RESUMO
BACKGROUND: Kearns-Sayre Syndrome (KSS) and Pearson Marrow-Pancreas Syndrome (PMPS) are among the classic phenotypes caused by mitochondrial DNA (mtDNA) deletions. KSS is a rare mitochondrial disease defined by a classic triad of progressive external ophthalmoplegia, atypical pigmentary retinopathy, and onset before 20 years. PMPS presents in the first year of life with bone marrow failure and exocrine pancreatic dysfunction, and can evolve into KSS later in life. Even though an mtDNA deletion is the most frequent mutation in KSS and PMPS, cases of duplications and molecular rearrangements have also been described. In Colombia, few case reports of KSS and PMPS have been published in indexed journals or have been registered in scientific events. METHODS: We discuss clinical and genetic aspects of two case reports of pediatric female patients, with initial clinical diagnosis of PMPS who later evolved into KSS, with confirmatory molecular studies of an mtDNA deletion and an mtDNA duplication. RESULTS: A large-scale mtDNA deletion, NC_012920.1:m.8286_14416del, was confirmed by Southern Blot in patient 1. An mtDNA duplication of 7.9 kb was confirmed by MLPA in patient 2. CONCLUSIONS: Our findings are compatible with the phenotypic and genetic presentation of PMPS and KSS. We present the first molecularly confirmed case reports of Colombian patients, diagnosed initially with PMPS, who later evolved to KSS.
Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Criança , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Diagnóstico Diferencial , Feminino , Duplicação Gênica , Humanos , Síndrome de Kearns-Sayre/patologia , Erros Inatos do Metabolismo Lipídico/patologia , Doenças Mitocondriais/patologia , Doenças Musculares/patologia , Fenótipo , Deleção de SequênciaRESUMO
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
Medium-chain fatty acids and acylcarnitines accumulate in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most frequent fatty acid oxidation defect clinically characterized by episodic crises with vomiting, seizures and coma. Considering that the pathophysiology of the neurological symptoms observed in MCADD is poorly known and, to our knowledge, there is no report on the involvement of acylcarnitines in the brain damage presented by the affected patients, the objective of the present study was to investigate the in vitro effects of hexanoylcarnitine (HC), octanoylcarnitine, decanoylcarnitine (DC) and cis-4-decenoylcarnitine (cDC) at concentrations varying from 0.01 to 1.0mM on important oxidative stress parameters in cerebral cortex of young rats. HC, DC and cDC significantly induced lipid peroxidation, as determined by increased thiobarbituric acid-reactive substances (TBA-RS) values. In addition, carbonyl formation was significantly augmented and sulfhydryl content diminished by DC, reflecting induction of protein oxidative damage. HC, DC and cDC also decreased glutathione (GSH) levels, the most important brain antioxidant defense. Furthermore, DC-induced elevation of TBA-RS values and decrease of GSH levels were prevented by the free radical scavengers melatonin and α-tocopherol, indicating the involvement of reactive oxygen species in these effects. We also found that l-carnitine itself did not induce lipid and protein oxidative damage, neither reduced the antioxidant defenses. Our present data show that the major medium-chain acylcarnitines accumulating in MCADD elicit oxidative stress in rat brain. It is therefore presumed that these compounds may be involved to a certain extent in the pathogenesis of the neurologic dysfunction of MCADD.
