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Ultrastructural changes in skeletal muscle biopsy in a 24-year-old female patient with clinically suspected mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome are presented. We observed proliferation and/or pleomorphism of mitochondria in skeletal muscle and smooth muscle cells of arterioles, as well as in pericytes of capillaries. Paracrystalline inclusions were found only in damaged mitochondria of skeletal muscle. Genetic testing revealed a point mutation in A3243G tRNALeu(UUR) typical for MELAS syndrome. We conclude that differentiated pathological changes of mitochondria in the studied types of cells may be associated with the different energy requirements of these cells.
Assuntos
Síndrome MELAS/patologia , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Feminino , Humanos , Síndrome MELAS/genética , RNA de Transferência de Leucina/genética , Adulto JovemRESUMO
The A3243G mutation is one of the most frequent mutations of mitochondrial DNA. The phenotypic expression of the A3243G mutation is variable and causes a wide range of syndromic and non-syndromic clinical disorders. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is the most frequent syndromic manifestation of the A3243G mutation. Stroke-like episodes seem to be the dominant feature of MELAS. We have investigated the case of a family with A3243G mutation, in which a dominant symptom in three generations was the maternally inherited hearing loss with absence of stroke-like episodes. Besides deafness, we found also other clinical features such as myopathy, neuropathy, migraine, ataxia, short stature, diabetes mellitus, and cardiomyopathy.
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DNA Mitocondrial/genética , Surdez/genética , Síndrome MELAS/genética , Substituição de Aminoácidos/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação/genética , Linhagem , FenótipoRESUMO
Background: Mitochondrial myopathy is a group of diseases caused by abnormal mitochondrial structure or function. The mitochondrial myopathy impacts muscles of the whole body and exhibits variable symptoms. Respiratory muscle deficits deteriorate pulmonary function in patients with severe pneumonia. Case presentation: We report the case of a male patient with severe pneumonia-induced respiratory failure. He was abnormally dependent invasive ventilator-assisted ventilation after his condition had improved. Then we found abnormal ventilator waveform and a decline in muscle strength of him. Mitochondrial myopathy was ultimately confirmed by muscle pathological biopsy and body fluid genetic testing. Vitamin B complex, coenzyme Q10, Neprinol AFD, l-arginine, and MITO-TONIC were used to improve mitochondrial function and muscle metabolism. After treatment, discomfort associated with chest tightness, fatigue, cough, and sputum disappeared, and the patient was discharged. Conclusion: This case presented an uncommon cause of difficult weaning and extubation-acute onset of mitochondrial myopathy. Muscle biopsy and genetic testing of body fluid are essential for diagnosing mitochondrial myopathy. The A3243G mutation in the MT-TL1 gene of mitochondrial DNA contributes to pathogenesis of this case.
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Isolated mitochondrial myopathy refers to the condition of mitochondrial disorders that primarily affect the skeletal muscle system. Here we report on a case of a patient who presented with acute respiratory failure as the initial and predominant clinical manifestation after using anesthetic drugs. The diagnosis of mitochondrial myopathy was made by histochemical findings of ragged red fibers with a modified Gomori trichrome Stain in the skeletal muscle biopsy and the genetic detection of an A3243G point mutation in the tRNALeu (UUR) gene of mitochondrial DNA (mtDNA) in a peripheral blood specimen. The patient revealed a benign clinical outcome with ventilator assistance and a cocktail treatment. Further, we performed a literature review on patients with respiratory failure as the early and predominant manifestation in adult-onset isolated mitochondrial myopathy. Eleven cases in nine studies (including our case) have been reported, and five of whom underwent DNA analysis all harbored the A3243G mutation in the tRNALeu gene of the mtDNA. Use of sedative drugs tends to induce acute respiratory failure in such cases.
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We report the case of a mother and two children who shared a mitochondrial DNA A3243G mutation. The mother had diabetes mellitus, neurogenic bladder, bradykinesia, dystonia, and slowly progressive cerebellar ataxia. Her two daughters were diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes at adolescence. They all presented with gastrointestinal symptoms at an advanced clinical stage. They were diagnosed with chronic intestinal pseudo-obstruction, and they were resistant to therapy. The mother and her youngest daughter died from aspiration pneumonia because of vomiting. The determination of chronic intestinal pseudo-obstruction is an important prognostic factor in patients with the mitochondrial DNA A3243G variant.
