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1.
J Med Genet ; 52(8): 532-40, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25787132

RESUMO

BACKGROUND: Mitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial DNA or POLG are often present, other nuclear defects in mitochondrial DNA replication and protein translation have been associated with a severe epileptic encephalopathy. METHODS AND RESULTS: We identified a proband with an epileptic encephalopathy, complex movement disorder and a combined mitochondrial respiratory chain enzyme deficiency. The child presented with neurological regression, complex movement disorder and intractable seizures. A combined deficiency of mitochondrial complexes I, III and IV was noted in liver tissue, along with increased mitochondrial DNA content in skeletal muscle. Incomplete assembly of complex V, using blue native polyacrylamide gel electrophoretic analysis and complex I, using western blotting, suggested a disorder of mitochondrial transcription or translation. Exome sequencing identified compound heterozygous mutations in CARS2, a mitochondrial aminoacyl-tRNA synthetase. Both mutations affect highly conserved amino acids located within the functional ligase domain of the cysteinyl-tRNA synthase. A specific decrease in the amount of charged mt-tRNA(Cys) was detected in patient fibroblasts compared with controls. Retroviral transfection of the wild-type CARS2 into patient skin fibroblasts led to the correction of the incomplete assembly of complex V, providing functional evidence for the role of CARS2 mutations in disease aetiology. CONCLUSIONS: Our findings indicate that mutations in CARS2 result in a mitochondrial translational defect as seen in individuals with mitochondrial epileptic encephalopathy.


Assuntos
Aminoacil-tRNA Sintetases/genética , Encefalopatias/genética , Epilepsia/genética , Sequência de Aminoácidos , Aminoacilação , Criança , Análise Mutacional de DNA , Exoma , Humanos , Masculino , Dados de Sequência Molecular , RNA de Transferência/metabolismo , Alinhamento de Sequência
2.
Clin Infect Dis ; 42(8): 1111-7, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16575728

RESUMO

BACKGROUND: Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled. METHODS: We studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo. RESULTS: In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal. CONCLUSION: These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.


Assuntos
Acetamidas/farmacologia , Acetamidas/uso terapêutico , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/metabolismo , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Inibidores da Síntese de Proteínas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Animais , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Quimioterapia Combinada , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Linezolida , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/ultraestrutura , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/ultraestrutura , Inibidores da Síntese de Proteínas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Rifampina/uso terapêutico
3.
Seizure ; 14(6): 412-21, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16087358

RESUMO

Steroids and adrenocorticotrophic hormone (ACTH) have been used for the treatment of infantile spasms for several years. However, the use of steroids in the treatment of epilepsy beyond infantile spasms has been limited to only a few studies. We report the experience with steroids in 32 children with intractable epilepsy, not including West syndrome. In 47% there was a decrease in seizure frequency, 25% became seizure free, 11% had a seizure reduction of >50% and 11% had a seizure reduction of <50%. Our study confirms the conclusions of few previous reports of effective adjunctive steroid treatment for children with intractable epilepsy. The possible side effects, however, especially during prolonged therapy remain an important concern.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Esteroides/uso terapêutico , Administração Oral , Hormônio Adrenocorticotrópico/administração & dosagem , Hormônio Adrenocorticotrópico/uso terapêutico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Resistência a Medicamentos , Feminino , Humanos , Injeções Intramusculares , Masculino , Recidiva , Estudos Retrospectivos , Esteroides/administração & dosagem , Esteroides/efeitos adversos
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