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1.
Chin Med J (Engl) ; 132(3): 269-274, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30681492

RESUMO

BACKGROUND: Studies on the relationship between antiepileptic drug (AED) administration and clinical outcomes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) remain scarce. Levetiracetam (LEV) is an AED that is neuroprotective in various neurologic disorders. This study aimed to determine the impact of LEV on the outcome of MELAS. METHODS: A retrospective, single-center study was performed based on a large cohort of patients with MELAS with a history of seizures (n = 102). Decisions on antiepileptic therapies were made empirically. Patients were followed up for 1 to 8 years (median, 4 years) and divided into 2 groups based on whether LEV was administered (LEV or non-LEV). The modified Rankin scale (mRS) scores and mortality risks were analyzed in all patients. RESULTS: LEV, carbamazepine, benzodiazepines, topiramate, oxcarbazepine, valproate, and lamotrigine were administered in 48, 37, 18, 13, 11, 9, and 9 patients, singly or in combination, respectively. The mean mRS score of the LEV group (n = 48) was lower than that of the non-LEV group (n = 54; mean ±â€Šstandard deviation, 2.79 ±â€Š1.47 vs. 3.83 ±â€Š1.93, P = 0.006) up to the end of the study. Nevertheless, there was no difference in the proportion of subjects without disability (mRS ranging 0-1) between the groups (P = 0.37). The multivariate regressions revealed that LEV treatment was associated with lower mRS scores (odds ratio 0.32, 95% confidence interval [CI] 0.15-0.68, P = 0.003) and mortality rates (hazard ratio 0.24, 95% CI 0.08-0.74, P = 0.013). There was a significant difference in the Kaplan-Meier survival curves between the groups (χ = 4.29, P = 0.04). CONCLUSIONS: The LEV administration is associated with lower mortality in patients with MELAS in this retrospective study. Further laboratory research and prospective cohort studies are needed to confirm whether LEV has neuroprotective effects on patients with mitochondrial diseases.


Assuntos
Acidose Láctica/tratamento farmacológico , Acidose Láctica/mortalidade , Anticonvulsivantes/uso terapêutico , Levetiracetam/uso terapêutico , Encefalomiopatias Mitocondriais/tratamento farmacológico , Encefalomiopatias Mitocondriais/mortalidade , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/mortalidade , Adolescente , Carbamazepina/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lamotrigina/uso terapêutico , Levetiracetam/administração & dosagem , Masculino , Oxcarbazepina/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Topiramato/uso terapêutico , Ácido Valproico/uso terapêutico
2.
Mitochondrion ; 46: 228-235, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30004022

RESUMO

We studied the biomarker patterns related to axonal injury, astrogliosis and amyloid metabolism in cerebrospinal fluid (CSF) of children and adolescents with mitochondrial encephalopathy and identified correlations with phenotype and survival outcome. Forty-six pediatric patients with genetically verified mitochondrial encephalopathy and twenty-two controls investigated at the Queen Silvia Children's Hospital, Sweden, were included. CSF lactate and neurofilament light (NF-L) were significantly increased in patients with mitochondrial encephalopathy compared to controls. Elevated CSF NF-L was associated with abnormal brain MRI and poorer survival. We suggest that CSF NF-L may be used in both clinical and research settings for monitoring the neurodegenerative process in mitochondrial disease.


