RESUMO
Several mitochondrial diseases are known to occasionally involve the cerebral white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome, but in these cases the major finding is alteration in the basal ganglia and brainstem. Here we report on severe diffuse white matter involvement and respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5 unrelated families. It is interesting that white matter lesions were the only abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst-like white matter lesions were found in 2 of 5 probands. Respiratory chain deficiency should be considered in the diagnosis of severe white matter involvement in childhood.
Assuntos
Encefalomiopatias Mitocondriais/etiologia , Adolescente , Encéfalo/patologia , Criança , Deficiência de Citocromo-c Oxidase , DNA Mitocondrial/genética , Transporte de Elétrons , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/patologia , Fosforilação Oxidativa , Succinato Citocromo c Oxirredutase/deficiênciaRESUMO
Inborn errors of oxidative phosphorylation have been recognized as possible causes of hepatic failure in the neonate, and respiratory enzyme deficiencies have been described in the liver of affected individuals. On the basis of a series of 22 cases, we describe respiratory enzyme deficiency as a cause of early-onset fatal hepatic failure with frequent neurologic involvement. In addition, we have identified a delayed-onset form of hepatic failure with a milder clinical course and inconstant neurologic involvement. Thus we suggest that genetic defects of oxidative phosphorylation be considered as a cause of liver dysfunction in infancy, regardless of the severity of the disease.
Assuntos
Falência Hepática/genética , Erros Inatos do Metabolismo/genética , Complexos Multienzimáticos/deficiência , Fosforilação Oxidativa , Alanina Transaminase/metabolismo , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Falência Hepática/enzimologia , Falência Hepática/mortalidade , Erros Inatos do Metabolismo/enzimologia , Complexos Multienzimáticos/metabolismoRESUMO
We report a mitochondrial DNA deletion (2.6 kb) in a boy with tubulointerstitial nephritis in whom chronic renal failure and leukodystrophy subsequently developed. Elevated lactate values in plasma and cerebrospinal fluid were suggestive of a defect in the mitochondrial respiratory chain. High amounts of deleted mitochondrial DNA were present in muscle and cerebral white matter. On the basis of this observation, we suggest giving consideration to genetic defects of oxidative phosphorylation in any attempt to determine the origin of unexplained chronic tubulointerstitial nephritis, especially when seemingly unrelated organs are involved.
Assuntos
Doença de Canavan/diagnóstico , DNA Mitocondrial/análise , Deleção de Genes , Nefrite Intersticial/etiologia , Sequência de Bases , Encéfalo/enzimologia , Encéfalo/patologia , Doença de Canavan/complicações , Doença de Canavan/genética , Doença de Canavan/patologia , Criança , Doença Crônica , Transporte de Elétrons/fisiologia , Humanos , Falência Renal Crônica/etiologia , Masculino , Dados de Sequência Molecular , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Nefrite Intersticial/complicações , Nefrite Intersticial/patologiaRESUMO
Considering the high proportion of unexplained hypertrophic cardiomyopathies on the one hand and the occurrence of cardiomyopathies in several mitochondrial disorders on the other, we hypothesized that isolated hypertrophic cardiomyopathies in infancy could occasionally be the result of defects of oxidative phosphorylation. By means of a scaled-down technique, we were able to investigate oxidative phosphorylation on minute amounts of endomyocardial tissue (1 mg) in three patients with concentric hypertrophic cardiomyopathy (shortening fraction in diameter, 18% to 27%; normal mean +/- 1 SD, 33 +/- 3%) and in control subjects. Although the absolute respiratory chain enzyme activities in the endomyocardial biopsy specimens of the patients were within the low normal range, the determination of the activity ratios allowed us to ascribe hypertrophic cardiomyopathies to respiratory chain enzyme abnormalities in all three cases (complex I, two cases; multiple enzyme deficiency, one case). The respiratory chain enzyme activity ratios, which are normally constant irrespective of the tissue tested, were markedly abnormal in all three patients (cytochrome c oxidase/reduced nicotinamide-adenine dinucleotide cytochrome c reductase, 4.6 to 10.4; normal mean +/- 1 SD, 2.9 +/- 0.5). We conclude that mitochondrial disorders should be regarded as potential causes of hypertrophic cardiomyopathy in early infancy. Because cardiac catheterization is routinely performed for hemodynamic investigation of cardiomyopathies, we suggest that endomyocardial biopsies be considered as a tool for early detection of mitochondrial cardiomyopathies, especially in hypertrophic forms of the disease.
Assuntos
Cardiomegalia/metabolismo , Endocárdio/patologia , Mitocôndrias Cardíacas/enzimologia , Miopatias Mitocondriais/patologia , Biópsia , Cardiomegalia/etiologia , Cardiomegalia/patologia , Transporte de Elétrons , Endocárdio/enzimologia , Endocárdio/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mitocôndrias Hepáticas/enzimologia , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/metabolismo , Fosforilação Oxidativa , Estudos ProspectivosRESUMO
We report an inborn error of the tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase deficiency, in three siblings with hypotonia, metabolic acidosis, and hyperlactatemia immediately after birth. Neurologic deterioration resulted in death at about 30 months of age. We propose low molar ratios of ketone bodies in plasma of neonates with congenital lactic acidosis as an indication of dysfunction of the tricarboxylic acid cycle.