Assuntos
Córtex Cerebral/fisiopatologia , Homeostase/fisiologia , Erros Inatos do Metabolismo Lipídico/patologia , Acil-CoA Desidrogenase/deficiência , Animais , Carnitina/análogos & derivados , Carnitina/toxicidade , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Glutationa/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/ética , Erros Inatos do Metabolismo Lipídico/induzido quimicamente , Erros Inatos do Metabolismo Lipídico/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Melatonina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , alfa-Tocoferol/administração & dosagemRESUMO
Las miopatías por depósito de lípidos son la expresión fundamental de los trastornos del metabolismo lipídico muscular. En el presente estudio exponemos cuatro casos de la entidad y señalamos las características clínicas, histopatológicas y bioquímicas que están presentes en los defectos genéticos del metabolismo de los ácidos grasos del músculo esquelético. En tres casos los hallazgos fueron compatibles con el diagnóstico de la entidad por déficit de carnitina y en uno por déficit de flavoproteínas. Tres correspondieron a pacientes del sexo femenino. Concluimos que con una correlación sistemática de los datos clínicos y paraclínicos, así como también del estudio morfológico, se puede inferir la posible etiología de estas miopatías, cuyo diagnóstico definitivo es por medio del análisis bioquímico
Assuntos
Humanos , Masculino , Adolescente , Adulto , Feminino , Lactente , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Doenças Musculares , Músculo Esquelético/anormalidades , Medicina , VenezuelaRESUMO
OBJECTIVE: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.
Assuntos
Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/complicações , Fígado/patologia , Morte Súbita do Lactente/etiologia , 3-Hidroxiacil-CoA Desidrogenases/deficiência , Acil-CoA Desidrogenase , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Carnitina/metabolismo , Estudos de Casos e Controles , Feminino , Glutaratos/sangue , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Fígado/metabolismo , Masculino , Triagem Neonatal/métodos , Oxirredução , Estudos Retrospectivos , Morte Súbita do Lactente/patologiaRESUMO
A term neonate became lethargic and hypotonic at 46 hours of age and died 10 hours later despite supportive therapy. Urinary organic acids indicated medium-chain acyl-coenzyme A dehydrogenase deficiency, and DNA studies confirmed this disorder. Neonatal symptoms in this enzyme deficiency have rarely been reported, and recent reviews have ignored or discounted this presentation.
Assuntos
DNA/genética , Ácidos Graxos Dessaturases/deficiência , Erros Inatos do Metabolismo Lipídico/metabolismo , Acil-CoA Desidrogenase , Ácidos Graxos Dessaturases/análise , Ácidos Graxos Dessaturases/genética , Ácidos Graxos/urina , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Mutação , Reação em Cadeia da Polimerase , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Cholesterol ester storage disease (CESD) is infrequent in children. Four new cases in two nonrelated families are presented. Acid lipase deficiency in the leukocytes of the patients and reduced activity (50%) in those of parents were demonstrated. Clinical manifestations varied from neonatal cholestasis to asymptomatic hepatomegaly. Hepatic histology showed lipid vacuoles and cholesterol ester storage in hepatocytes and Kupffer cells. Increased levels of cholesterol and hepatomegaly were the first findings. There is as yet no specific treatment for CESD; however, the early detection of cases would make possible the timely control of complications.
Assuntos
Ésteres do Colesterol/metabolismo , Erros Inatos do Metabolismo Lipídico , Criança , Feminino , Hepatomegalia/enzimologia , Homozigoto , Humanos , Hipercolesterolemia/metabolismo , Células de Kupffer/enzimologia , Leucócitos/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Lipase Lipoproteica/deficiência , Fígado/enzimologia , Fígado/patologia , MasculinoAssuntos
Doenças Desmielinizantes/patologia , Esclerose Cerebral Difusa de Schilder/patologia , Bainha de Mielina/patologia , Adrenoleucodistrofia/patologia , Fatores Etários , Feminino , Humanos , Lactente , Leucodistrofia de Células Globoides/patologia , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Bainha de Mielina/metabolismoRESUMO
Of three siblings affected with cholesterol ester storage disease, two died at ages 7 and 9 years, respectively, with hepatic scarring and portal hypertension. Lipid storage was documented in both patients, as were esophageal varices and aortic plaques in the older child. The third affected sibling, followed to 13 years of age, has hepatomegaly, hyperlipidemia, short stature, adrenal calcification, and acid lipase deficiency. Leukocyte extracts demonstrated deficiency of acid lipase in this patient. This autosomal recessive condition may be allelic with Wolman disease with a more malignant course in this family than in most reported cases.