Assuntos
Doença de Leigh/diagnóstico , Doença de Leigh/etiologia , Debilidade Muscular/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Baclofeno/uso terapêutico , Carnitina/uso terapêutico , Pré-Escolar , Diagnóstico Diferencial , Dieta Cetogênica/métodos , Humanos , Doença de Leigh/terapia , Masculino , Relaxantes Musculares Centrais/uso terapêutico , Debilidade Muscular/tratamento farmacológico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Ubiquinona/análogos & derivados , Ubiquinona/uso terapêutico , Vitaminas/uso terapêuticoRESUMO
Pyruvate dehydrogenase deficiency is a rare mitochondrial disease leading to energy deficiency in the cells. This particularly affects the central nervous system, resulting in a broad range of neurological symptoms.
Assuntos
Doença da Deficiência do Complexo de Piruvato Desidrogenase , Diagnóstico Diferencial , Ácido Dicloroacético/administração & dosagem , Ácido Dicloroacético/uso terapêutico , Dieta Cetogênica , Humanos , Complexo Piruvato Desidrogenase/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/enzimologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Tiamina/administração & dosagem , Tiamina/uso terapêuticoAssuntos
Acidose , Dieta Cetogênica/métodos , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Complexo Piruvato Desidrogenase/genética , Equilíbrio Ácido-Base , Acidose/diagnóstico , Acidose/etiologia , Acidose/metabolismo , Acidose/terapia , Criança , Diagnóstico Diferencial , Gerenciamento Clínico , Etnicidade , Feminino , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/etiologia , Humanos , Concentração de Íons de Hidrogênio , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/etiologia , Mutação , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/fisiopatologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapiaRESUMO
We present the case of a female infant referred for prenatal MR evaluation of ventriculomegaly, which had been attributed by the referring obstetrician to aqueductal stenosis. Fetal MR confirmed ventriculomegaly but also demonstrated cerebral volume loss and white matter abnormalities. After birth, the infant developed persistent lactic acidosis. A diagnosis of pyruvate dehydrogenase complex deficiency was made on the basis of metabolic and molecular genetic studies. Ventriculomegaly is a common referral reason for fetal MR, yet there are few published reports of the radiographic findings that accompany inborn errors of metabolism, one potentially under-recognized cause of enlarged ventricles. This case contributes to this small body of literature on the imaging features of pyruvate dehydrogenase complex deficiency by describing pre- and postnatal MR findings and key clinical details. Our report emphasizes the necessity of considering pyruvate dehydrogenase complex deficiency and other metabolic disorders as potential etiologies for fetal ventriculomegaly since prompt diagnosis may allow for early initiation of treatment and improve outcome.
Assuntos
Imageamento por Ressonância Magnética/métodos , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico por imagem , Ultrassonografia Pré-Natal/métodos , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , Gravidez , Diagnóstico Pré-Natal , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapiaAssuntos
Síndrome de Down/complicações , Futilidade Médica/legislação & jurisprudência , Cuidados Paliativos/legislação & jurisprudência , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Síndrome de Down/terapia , Permeabilidade do Canal Arterial/complicações , Permeabilidade do Canal Arterial/cirurgia , Humanos , Lactente , Masculino , New South Wales , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Respiração Artificial , Medição de Risco/legislação & jurisprudênciaRESUMO
Pyruvate dehydrogenase complex (PDHC) deficiency causes encephalomyopathies, of which there are four major categories: (1) neonatal encephalopathy with lactic acidosis; (2) an early infantile form, which (3) at times resembles Leigh syndrome; and (4) a later-onset form. Long-term clinical and radiological follow-up is still incompletely elucidated. We report a 12-year-old male with intermittent-relapsing PDHC deficiency who presented with three typical acute episodes of metabolic decompensation over 7 years. Neuroimaging showed reversible signal abnormalities in the basal ganglia, inferior olivary nuclei, periaqueductal grey matter, and dentate nuclei, with evidence of lactate on magnetic resonance spectroscopy. Molecular analysis of PDH1A revealed a novel hemizygous c.1045G>A mutation, predicting a p.A349T missense mutation. He was treated with thiamine supplementation and, while on this regimen, he experienced several intercurrent febrile episodes without neurological compromise. This case report stresses the importance of performing neuroimaging during acute clinical episodes because brain lesions in PDHC deficiency may be transient and reversible, and false-negative results may mislead the diagnosis and delay the treatment.
