RESUMO
We discuss two adult siblings who presented with symptoms of myalgia and rhabdomyolysis following exercise with myoglobinuria; genetic testing confirmed carnitine palmitoyltransferase II deficiency and resulted in institution of appropriate crisis management and dietary advice. We explore the phenotypic variability of this commonest fatty oxidation defect that remains under-diagnosed in the adult population and provide clues for early recognition and diagnosis.
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We report a baby with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency who presented on day 2 with poor feeding and lethargy. She was floppy with hypoglycaemia (1.8 mmol/l) and hyperammonaemia (182 µmol/l). Despite correction of these and a continuous intravenous infusion of glucose at 4.5-6.2 mg/kg/min, she developed generalised tonic clonic seizures on day 3. She also suffered two episodes of pulseless ventricular tachycardia, from which she was resuscitated successfully. Unfortunately, she died on day 5, following a third episode of pulseless ventricular tachycardia. Arrhythmias are generally thought to be rarer in MCAD deficiency than in disorders of long-chain fatty acid oxidation. This is, however, the sixth report of ventricular tachyarrhythmias in MCAD deficiency. Five of these involved neonates and it may be that patients with MCAD deficiency are particularly prone to ventricular arrhythmias in the newborn period. Three of the patients (including ours) had normal blood glucose concentrations at the time of the arrhythmias and had been receiving intravenous glucose for many hours. These cases suggest that arrhythmias can be induced by medium-chain acylcarnitines or other metabolites accumulating in MCAD deficiency. Ventricular tachyarrhythmias can occur in MCAD deficiency, especially in neonates.
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Liver dysfunction usually accompanies metabolic decompensation in fatty acid oxidation disorders, including carnitine palmitoyltransferase (CPT) Ia deficiency. Typically, the liver is enlarged with raised plasma transaminase activities and steatosis on histological examination. In contrast, cholestatic jaundice is rare, having only been reported in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We report a 3-year-old boy with CPT Ia deficiency who developed hepatomegaly and cholestatic jaundice following a viral illness. No cause for the jaundice could be found, apart from the fatty acid oxidation disorder. Liver histology showed diffuse, predominately macrovesicular steatosis, hepatocellular and canalicular cholestasis but no bile duct paucity or evidence of large duct obstruction. The liver dysfunction resolved in 4-7 weeks.
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BACKGROUND: Mitochondrial DNA (mtDNA) mutations are important causes of human genetic disease, with mutations in tRNA genes particularly prevalent. In many patients, mutations are heteroplasmic, affecting a population of mtDNA molecules. Establishing the pathogenicity of homoplasmic mitochondrial tRNA (mt-tRNA) mutations, in which the mutation is present in every mtDNA molecule, is extremely difficult. These mutations must conform to specific pathogenic criteria, documenting unequivocally a functional defect of the mutant mt-tRNA. AIMS: To investigate the pathogenic nature of two homoplasmic mt-tRNA(Thr) deletions, m.15940delT (previously reported as pathogenic) and m.15937delA, by assessing the steady state levels of the mutant mt-tRNA in tissue and cell-line samples from six unrelated families, in which affected individuals were thoroughly investigated for mitochondrial DNA disease on the basis of clinical presentations. Rates of de novo mitochondrial protein synthesis were also examined in control and m.15937delA mutant fibroblasts. RESULTS: Our data strongly suggest that both single nucleotide deletions are neutral polymorphisms; no obvious defects were apparent in either steady state mt-tRNA(Thr) levels or rates of mitochondrial protein synthesis. CONCLUSIONS: These findings have important implications for the investigation of other families with suspected mtDNA disease, in particular the requirement to fulfil strict and established pathogenic criteria in order to avoid misattribution of pathogenicity to mt-tRNA variants.
Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação , RNA de Transferência de Treonina/genética , RNA/genética , Adulto , Biópsia , Células Cultivadas , Criança , Análise Mutacional de DNA , Feminino , Fibroblastos , Humanos , Lactente , Masculino , Mitocôndrias Cardíacas/genética , Mitocôndrias Musculares/genética , Doenças Mitocondriais/fisiopatologia , Músculo Esquelético , Polimorfismo Genético , RNA Mitocondrial , Pele/citologiaRESUMO
We report a patient with carnitine palmitoyltransferase I (CPT I) deficiency, who presented with acute encephalopathy at 6 months of age. This was precipitated by an episode of gastroenteritis. No hypoglycaemia was documented, but there was hepatomegaly; blood tests revealed raised transaminases, a coagulopathy and severe hypertriglyceridaemia (48.8 mmol/L) and hypercholesterolaemia (9.5 mmol/L). The hyperlipidaemia resolved within 3 days of treatment and did not recur. At 2 years of age, the patient's liver function, growth and development are all normal. Hyperlipidaemia has been reported during acute illness in previous patients with CPT I deficiency but it is not a well-recognized feature; it should alert metabolic specialists to this potential diagnosis.
Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Hiperlipidemias/complicações , Hiperlipidemias/diagnóstico , Hiperlipidemias/enzimologia , Erros Inatos do Metabolismo/complicações , Encefalopatias/diagnóstico , Pré-Escolar , Humanos , Erros Inatos do Metabolismo/diagnósticoRESUMO
BACKGROUND: Mitochondrial diseases are an important group of neurometabolic disorders in children with varied clinical presentations and diagnosis that can be difficult to confirm. AIM: To report the significance of reduced respiratory chain enzyme (RCE) activity in muscle biopsy samples from children. METHODS: Retrospective odds ratio was used to compare clinical and biochemical features, DNA studies, neuroimaging, and muscle biopsies in 18 children with and 48 without reduced RCE activity. RESULTS: Children with reduced RCE activity were significantly more likely to have consanguineous parents, to present with acute encephalopathy and lactic acidaemia and/or within the first year of life; to have an axonal neuropathy, CSF lactate >4 mmol/l; and/or to have signal change in the basal ganglia. There were positive associations with a maternal family history of possible mitochondrial cytopathy; a presentation with failure to thrive and lactic acidaemia, ragged red fibres, reduced fibroblast fatty acid oxidation and with an abnormal allopurinol loading test. There was no association with ophthalmic abnormalities, deafness, epilepsy or myopathy. CONCLUSION: The association of these clinical, biochemical and radiological features with reduced RCE activity suggests a possible causative link.
Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Músculos/enzimologia , Adolescente , Fatores Etários , Encéfalo/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Consanguinidade , Feminino , Humanos , Lactente , Ácido Láctico/metabolismo , Masculino , Doenças Mitocondriais/enzimologiaRESUMO
We describe two unrelated cases of ornithine aminotransferase (OAT) deficiency with rare neonatal presentation of hyperammonaemia. The diagnosis in the neonatal presentation of OAT deficiency is hampered as hyperornithinaemia is absent. Enzyme and mutation studies confirmed the diagnosis. OAT deficiency should be included in differential diagnosis of neonatal hyperammonaemia.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Ornitina-Oxo-Ácido Transaminase/deficiência , Amônia/sangue , Arginina/sangue , Citrulina/sangue , Diagnóstico Diferencial , Feminino , Fibroblastos/metabolismo , Glutamina/sangue , Humanos , Hiperamonemia/sangue , Hiperamonemia/diagnóstico , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Ornitina/sangue , Ácido Orótico/sangueRESUMO
General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0+/-0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Mitocôndrias/patologia , Complexos Multienzimáticos/deficiência , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Carnitina/análogos & derivados , Carnitina/metabolismo , Éxons , Ácidos Graxos/metabolismo , Fibroblastos/metabolismo , Homozigoto , Humanos , Masculino , Proteína Mitocondrial Trifuncional , Mutação , Fenótipo , Polineuropatias/diagnóstico , Polineuropatias/genética , Prognóstico , Rabdomiólise/diagnóstico , Rabdomiólise/genéticaRESUMO
The truncating R254X mutation in the OCTN2 gene results in defective high-affinity carnitine transport and has been previously described as a founder mutation in the Chinese population. We now report a Saudi Arabian kindred with this same mutation, suggesting that it may be a recurrent mutation or a very ancient founder mutation. Western blot analysis of skin fibroblast lysates from the proband with our specific anti-murine OCTN2 antibody revealed the absence of the OCTN2 protein.
Assuntos
Mutação , Proteínas de Transporte de Cátions Orgânicos/genética , Western Blotting , Pré-Escolar , DNA/análise , Feminino , Fibroblastos/química , Humanos , Proteínas de Transporte de Cátions Orgânicos/deficiência , Arábia Saudita , Membro 5 da Família 22 de Carreadores de SolutoRESUMO
Blood spot carnitine profiles are widely used to screen for disorders of fatty acid oxidation. This case report emphasizes that a borderline concentration of free carnitine does not exclude the diagnosis of primary carnitine deficiency. Concurrent measurement of carnitine in the plasma and urine is a more sensitive test.
Assuntos
Cardiomiopatia Dilatada/etiologia , Carnitina/deficiência , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Carnitina/sangue , Aberrações Cromossômicas , Diagnóstico Diferencial , Ecocardiografia , Feminino , Genes Recessivos , Humanos , Lactente , Proteínas de Transporte de Cátions Orgânicos/deficiência , Proteínas de Transporte de Cátions Orgânicos/genética , Membro 5 da Família 22 de Carreadores de SolutoRESUMO
We report a patient with lipid-storage myopathy due to multiple acyl-CoA dehydrogenation deficiency (MADD). Molecular genetic analysis showed that she was compound heterozygous for mutations in the gene for electron transfer flavoprotein:ubiquinone oxidoreductase (ETFQO). Despite a good initial response to treatment, she developed respiratory insufficiency at age 14 years and has required long-term overnight ventilation. Thus, MADD is one of the few conditions that can cause a myopathy with weakness of the respiratory muscles out of proportion to the limb muscles.