Assuntos
Líquido Cefalorraquidiano/química , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/patologia , Proteínas de Neurofilamentos/análise , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Encefalomiopatias Mitocondriais/mortalidade , Prognóstico , Análise de Sobrevida , Suécia
4.
J Med Genet ; 52(9): 627-35, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26185144

RESUMO

BACKGROUND: The identification of the molecular basis of mitochondrial disorders continues to be challenging and expensive. The increasing usage of next-generation sequencing is facilitating the discovery of the genetic aetiology of heterogeneous phenotypes associated with these conditions. Coenzyme Q(10) (CoQ(10)) is an essential cofactor for mitochondrial respiratory chain complexes and other biochemical pathways. Mutations in genes involved in CoQ(10) biosynthesis cause primary CoQ(10) deficiency syndromes that can be treated with oral supplementation of ubiquinone. METHODS: We used whole exome sequencing to evaluate six probands from four unrelated families with clinical findings suggestive of a mitochondrial disorder. Clinical data were obtained by chart review, parental interviews, direct patient assessment and biochemical and pathological evaluation. RESULTS: We identified five recessive missense mutations in COQ4 segregating with disease in all four families. One mutation was found in a homozygous state in two unrelated Ashkenazi Jewish probands. All patients were female, and presented on the first day of life, and died in the neonatal period or early infancy. Clinical findings included hypotonia (6/6), encephalopathy with EEG abnormalities (4/4), neonatal seizures (3/6), cerebellar atrophy (4/5), cardiomyopathy (5/6) and lactic acidosis (4/6). Autopsy findings in two patients revealed neuron loss and reactive astrocytosis or cerebellar and brainstem hypoplasia and microdysgenesis. CONCLUSIONS: Mutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ(10) biosynthesis.


Assuntos
Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto , Feminino , Humanos , Recém-Nascido , Judeus , Encefalomiopatias Mitocondriais/mortalidade , Encefalomiopatias Mitocondriais/fisiopatologia , Gravidez , Análise de Sequência de DNA , Ubiquinona/biossíntese
5.
Brain ; 137(Pt 5): 1337-49, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24727567

RESUMO

Balanced pools of deoxyribonucleoside triphosphate precursors are required for DNA replication, and alterations of this balance are relevant to human mitochondrial diseases including mitochondrial neurogastrointestinal encephalopathy. In this disease, autosomal recessive TYMP mutations cause severe reductions of thymidine phosphorylase activity; marked elevations of the pyrimidine nucleosides thymidine and deoxyuridine in plasma and tissues, and somatic multiple deletions, depletion and site-specific point mutations of mitochondrial DNA. Thymidine phosphorylase and uridine phosphorylase double knockout mice recapitulated several features of these patients including thymidine phosphorylase activity deficiency, elevated thymidine and deoxyuridine in tissues, mitochondrial DNA depletion, respiratory chain defects and white matter changes. However, in contrast to patients with this disease, mutant mice showed mitochondrial alterations only in the brain. To test the hypothesis that elevated levels of nucleotides cause unbalanced deoxyribonucleoside triphosphate pools and, in turn, pathogenic mitochondrial DNA instability, we have stressed double knockout mice with exogenous thymidine and deoxyuridine, and assessed clinical, neuroradiological, histological, molecular, and biochemical consequences. Mutant mice treated with exogenous thymidine and deoxyuridine showed reduced survival, body weight, and muscle strength, relative to untreated animals. Moreover, in treated mutants, leukoencephalopathy, a hallmark of the disease, was enhanced and the small intestine showed a reduction of smooth muscle cells and increased fibrosis. Levels of mitochondrial DNA were depleted not only in the brain but also in the small intestine, and deoxyribonucleoside triphosphate imbalance was observed in the brain. The relative proportion, rather than the absolute amount of deoxyribonucleoside triphosphate, was critical for mitochondrial DNA maintenance. Thus, our results demonstrate that stress of exogenous pyrimidine nucleosides enhances the mitochondrial phenotype of our knockout mice. Our mouse studies provide insights into the pathogenic role of thymidine and deoxyuridine imbalance in mitochondrial neurogastrointestinal encephalopathy and an excellent model to study new therapeutic approaches.