Assuntos
Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Alelos , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Economia , Hemizigoto , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Recidiva , Tiamina/uso terapêuticoRESUMO
Pyruvate dehydrogenase (PDH) is a crucial multienzyme system linking glycolysis to the tricarboxylic acid cycle by catalysing the decarboxylation of pyruvate to acetyl-CoA. Deficiency in pyruvate dehydrogenase is most commonly secondary to mutations in the X-linked PDHA1 gene encoding the E1 alpha subunit. There is a wide range of clinical presentations from severe neonatal lactic acidosis to chronic encephalopathy (Leigh syndrome). In recent years, a small subset of patients was recognized with less severe involvement, presenting initially only with intermittent symptoms, mainly of ataxia. Most of these patients remain stable for a number of years before developing progressive neurological deterioration around puberty at the latest. There does not appear to be a reliable correlation between genotype, phenotype, or enzyme activity. This makes counselling in a clinical setting challenging. We report a case with a previously known common mutation in PDHA1 (R263G) with an excellent outcome at 18 years of age. Previous patients with this mutation have presented with mental retardation and/or Leigh syndrome, while our patient's clinical outcome is exceptional. He is cognitively normal and has normal brain MRI. His management includes a stringent carbohydrate-free diet, as well as supplementation with thiamine, carnitine and vitamin E. This case further broadens the clinical spectrum, including now an example of a cognitively normal adult with PDH deficiency.
Assuntos
Cognição , Mutação , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Adolescente , Análise Mutacional de DNA , Dieta com Restrição de Carboidratos , Suplementos Nutricionais , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Fenótipo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/enzimologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/psicologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Resultado do TratamentoAssuntos
Anestesia Geral/métodos , Paralisia/cirurgia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Pré-Escolar , Feminino , Humanos , Paralisia/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Tiamina/uso terapêutico , Complexo Vitamínico B/uso terapêuticoRESUMO
We determined the ability of self-complementary adeno-associated virus (scAAV) vectors to deliver and express the pyruvate dehydrogenase E1alpha subunit gene (PDHA1) in primary cultures of skin fibroblasts from 3 patients with defined mutations in PHDA1 and 3 healthy subjects. Cells were transduced with scAAV vectors containing the cytomegalovirus promoter-driven enhanced green fluorescent protein (EGFP) reporter gene at a vector:cell ratio of 200. Transgene expression was measured 72h later. The transduction efficiency of scAAV2 and scAAV6 vectors was 3- to 5-fold higher than that of the other serotypes, which were subsequently used to transduce fibroblasts with wild-type PDHA1 cDNA under the control of the chicken beta-action (CBA) promoter at a vector:cell ratio of 1000. Total PDH-specific activity and E1alpha protein expression were determined 10 days post-transduction. Both vectors increased E1alpha expression 40-60% in both control and patient cells, and increased PDH activity in two patient cell lines. We also used dichloroacetate (DCA) to maximally activate PDH through dephosphorylation of E1alpha. Exposure for 24h to 5mM DCA increased PDH activity in non-transduced control (mean 37% increase) and PDH deficient (mean 44% increase) cells. Exposure of transduced patient fibroblasts to DCA increased PDH activity up to 90% of the activity measured in untreated control cells. DCA also increased expression of E1alpha protein and, to variable extents, that of other components of the PDH complex in both non-transduced and transduced cells. These data suggest that a combined gene delivery and pharmacological approach may hold promise for the treatment of PDH deficiency.
Assuntos
Dependovirus/genética , Ácido Dicloroacético/uso terapêutico , Terapia Genética/métodos , Vetores Genéticos , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Células Cultivadas , Fibroblastos , Humanos , Piruvato Desidrogenase (Lipoamida)/biossíntese , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Transdução GenéticaRESUMO
Pyruvate dehydrogenase deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. Most cases are caused by mutations in the X-linked gene for the E1alpha subunit of the complex. Mutations in DLAT, the gene encoding dihydrolipoamide acetyltransferase, the E2 core component of the complex, have not been described previously. We report two unrelated patients with pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both patients are less severely affected than typical patients with E1alpha mutations and both have survived well into childhood. Episodic dystonia was the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent. The patients had neuroradiological evidence of discrete lesions restricted to the globus pallidus, and both are homozygous for different mutations in the DLAT gene. The clinical presentation and neuroradiological findings are not typical of pyruvate dehydrogenase deficiency and extend the clinical and mutational spectrum of this condition.