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DNA Mitocondrial/genética , Predisposição Genética para Doença , Pseudo-Obstrução Intestinal/genética , Síndrome MELAS/genética , Síndrome MELAS/terapia , Mutação Puntual/genética , Adulto , Análise Mutacional de DNA , Evolução Fatal , Feminino , Humanos , Pseudo-Obstrução Intestinal/diagnóstico , Síndrome MELAS/diagnóstico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: MELAS syndrome -myopathy, encephalopathy, lactic acidosis and stroke-like episodes- is a maternally-inherited mitochondrial cytopathy related to several mitochondrial DNA mutations, with the A3243G mutation in tRNALeu gene being the most frequent of them. PATIENTS AND METHODS: Apart from its typical symptomatology, patients usually exhibit a maternally-inherited history of neurosensory deafness and insulin-dependent type 2 diabetes mellitus (T2DM). Recent studies have shown that few patients carrying a A3243G mutation also suffer from renal dysfunction, usually in form of focal segmental glomerulosclerosis (FSGS). RESULTS: In this study we examine kidney involvement in 2 unrelated patients with a A3243G mutation by genetic testing. Both have a maternally-inherited neurosensory deafness and insulin-dependent T2DM. A renal biopsy was performed in both patients. One patient developed nephrotic proteinuria and renal insufficiency, with FSGS findings being observed in the kidney biopsy, whereas the other suffered from mild proteinuria and renal insufficiency, with non-specific glomerular changes. CONCLUSION: The presence of FSGS or other kidney involvement accompanied by hereditary neurosensory deafness and T2DM could be suggestive of a A3243G tRNALeu mutation and should prompt a genetic testing and an evaluation of potential extrarenal involvement.
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Glomerulosclerose Segmentar e Focal/etiologia , Síndrome MELAS/diagnóstico , Insuficiência Renal/etiologia , Adulto , Feminino , Glomerulosclerose Segmentar e Focal/diagnóstico , Humanos , Síndrome MELAS/complicações , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/diagnósticoRESUMO
OBJECTIVE: The aim of this study was to investigate the clinically latent brain atrophy of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) harboring a mitochondrial DNA A3243G mutation (A3243G) and A3243G carriers without stroke-like episodes (SEs). METHODS: We used voxel-based morphometry (VBM) with magnetic resonance imaging to investigate gray matter (GM) and white matter (WM) volume reductions in four MELAS patients and in five A3243G carriers compared to 16 healthy controls. In addition, we investigated the regions of previous SEs using conventional MRI. RESULTS: All four MELAS patients showed significant GM volume reductions in the left superior parietal lobule (SPL), right precuneus, right middle temporal gyrus (MTG), and bilateral posterior lobes of the cerebellum. These areas of GM volume reduction were beyond the regions of previous SEs. As for A3243G carriers, GM volume reductions in the left SPL, right precuneus, right MTG, and bilateral posterior lobes of the cerebellum were detected in three, one, two, and five subjects, respectively. All four MELAS patients showed significant WM volume reductions in the bilateral or unilateral temporal sub-gyral regions, which were included in the regions of previous SEs. No A3243G carriers showed WM volume reductions. CONCLUSION: The distribution patterns of GM volume reductions in VBM may reflect a common vulnerability of the brains among MELAS patients and A3243G carriers.
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Atrofia/patologia , Encéfalo/patologia , DNA Mitocondrial/genética , Síndrome MELAS/patologia , Mutação Puntual , Adolescente , Adulto , Antropometria , Atrofia/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
To investigate the mitochondrial mutations in patients suffering from both mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and maternally inherited diabetes. MELAS was confirmed by muscle biopsy performed from the biceps muscle of the proband. Mitochondrial DNA (mtDNA) was isolated from peripheral blood mononuclear cells. The significant mtDNA loci of other 14 family members were further detected according to the sequencing results of the proband. Direct sequencing of PCR products was used to identify the mitochondrial mutations. The proband (III 1) and her brother (III 3) both harbored the tRNALeu (UUR) A3243G mutation, with heteroplasmic levels of 50% and 33% respectively. Moreover, another two mitochondrial variants, A8860G and A15326G, were also detected in the samples of all the family members. MELAS and diabetes can coexist in one patient, and the main cause for these diseases is the tRNALeu (UUR) A3243G mutation. However, other gene variants may contribute to its pathogenesis. This case also supports the concept that both syndromes can be regarded as two phenotypes of the same disease.