Assuntos
Desoxirribonucleosídeos/efeitos adversos , Pseudo-Obstrução Intestinal/induzido quimicamente , Pseudo-Obstrução Intestinal/genética , Encefalomiopatias Mitocondriais/induzido quimicamente , Encefalomiopatias Mitocondriais/genética , Fatores Etários , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Encéfalo/patologia , Desoxirribonucleosídeos/metabolismo , Modelos Animais de Doenças , Pseudo-Obstrução Intestinal/mortalidade , Pseudo-Obstrução Intestinal/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/genética , Encefalomiopatias Mitocondriais/mortalidade , Encefalomiopatias Mitocondriais/fisiopatologia , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Força Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular Oculofaríngea , Oftalmoplegia/congênito , Transtornos Psicomotores/etiologia , Transtornos Psicomotores/genética , Succinato Desidrogenase/metabolismo , Timidina/efeitos adversos , Timidina/metabolismo , Timidina Fosforilase/deficiência , Uridina Fosforilase/deficiência
6.
Brain ; 136(Pt 5): 1544-54, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23599390

RESUMO

Whole exome sequencing is a powerful tool to detect novel pathogenic mutations in patients with suspected mitochondrial disease. However, the interpretation of novel genetic variants is not always straightforward. Here, we present two siblings with a severe neonatal encephalopathy caused by complex V deficiency. The aim of this study was to uncover the underlying genetic defect using the combination of enzymatic testing and whole exome sequence analysis, and to provide evidence for causality by functional follow-up. Measurement of the oxygen consumption rate and enzyme analysis in fibroblasts were performed. Immunoblotting techniques were applied to study complex V assembly. The coding regions of the genome were analysed. Three-dimensional modelling was applied. Exome sequencing of the two siblings with complex V deficiency revealed a heterozygous mutation in the ATP5A1 gene, coding for complex V subunit α. The father carried the variant heterozygously. At the messenger RNA level, only the mutated allele was expressed in the patients, whereas the father expressed both the wild-type and the mutant allele. Gene expression data indicate that the maternal allele is not expressed, which is supported by the observation that the ATP5A1 expression levels in the patients and their mother are reduced to ∼50%. Complementation with wild-type ATP5A1 restored complex V in the patient fibroblasts, confirming pathogenicity of the defect. At the protein level, the mutation results in a disturbed interaction of the α-subunit with the ß-subunit of complex V, which interferes with the stability of the complex. This study demonstrates the important value of functional studies in the diagnostic work-up of mitochondrial patients, in order to guide genetic variant prioritization, and to validate gene defects.


Assuntos
Encefalomiopatias Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Células Cultivadas , Humanos , Recém-Nascido , Encefalomiopatias Mitocondriais/mortalidade , ATPases Mitocondriais Próton-Translocadoras/química , Fatores Acopladores da Fosforilação Oxidativa/química , Fatores Acopladores da Fosforilação Oxidativa/genética , Estrutura Secundária de Proteína
7.
J Med Genet ; 47(10): 670-6, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20693550

RESUMO

BACKGROUND: Succinate-CoA ligase deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Mutations in SUCLA2, the gene encoding a ß subunit of succinate-CoA ligase, have been reported in 17 patients until now. Mutations in SUCLG1, encoding the α subunit of the enzyme, have been described in two pedigrees only. METHODS AND FINDINGS: In this study, two unrelated patients harbouring three novel pathogenic mutations in SUCLG1 were reported. The first patient had a severe disease at birth. He was compound heterozygous for a missense mutation (p.Pro170Arg) and a c.97+3G>C mutation, which leads to the complete skipping of exon 1 in a minigene expression system. The involvement of SUCLG1 was confirmed by western blot analysis, which showed absence of SUCLG1 protein in fibroblasts. The second patient has a milder phenotype, similar to that of patients with SUCLA2 mutations, and is still alive at 12 years of age. Western blot analysis showed some residual SUCLG1 protein in patient's fibroblasts. CONCLUSIONS: Our results suggest that SUCLG1 mutations that lead to complete absence of SUCLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2-like phenotype is found in patients with residual SUCLG1 protein. Furthermore, it is shown that in the absence of SUCLG1 protein, no SUCLA2 protein is found in fibroblasts by western blot analysis. This result is consistent with a degradation of SUCLA2 when its heterodimer partner, SUCLG1, is absent.


