RESUMO
Mitochondrial diseases are a complex and heterogeneous group of genetic disorders that occur as a result of either nuclear DNA or mitochondrial DNA pathogenic variants, leading to a decrease in oxidative phosphorylation and cellular energy (ATP) production. Increasing knowledge about molecular, biochemical, and genetic abnormalities related to mitochondrial dysfunction has expanded the neuroimaging phenotypes of mitochondrial disorders. As a consequence of this growing field, the imaging recognition patterns of mitochondrial cytopathies are continually evolving. In this review, we describe the main neuroimaging characteristics of pediatric mitochondrial diseases, ranging from classical to more recent and challenging features. Due to the increased knowledge about the imaging findings of mitochondrial cytopathies, the pediatric neuroradiologist plays a crucial role in the diagnosis and evaluation of these patients.
Assuntos
Encéfalo/diagnóstico por imagem , Síndrome de Kearns-Sayre/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Miopatias Mitocondriais/diagnóstico por imagem , Neuroimagem/métodos , Encéfalo/patologia , Humanos , Síndrome de Kearns-Sayre/patologia , Miopatias Mitocondriais/patologiaRESUMO
Patients with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency commonly present liver dysfunction whose pathogenesis is unknown. We studied the effects of long-chain 3-hydroxylated fatty acids (LCHFA) that accumulate in LCHAD deficiency on liver bioenergetics using mitochondrial preparations from young rats. We provide strong evidence that 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, the monocarboxylic acids that are found at the highest tissue concentrations in this disorder, act as metabolic inhibitors and uncouplers of oxidative phosphorylation. These conclusions are based on the findings that these fatty acids decreased ADP-stimulated (state 3) and uncoupled respiration, mitochondrial membrane potential and NAD(P)H content, and, in contrast, increased resting (state 4) respiration. We also verified that 3HTA and 3HPA markedly reduced Ca2+ retention capacity and induced swelling in Ca2+-loaded mitochondria. These effects were mediated by mitochondrial permeability transition (MPT) induction since they were totally prevented by the classical MPT inhibitors cyclosporin A and ADP, as well as by ruthenium red, a Ca2+ uptake blocker. Taken together, our data demonstrate that the major monocarboxylic LCHFA accumulating in LCHAD deficiency disrupt energy mitochondrial homeostasis in the liver. It is proposed that this pathomechanism may explain at least in part the hepatic alterations characteristic of the affected patients.
Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Cardiomiopatias/patologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/farmacologia , Erros Inatos do Metabolismo Lipídico/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Miopatias Mitocondriais/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Doenças do Sistema Nervoso/patologia , Rabdomiólise/patologia , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Animais , Transporte Biológico , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias Hepáticas/metabolismo , Membranas Mitocondriais/metabolismo , Miopatias Mitocondriais/metabolismo , Proteína Mitocondrial Trifuncional/deficiência , NADP/metabolismo , Doenças do Sistema Nervoso/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Rabdomiólise/metabolismoRESUMO
We have described that administration of seeds or parts of the seed of Senna occidentalis (coffee senna) for long periods, induces histochemical changes in the skeletal muscles of hens and rats that are characteristic of a mitochondrial myopathy--as decrease of SDH and COX activity, with some COX negative fibers. In this experimental model of mitochondrial myopathy, as in many human mitochondrial diseases, there is a random distribution of COX negative fibers. Some fibers are completely COX negative while others are partially negative and others are completely positive. In the present work we have studied the distribution of COX negative mitochondria at transmission electron microscopy in skeletal muscle of rats in this experimental myopathy. In myofibers of intoxicated animals the expression of COX was heterogeneous. The histochemical reaction was observed in the internal membrane (more evident in mitochondrial cristae) of all mitochondria of some myofibers, while it was almost absent in other myofibers. In these myofibers the great part of the mitochondria were negative for COX reaction while other ones had a weak expression of this enzyme (dot or focal expression of COX). Our results indicated that the COX mitochondrial activity is heterogeneously impaired in myofibers of rats intoxicated with S. occidentalis. These abnormalities remember those observed in some types of human mitochondrial myopathies.