Assuntos
Autoantígenos/genética , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/enzimologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Western Blotting/métodos , Química Encefálica/genética , Criança , Análise Mutacional de DNA/métodos , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase , Fibroblastos/enzimologia , Globo Pálido/patologia , Ácido Glutâmico/genética , Humanos , Leucina/genética , Imageamento por Ressonância Magnética/métodos , Masculino , Mutação , Fenilalanina/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/patologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Transfecção/métodosRESUMO
Here we review the rationale for considering the pyruvate dehydrogenase multienzyme complex (PDC) as a target for gene therapy for defects in mitochondrial energetics. PDC is entirely nuclear encoded and is situated in the mitochondrial inner membrane. The complex catalyzes the rate-determining step in aerobic carbohydrate metabolism and plays a critical role in the efficient conversion of substrate fuel into energy by cells. PDC activity is regulated in large part by reversible phosphorylation (inactivation) of its E1alpha subunit. Congenital defects in PDC are usually due to mutations in E1alpha and are typified by lactic acidosis, neurodegeneration and early death. Acquired deficiency in PDC has been implicated in the etiopathology of several other metabolic or neurodegenerative disorders. Recently, a vector using recombinant adeno-associated virus (rAAV) that contained a fusion protein of full-length E1alpha and the reporter gene green fluorescent protein was used to deliver wild type E1alpha into mitochondria after injection of the construct in vivo into the central nervous system of rats and in vitro into human cells. Transduction of cultured fibroblasts from a male patient with E1alpha deficiency led to partial restoration of PDC activity, as determined by decarboxylation of 14C-pyruvate. These data indicate that at least partial correction of PDC defects may be feasible by gene transfer. Furthermore, the combination of AAV-mediated delivery of E1alpha with pharmacologic activation (dephosphorylation) of the wild type enzyme subunit may provide an optimal therapeutic strategy for patients with acquired or congenital deficiencies in mitochondrial energy metabolism.
Assuntos
Dependovirus/genética , Terapia Genética , Vetores Genéticos , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Complexo Piruvato Desidrogenase/uso terapêutico , Animais , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismoRESUMO
The authors present a 25-year-old woman who was admitted to the ICU for treatment of shock, respiratory failure, and acidosis related to congenital lactic acidosis from pyruvate dehydrogenase deficiency. To aid in ongoing management of the metabolic acidosis, the Paratrend blood gas monitoring sensor was inserted through a peripheral venous site to provide a continuous measurement of pH and partial pressure of carbon dioxide (Pco2). With the venous insertion of the Paratrend, a clinically useful correlation with arterial blood gas values was noted. Linear regression analysis of the pH values from the venous blood gas analyses and the Paratrend monitor revealed r2 = 0.71 with p = 0.001 and r2 = 0.78 with a p = 0.0003 for the Pco2 values. Our preliminary experience suggests that venous placement of the Paratrend monitor can be used to provide clinically useful, continuous measurement of pH and Pco2.
Assuntos
Acidose Láctica/complicações , Acidose Láctica/fisiopatologia , Braço/irrigação sanguínea , Braço/fisiopatologia , Concentração de Íons de Hidrogênio , Monitorização Ambulatorial/métodos , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/fisiopatologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Choque/etiologia , Choque/fisiopatologia , Veias/fisiopatologia , Acidose Láctica/congênito , Adulto , Feminino , Humanos , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Insuficiência Respiratória/terapia , Choque/terapiaAssuntos
Doença da Deficiência do Complexo de Piruvato Desidrogenase , Criança , Pré-Escolar , Diagnóstico Diferencial , Humanos , Lactente , Recém-Nascido , Mutação , Prognóstico , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapiaAssuntos
Linfócitos/enzimologia , Debilidade Muscular/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Pré-Escolar , Humanos , Masculino , Debilidade Muscular/patologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Complexo Piruvato Desidrogenase/análise , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Tiamina/administração & dosagemRESUMO
Congenital lactic acidoses form a heterogeneous group of disorders: this paper considers primarily defects of the pyruvate dehydrogenase complex and the respiratory chain. Attempts to treat these disorders are hampered by uncertainty concerning the pathophysiology and by the central role of the enzymes in cellular metabolism. Few strategies are of proven efficacy, though many have been tried, including dietary manipulation, enhancement of residual enzyme activity, artificial electron acceptors and free-radical scavengers. Evaluation of treatment is complicated by the rarity, heterogeneity and unpredictable course of the diseases. Double-blind placebo-controlled trials are needed.
Assuntos
Acidose Láctica/congênito , Acidose Láctica/terapia , Erros Inatos do Metabolismo/terapia , Ensaios Clínicos como Assunto , Transporte de Elétrons , Humanos , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapiaRESUMO
We experienced a case of pyruvate dehydrogenase deficiency observed by proton magnetic resonance spectroscopy (1H MRS). This case was diagnosed as West syndrome by characteristic convulsion and the periodic hypsarrhythmia pattern of EEG. At the age of 11 months, the first examination of 1H MRS revealed a high peak of lactate, and the high concentration of lactate and pyruvate was confirmed in sampled cerebrospinal fluid (CSF). Deficiency of pyruvate dehydrogenase complex was finally diagnosed by genetic examination. Dichloroacetate was administered to the patient as therapy. Decrease of lactate in the brain was found by 1H MRS. Lactate and pyruvate in the CSF was also decreased. In accordance with the suspension of dichloroacetate, increase of lactate in the brain was detected and the convulsions reappeared. After readministration of dichloroacetate, the patient was almost symptom free and lactate in the brain and CSF had decreased to the normal extent. We considered that 1H MRS provides useful information for screening metabolic disorders of infants and assessing the efficacy of therapy.