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Povo Asiático/genética , DNA Mitocondrial/genética , Diabetes Mellitus/genética , Síndrome MELAS/genética , Mutação , RNA de Transferência de Leucina/genética , Adulto , Sequência de Bases , Biópsia , China , Análise Mutacional de DNA , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/etnologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/etnologia , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Adulto JovemAssuntos
Síndrome MELAS , Miopatias Mitocondriais , Acidose Láctica , DNA Mitocondrial , Humanos , Mutação , Acidente Vascular CerebralRESUMO
A 61-year-old diabetic woman with a mitochondrial A3243G mutation was hospitalized for evaluation of breathlessness, general fatigue, and leg edema. Chest radiography revealed cardiomegaly with massive pleural effusion. Serum lactate, pyruvate, and brain natriuretic peptide concentrations were elevated. Transthoracic echocardiography revealed a restrictive pattern of transmitral flow, although systolic function of the left ventricle was only mildly impaired. Based on these findings and her clinical course, the patient was diagnosed with right-sided heart failure caused by mitochondrial cardiomyopathy associated with a restrictive transmitral filling pattern. Treatment with furosemide, enalapril, and eplerenone was effective, and improvement in her symptoms was associated with amelioration of transthoracic echocardiographic findings and a reduction in serum brain natriuretic peptide levels. Previous reports have indicated heterogeneity in the clinical features of mitochondrial cardiomyopathy in patients carrying the A3243G mutation; the present case highlights the substantial variability in the clinical features of this disease.
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PURPOSE:Mitochondrial disorder is a progressive disease, but there are no specific treatment modalities to prevent the progression. Also, there has been little understanding on the pattern of disease progression nor natural history. The aim of this study was to elucidate the initial clinical phenotypes, patterns of the disease progression, and its natural history of the patients with mitochondrial A3243G mutation. METHODS:Among the patients with biochemically or genetically confirmed mitochondrial disorders, 7 patients with A3243G mutation were included in a 7 year follow-up observation(range: 3-11 years). We classified the patients into two groups by the initial clinical presentations:systemic and neurologic onset. They were clinically evaluated with serial brain MRI and MRS for the evaluation of the disease evolution patterns. RESULTS:The clinical manifestations of mitochondrial A3243G mutation were extremely variable; seizure, headache, dementia, myopathy, sensorineural hearing loss, external ophthalmoplegia, diabetes mellitus, cardiomyopathy, easy fatigability, and short stature. Among the 7 patients, 4 patients initially presented neurologic symptom such as seizure(3) and headache(1), and 3 patients systemic symptoms such as DM(2) and easy fatigability(1). All the patients with neurologic onset showed relentless progression with recurrent stroke- like episodes and intractable seizures, and finally fell into be functionally dependent states or death. All the patients with systemic onset showed clinically silent periods for 3-10 years, and still they were in functionally independent states despite subsequent neurologic symptoms. CONCLUSION:We could find out the relationship between initial clinical phenotypes and final outcomes in mitochondrial A3243G mutation. However, the population is small in this study so that a larger scaled analysis is needed.
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Humanos , Encéfalo , Cardiomiopatias , Demência , Diabetes Mellitus , Progressão da Doença , Seguimentos , Cefaleia , Perda Auditiva Neurossensorial , Imageamento por Ressonância Magnética , Doenças Mitocondriais , Doenças Musculares , História Natural , Manifestações Neurológicas , Oftalmoplegia , Fenótipo , RNA de Transferência , ConvulsõesRESUMO
OBJECTIVE: Mitochondrial gene mutations may play a role in the development of gestational diabetes mellitus. This study has assisted to confirm the relationship between the mitochondrial DNA copy number and the GDM. METHODS: Peripheral blood samples were collected from 68 patients with GDM and from 79 controls. For the quantification of mtDNA content, a comparative analysis was performed by the amplification of endogenous control (nuclear DNA, 28S rRNA). The mitochondrial A3243G mutation analysis performed. RESULTS: The ratio of mtDNA/28S rRNA was 1.2053 +/- 0.8307 in GDM patients and 1.7975 +/- 1.1355 in control group (p=0.0004), respectively. Among 68 GDM patients, the mutation in tRNA nt 3243 was detected in only one subject. The A3243G mutation in tRNA- Leu gene, implicated in GDM was reported in 1 of 68 (1.47%) but not in controls. CONCLUSION: In this investigation, blood samples from GDM patients using the real-time polymerase chain reaction will be applied to confirm the relationship between the mitochondrial DNA copy number and the GDM. It is hypothesized that this method will help to predict GDM, and aid in developing early diagnostic methods and treatment modalities.