Assuntos
Ácido Metilmalônico/urina , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/fisiopatologia , Mutação , Índice de Gravidade de Doença , Succinato-CoA Ligases/genética , Sequência de Aminoácidos , Criança , Evolução Fatal , Humanos , Lactente , Masculino , Ácido Metilmalônico/sangue , Encefalomiopatias Mitocondriais/mortalidade , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Fenótipo , Succinato-CoA Ligases/química , Succinato-CoA Ligases/deficiência , Succinato-CoA Ligases/metabolismo
8.
Cell Metab ; 7(4): 312-20, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18396137

RESUMO

To study effects of mitochondrial complex I (CI, NADH:ubiquinone oxidoreductase) deficiency, we inactivated the Ndufs4 gene, which encodes an 18 kDa subunit of the 45-protein CI complex. Although small, Ndufs4 knockout (KO) mice appeared healthy until approximately 5 weeks of age, when ataxic signs began, progressing to death at approximately 7 weeks. KO mice manifested encephalomyopathy including a retarded growth rate, lethargy, loss of motor skill, blindness, and elevated serum lactate. CI activity in submitochondrial particles from KO mice was undetectable by spectrophotometric assays. However, CI-driven oxygen consumption by intact tissue was about half that of controls. Native gel electrophoresis revealed reduced levels of intact CI. These data suggest that CI fails to assemble properly or is unstable without NDUFS4. KO muscle has normal morphology but low NADH dehydrogenase activity and subsarcolemmal aggregates of mitochondria. Nonetheless, total oxygen consumption and muscle ATP and phosphocreatine concentrations measured in vivo were within normal parameters.


Assuntos
Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Encefalomiopatias Mitocondriais/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Respiração Celular , Complexo I de Transporte de Elétrons/genética , Feminino , Fígado/enzimologia , Camundongos , Camundongos Knockout , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/mortalidade , Músculo Esquelético/citologia , Músculo Esquelético/ultraestrutura , NADH Desidrogenase/deficiência , NADH Desidrogenase/genética , NADH Desidrogenase/metabolismo , Consumo de Oxigênio , Fenótipo , Análise de Sobrevida , Fatores de Tempo
9.
Pediatrics ; 119(4): 722-33, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17403843

RESUMO

OBJECTIVES: We sought to determine the clinical spectrum, survival, and long-term functional outcome of a cohort of pediatric patients with mitochondrial diseases and to identify prognostic factors. METHODS: Medical charts were reviewed for 73 children diagnosed between 1985 and 2005. The functional status of living patients was assessed prospectively by using the standardized Functional Independence Measure scales. RESULTS: Patients fell into 7 phenotypic categories: neonatal-onset lactic acidosis (10%), Leigh syndrome (18%), nonspecific encephalopathy (32%), mitochondrial (encephalo)myopathy (19%), intermittent neurologic (5%), visceral (11%), and Leber hereditary optic neuropathy (5%). Age at first symptoms ranged from prenatal to 16 years (median: 7 months). Neurologic symptoms were the most common (90%). Visceral involvement was observed in 29% of the patients. A biochemical or molecular diagnosis was identified for 81% of the patients as follows: deficiency of complex IV (27%), of pyruvate dehydrogenase or complex I (25% each), of multiple complexes (13%), and of pyruvate carboxylase (5%) or complexes II+III (5%). A mitochondrial DNA mutation was found in 20% of patients. At present, 46% of patients have died (median age: 13 months), 80% of whom were <3 years of age. Multivariate analysis showed that age at first symptoms was a major independent predictor of mortality: patients with first symptoms before 6 months had a highly increased risk of mortality. Cardiac or visceral involvement and neurologic crises were not independent prognostic factors. Living patients showed a wide range of independence levels that correlated positively with age at first symptoms. Among patients aged >5 years (n = 32), 62% had Functional Independence Measure quotients of >0.75. CONCLUSIONS: Mitochondrial diseases in children span a wide range of symptoms and severities. Age at first symptoms is the strongest predictor mortality. Despite a high mortality rate in the cohort, 62% of patients aged >5 years have only mild impairment or normal functional outcome.


