RESUMO
OBJECTIVES: To evaluate the clinical symptoms and biochemical findings and establish the genetic etiology in a cohort of pediatric patients with combined deficiencies of the mitochondrial respiratory chain complexes. STUDY DESIGN: Clinical and biochemical data were collected from 55 children. All patients were subjected to sequence analysis of the entire mitochondrial genome, except when the causative mutations had been identified based on the clinical picture. Whole exome sequencing/whole genome sequencing (WES/WGS) was performed in 32 patients. RESULTS: Onset of disease was generally early in life (median age, 6 weeks). The most common symptoms were muscle weakness, hypotonia, and developmental delay/intellectual disability. Nonneurologic symptoms were frequent. Disease causing mutations were found in 20 different nuclear genes, and 7 patients had mutations in mitochondrial DNA. Causative variants were found in 18 of the 32 patients subjected to WES/WGS. Interestingly, many patients had low levels of coenzyme Q10 in muscle, irrespective of genetic cause. CONCLUSIONS: Children with combined enzyme defects display a diversity of clinical symptoms with varying age of presentation. We established the genetic diagnosis in 35 of the 55 patients (64%). The high diagnostic yield was achieved by the introduction of massive parallel sequencing, which also revealed novel genes and enabled elucidation of new disease mechanisms.
Assuntos
DNA Mitocondrial/genética , Doenças Metabólicas/genética , Doenças Mitocondriais/genética , Mutação , Ubiquinona/análogos & derivados , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Humanos , Lactente , Recém-Nascido , Doenças Metabólicas/enzimologia , Doenças Mitocondriais/enzimologia , Ubiquinona/sangue , Sequenciamento do Exoma , Adulto JovemRESUMO
In recent years, the analytical determination of coenzyme Q10 (CoQ10) has gained importance in clinical diagnosis and in pharmaceutical quality control. CoQ10 is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases and patients with these conditions may benefit from administration of supplements of CoQ10. In this regard, it has been observed that the best benefits are obtained when CoQ10 deficiency is diagnosed and treated early. Therefore, it is of great value to develop analytical methods for the detection and quantification of CoQ10 in this type of disease. The methods above mentioned should be simple enough to be used in routine clinical laboratories as well as in quality control of pharmaceutical formulations containing CoQ10. Here, we discuss the advantages and disadvantages of different methods of CoQ10 analysis.
Assuntos
Ubiquinona/análogos & derivados , Ataxia/diagnóstico , Ataxia/enzimologia , Cromatografia Líquida de Alta Pressão , Eletroforese Capilar , Humanos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/enzimologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/enzimologia , Preparações Farmacêuticas/química , Espectrofotometria , Ubiquinona/análise , Ubiquinona/sangue , Ubiquinona/química , Ubiquinona/deficiência , Ubiquinona/isolamento & purificaçãoRESUMO
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by a combination of reciprocal social deficits, communication impairment, and rigid ritualistic interest and stereotypies. The etiology is generally multifactorial, including genetic, immunological and/or environmental factors. A group of ASD has been linked to mitochondrial dysfunction with subsequent deficiency in energy production. Patients with ASD and mitochondrial disease often show signs and symptoms uncommon to idiopathic ASD such as cardiac, pancreatic or liver dysfunction, cardiac, growth retardation, fatigability, but in some cases semiology is different. We show two clinical cases of ASD associated to a deficiency of the mitochondrial respiratory chain (complex I+III and IV) with different clinical presentations. In one case, signs and symptoms of mitochondrial disorder were mild and the second diagnosis was attained many years after that of ASD. These findings support the recent growing body of evidence that ASD can be associated with mitochondrial disorder. Children with ASD and abnormal neurologic or systemic findings should be evaluated for mitochondrial disorder.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/complicações , Mitocôndrias/enzimologia , Doenças Mitocondriais/complicações , Criança , Transtornos Globais do Desenvolvimento Infantil/enzimologia , Pré-Escolar , Transporte de Elétrons/fisiologia , Feminino , Humanos , Ácido Láctico/sangue , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/enzimologiaRESUMO
We describe the clinical, biochemical, and molecular characteristics of 31 patients with hepatic respiratory chain deficiencies to suggest possible guidelines for a liver biopsy. Initially, 67% of the children did not have any sign of hepatic dysfunction, and 35% presented exclusively with neurologic symptoms. Initial hyperlactacidemia was severe in 52%. Mortality was high (52%) and more marked in newborns; 28% never developed hepatic disease over time despite long-term follow-up. Hepatic, nonspecific multisystem initial symptoms, and constant hyperlactacidemia had significant statistical value as negative prognosis factors. We conclude that liver biopsy should be considered not only in patients with hepatic involvement, but also in patients with predominant neurologic disorders if there is a suspicion of a mitochondrial respiratory chain defect.
Assuntos
Hepatopatias/enzimologia , Hepatopatias/patologia , Fígado/enzimologia , Fígado/patologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/patologia , Pré-Escolar , Citrato (si)-Sintase/metabolismo , DNA Mitocondrial/metabolismo , Transporte de Elétrons/fisiologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Avaliação de Resultados em Cuidados de Saúde , Estudos RetrospectivosRESUMO
In 1992-1994, a disorder known as the epidemic neuropathy afflicted more than 50,000 Cubans. Three different forms of the illness were identified: epidemic optic neuropathy, peripheral neuropathy and mixed optic and peripheral neuropathy. The causes are still unknown. Skeletal muscle biopsy samples were analyzed by standard histological techniques and by biochemical assays. Elevated activities of citrate synthase, a non-respiratory-chain mitochondrial matrix enzyme, suggested possible mitochondrial proliferation in 7 of the 8 patients. Nicotinamide adenine dinucleotide phosphate (NADP(+)) levels were higher in the patients than in the controls (p = 0.04). Levels of nicotinamide adenine dinucleotide (NAD) and the reduced compounds NADH and NADPH were comparable in patients and controls. Elevations of succinate dehydrogenase and citrate synthase activities and high NADP(+) levels suggest that alterations of mitochondrial functions may be associated with this disorder.