Assuntos
Deficiência de Citocromo-c Oxidase , Mitocôndrias/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Sementes/toxicidade , Senna , Dieta , Modelos Animais de Doenças , Mitocôndrias/enzimologia , Mitocôndrias/ultraestrutura , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/etiologia , Miopatias Mitocondriais/patologia , Fibras Musculares Esqueléticas/enzimologia , Fibras Musculares Esqueléticas/ultraestrutura , Músculo Esquelético/enzimologia , Músculo Esquelético/ultraestrutura , Plantas Medicinais , Extrato de Senna/toxicidade , Senna/químicaRESUMO
One of the great challenges in molecular biology is to understand the mechanisms by which a particular genetic defect gives origin to a specific disease. Mitochondrial DNA is more susceptible than nuclear DNA to mutations. Mitochondrial mutations have been associated with a wide spectrum of disorders characterized by a complex phenotype and actually named mitochondrial cytopathies or oxidative phosphorylation diseases. The objective of this paper is to review the relevant genetic, clinical, and morphologic features of cardiac involvement in this heterogeneous but exciting group of diseases. The clinical features of cardiac involvement in mitochondrial cytopathies vary in the different subgroups of these disorders and in particular, mitochondrial mutations can causes characteristic cardiac abnormalities.
Assuntos
DNA Mitocondrial/genética , Miopatias Mitocondriais/genética , DNA Mitocondrial/fisiologia , Cardiopatias/genética , Humanos , Miopatias Mitocondriais/patologia , Mutação , Oxirredução , Fosforilação Oxidativa , FenótipoRESUMO
Progressive limitation of occular motility, accompanied by ptosis but usually without diplopia, occurs in many pathologic states, including mitochondrial diseases. A case with chronic progressive external ophthalmoplegia with onset during childhood, associated with proximal myopathy and dysphasia is presented. The muscle biopsy showed a myopathic pattern and abnormal subsarcolemmal mitochondrial deposits. Muscle biopsy for important in the correct diagnosis of this entity.
Assuntos
Miopatias Mitocondriais/complicações , Oftalmoplegia/etiologia , Adulto , Progressão da Doença , Feminino , Humanos , Miopatias Mitocondriais/patologiaRESUMO
Plants of the genus Senna (formerly Cassia) have been recognized as the cause of a natural and experimental syndrome of muscle degeneration frequently leading to death in animals. Histologically, it demonstrated skeletal and cardiac muscle necrosis, with floccular degeneration and proliferation of sarcolemmal nuclei. Recently, it was described as an experimental model of mitochondrial myopathy in hens chronically treated with Senna occidentalis. Currently, skeletal muscles of chicks intoxicated with seeds of the poisonous plant S. occidentalis were studied by histochemistry and electron microscopy. Since birth, the birds were fed ground dried seeds of this plant with a regular chicken ration at a dose of 4% for 11 days. Microscopic examination revealed, besides muscle-fiber atrophy, lipid storage in most fibers and a moderate amount of cytochrome oxidase-negative fibers. By electron microscopy, enlarged mitochondria with disrupted or excessively branched cristae were seen. This picture was characteristic of mitochondrial myopathy. These findings have hitherto remained unnoticed in skeletal muscle of young birds treated with S. occidentalis.
