygous state do not develop FA and, therefore, represent an ideal model to study the underlying metabolic defects that contribute to the diabetes associated with this disorder. In the present study, we have compared 11 first-degree relatives of FA patients (i.e., parents or heterozygous siblings of FA patients) with matched normal control subjects to study the parameters of glucose metabolism. An oral glucose tolerance test revealed diabetes in one of the heterozygous subjects who was excluded from further analyses. Using an octreotide-based quantification of insulin sensitivity, 8 of the remaining 10 study subjects showed pronounced insulin resistance, reflecting a significant difference from the control group (P = 0.001). In conclusion, a heterozygous expansion of the X25/frataxin GAA repeat in healthy individuals is associated with insulin resistance and might be considered a genetic co-factor in the pathogenesis of mitochondrial subtypes of diabetes.
Asunto(s)
Glucemia/metabolismo , Resistencia a la Insulina/genética , Proteínas de Unión a Hierro , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Expansión de Repetición de Trinucleótido , Femenino , Ataxia de Friedreich/genética , Genotipo , Prueba de Tolerancia a la Glucosa , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Núcleo Familiar , Octreótido , Valores de Referencia , FrataxinaRESUMEN
In healthy humans, insulin is secreted in an oscillatory manner. While the underlying mechanisms generating these oscillations are not fully established, increasing evidence suggests a central role for phosphofructo-1-kinase/muscle subtype (PFK1-M), which also serves as the predominantly active PFK1 subtype in the pancreatic beta-cell. The fact that normal oscillatory secretion is impaired in subjects with impaired glucose tolerance and healthy relatives of patients with type 2 diabetes suggests that this defect may be involved in the secretory dysfunction. To evaluate a possible link between inherited PFK1-M deficiency in humans (Tarui's disease or glycogenosis type VII) and altered insulin oscillations, in vivo studies were performed. We determined basal insulin oscillations during 2 h of frequent plasma sampling in two related teen-aged individuals with homozygous and heterozygous PFK1-M deficiency compared with nondeficient, unrelated control subjects. As predicted by the underlying hypothesis, normal oscillations in insulin secretion were completely abolished in the individual with homozygous deficiency of PFK1-M and significantly impaired in the heterozygous individual, as shown by spectral density and autocorrelation analyses. Thus, deficiency of PFK1-M subtype in humans appears to be associated with an impaired oscillatory insulin secretion pattern and may contribute to the commonly observed secretion defects occurring in type 2 diabetes.