Assuntos
Causas de Morte , DNA Mitocondrial/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Fragmentação do DNA , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Síndrome MELAS/diagnóstico , Síndrome MELAS/mortalidade , Síndrome MELAS/terapia , Masculino , Doenças Mitocondriais/genética , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/mortalidade , Encefalomiopatias Mitocondriais/terapia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/mortalidade , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/mortalidade , Probabilidade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo
10.
Lancet ; 354(9184): 1084-9, 1999 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-10509500

RESUMO

BACKGROUND: Zidovudine is commonly administered during pregnancy to prevent mother-to-child HIV-1 transmission. We investigated mitochondrial toxic effects in children exposed to zidovudine in utero and after birth. METHODS: We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France. Mitochondrial dysfunction was studied by spectrophotometry and polarography of respiratory-chain complexes in various tissues. FINDINGS: Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1. All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment. No mutation currently associated with constitutional disease was detected in any patient. INTERPRETATION: Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained. Further assessment of the toxic effects of these drugs is required.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/prevenção & controle , HIV-1 , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Lamivudina/efeitos adversos , Troca Materno-Fetal , Encefalomiopatias Mitocondriais/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Zidovudina/efeitos adversos , Acidose Láctica/induzido quimicamente , Fármacos Anti-HIV/administração & dosagem , Pré-Escolar , DNA Mitocondrial/efeitos dos fármacos , Feminino , França/epidemiologia , Infecções por HIV/epidemiologia , Humanos , Lactente , Lamivudina/administração & dosagem , Encefalomiopatias Mitocondriais/epidemiologia , Encefalomiopatias Mitocondriais/mortalidade , Encefalomiopatias Mitocondriais/fisiopatologia , Gravidez , Valores de Referência , Estudos Retrospectivos , Zidovudina/administração & dosagem
11.
Orv Hetil ; 136(24): 1275-9, 1995 Jun 11.
Artigo em Húngaro | MEDLINE | ID: mdl-7596586

RESUMO

The case of a female patient with cardio-encephalo-myopathy who died of her illness at one year of age, similarly to her three sisters, is reported. In autopsy samples, like muscle, heart, liver and cerebellum activities of several mitochondrial enzymes were determined. In the skeletal muscle serious decrease of carnitine acetyltransferase was observed (from the normal 4.8 U/g to 0.08 U/g wet weight), while in other tissues this activity was normal. In the muscle activities of several other mitochondrial enzymes were also decreased (cytochrome oxidase, NADH cytochrome C oxidoreductase, citrate synthase), while in other tissues there were no similar changes. Serious distortion was observed in the structure of the majority of mitochondria of muscle and heart by electronmicroscopy. The number of the Purkinje-cells in the cerebellum decreased, and the cells were shrunken, their axons were fragmented and disoriented. Also the structure of the mitochondria was abnormal in the Purkinje-cells, while it was normal in other areas of the cerebrum. In te tissues of the patient normal and deleted mitochondrial DNA coexisted as which could explain the genetic background of this disease at molecular level.


Assuntos
Cardiomiopatias , DNA Mitocondrial , Deleção de Genes , Encefalomiopatias Mitocondriais , Autopsia , Cardiomiopatias/genética , Cardiomiopatias/mortalidade , Cardiomiopatias/patologia , Evolução Fatal , Feminino , Humanos , Hungria , Lactente , Microscopia Eletrônica , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/mortalidade , Encefalomiopatias Mitocondriais/patologia
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