Assuntos
Ração Animal/toxicidade , Galinhas , Miopatias Mitocondriais/veterinária , Músculo Esquelético/efeitos dos fármacos , Doenças das Aves Domésticas/induzido quimicamente , Extrato de Senna/toxicidade , Animais , Atrofia/induzido quimicamente , Atrofia/patologia , Atrofia/veterinária , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/ultraestrutura , Miopatias Mitocondriais/induzido quimicamente , Miopatias Mitocondriais/patologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Oxirredutases/metabolismo , Plantas Tóxicas , Doenças das Aves Domésticas/patologia , SementesRESUMO
Histochemical and electron microscopic studies of biceps femoris, pectoralis major and rectus femoris of chronically treated birds with seeds of the poisonous plant Senna occidentalis (0.2% external/internal tegment), were performed. The muscles had similar features of human mitochondrial myopathy as ragged-red fibers, cytochrome-oxidase negative fibers, and weak activity of the oxidative enzymes. Fibers with lipid storage were also present. Acid phosphatase activity in rare muscle fibers was also detected, and represents probably a secondary degenerative process. By electron microscopy, enlarged mitochondria with disrupted or excessively branched cristae were seen. The present study presents a new experimental model of mitochondrial myopathy that may be useful for the best knowledge of this group of diseases and for experimental trials of drugs that could reverse the mitochondrial impairment in the mitochondrial myopathies.
Assuntos
Miopatias Mitocondriais/etiologia , Intoxicação por Plantas/patologia , Sementes , Extrato de Senna , Animais , Galinhas , Doença Crônica , Histocitoquímica , Humanos , Miopatias Mitocondriais/patologia , Valores de ReferênciaRESUMO
A 21 year old male ingested podophyllin in a suicide attempt. The disorder was marked by seizures, coma, peripheral neuropathy, renal failure and acute necrotizing myopathy, an unusual finding. The coma and systemic disturbances resolved within three weeks. The myopathy resolved in 7 weeks, demonstrating a high capacity of muscle recuperation. The sensorimotor peripheral neuropathy persisted until the patient's death 9 weeks after the ingestion, due to septicemia. This report confirms the transient central neurotoxicity of podophyllin and persistent peripheral neurotoxicity of podophyllin, and describes a reversible necrotizing myopathy associated to mitochondrial abnormalities, a still unreported feature of podophyllin toxicity.
Assuntos
Miopatias Mitocondriais/induzido quimicamente , Podofilina/intoxicação , Adulto , Humanos , Masculino , Miopatias Mitocondriais/patologia , Necrose , Sepse , SuicídioRESUMO
A 21 year old male ingested podophyllin in a suicide attempt. The disorder was marked by seizures, coma, peripheral neuropathy, renal failure and acute necrotizing myopathy, an unusual finding. The coma and systemic disturbance resolved within theree weeks. The myopathy resolved in 7 weeks, demonstrating a high capacity of muscle recuperation. The sensorimotor peripheral neuropathy persisted until the patient's death 9 weeks after the ingestion, due to septicemia. This report confirms the transient central neurotoxicity of podophyllin and persistent peripheral neurotoxicity of podophyllin, and describes a reversible necrotizing myopathy associated to mitochondrial abnormalities, a sitill unreported feature of podophillin toxicity.
Assuntos
Humanos , Masculino , Adulto , Miopatias Mitocondriais/induzido quimicamente , Podofilina/intoxicação , Miopatias Mitocondriais/patologia , Necrose , Sepse , SuicídioRESUMO
We studied 6 patients and 2 dogs that have been bitten by South American rattlesnake Crotalus durissus terrificus and one rabbit inoculated with crotalid venom. We analyzed sensory and motor peripheral nerve conduction, repetitive stimulation for studying neuromuscular transmission and electromyographies. Muscle biopsies were processed by histochemistry. All patients had peripheral mononeuropathy of the closest sensitive nerve to the area of snakebite. The neuromuscular transmission alterations were minimal. Muscle histochemistry of 4 patients, 2 dogs and 1 rabbit showed findings of mitochondrial myopathy. The majority of authors admit that crotalid venom causes myastenic syndrome. Our findings suggest that palpebral ptosis, myastenic facies and muscular weakness observed after crotalid poisoning are, probably, due to transient and reversible mitochondrial myopathy. As far as we know, this is the first report on the ability of the venom of this rattlesnake to cause local sensitive mononeuropathy and the first muscle histochemistry showing mitochondrial myopathy in humans poisoned by crotalid venom.