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Acil-CoA Desidrogenases/genética , Flavoproteínas Transferidoras de Elétrons/genética , Proteínas Ferro-Enxofre/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Metabolismo dos Lipídeos , Doenças Musculares/genética , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Acil-CoA Desidrogenases/deficiência , Adolescente , Idade de Início , Sequência de Bases , Western Blotting , Análise Mutacional de DNA , DNA Complementar/metabolismo , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Flavoproteínas Transferidoras de Elétrons/metabolismo , Feminino , Fibroblastos/metabolismo , Heterozigoto , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Doenças Musculares/diagnóstico , Fenótipo , Respiração ArtificialRESUMO
Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients representing the full clinical spectrum of disease. Severe and intermediate phenotypes show a clear correlation with biochemical indices and genetic analysis revealed causative mutations in most patients. Studies of mild phenotypes suggest a more complex interaction, with higher residual fatty acid oxidation, a wider range of CPT II activity (10-60%) but little evidence of genotype-phenotype correlation. Residual CPT II mutant protein from myopathic patients shows thermal instability at 41 degrees C. The common 'polymorphisms' V3681 and M647V are strikingly overrepresented in the myopathic patients, the implication being that they may significantly influence the manifestation of clinical disease and could therefore potentially be considered as a susceptibility variants. Among myopathic individuals, males comprised 88% of patients, suggesting increased susceptibility to clinical disease. A small number of symptomatic patients appear to have significant residual CPT II activity (42-60%) The synergistic interaction of partial deficiencies of CPT II, muscle adenosine monophosphate deaminase and possibly other enzymes of muscle energy metabolism in the aetiology of episodic myopathy deserves wider consideration.
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Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , AMP Desaminase/metabolismo , Adolescente , Adulto , Linhagem Celular , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Mutação/fisiologia , Oxirredução , Palmitatos/metabolismo , Polimorfismo Genético/genética , TemperaturaRESUMO
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (EC 1.1.1.178) deficiency is a recently described defect of isoleucine catabolism. The disorder is characterized by normal early development followed by a progressive loss of mental and motor skills. Deterioration may be rapid or may follow a slower decline with a possible stabilization of the disorder on a low-protein diet and appropriate medication. We report a 23-year-old man with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency with a very mild clinical course. He had apparently normal early development and remained relatively well until the age of 6 years, when he contracted measles. Following this illness, his motor skills and school progress deteriorated. At 15 years he had significant dysarthria, and generalized rigidity with some dystonic and unusual posturing. He was then treated with a low-protein high-carbohydrate diet with a good response in terms of balance and gait. At 18 years he was given benzhexol (Artane), increased slowly from 2 mg to 6 mg daily, resulting in improvement in tremor and dystonia. At 23 years he can dress himself and works in sheltered employment but remains severely dysarthric.
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Oxirredutases do Álcool/deficiência , Oxirredutases do Álcool/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , 3-Hidroxiacil-CoA Desidrogenases , Acetil-CoA C-Aciltransferase/sangue , Adulto , Oxirredutases do Álcool/sangue , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Biomarcadores , Eletroencefalografia , Transporte de Elétrons/genética , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Isoleucina/metabolismo , Masculino , Fenótipo , Desempenho Psicomotor , Tomografia Computadorizada por Raios XRESUMO
Carnitine palmitoyltransferase type I (CPT I) is unique among long-chain fatty acid oxidation enzymes in that there are two tissue-specific isoforms, 'hepatic' and 'muscle', which are encoded by two separate genes. The 'hepatic' isoform is expressed in liver, kidney and fibroblasts and at low levels in the heart, while the other isoform occurs in skeletal muscle and is the predominant form in heart. Reported patients with CPT I deficiency lack activity of the hepatic isoform and present before 30 months of age with hypoketotic hypoglycaemia, hepatomegaly with raised transaminases, seizures and coma. We discuss four new cases in three families showing, variously, renal tubular acidosis, transient hyperlipidaemia and, paradoxically, myopathy with elevated creatinine kinase or cardiac involvement in the neonatal period as additional features that deserve wider recognition.
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Carnitina O-Palmitoiltransferase/deficiência , Acidose Tubular Renal/enzimologia , Cardiomiopatias/enzimologia , Feminino , Humanos , Hiperlipidemias/enzimologia , Recém-Nascido , Masculino , Doenças Musculares/enzimologiaRESUMO
Carnitine-acylcarnitine translocase (CACT) deficiency is an inherited defect of the co-transport of free and esterified carnitine across the inner mitochondrial membrane. We report a case of CACT deficiency in a newborn who died at 72 h of age from severe, intractable cardiac tachyarrhythmia, despite an improvement in his neurological and biochemical status. Postmortem examination showed marked steatosis of myocardium, liver, and kidney. In addition, electron microscopic studies showed virtually complete elimination of mitochondria from cardiomyocytes. It appears that the correction of the acute metabolic derangements in this condition may not prevent rapid progression to death, suggesting that the rhythm disturbances in CACT deficiency result from prior and ongoing accumulation of toxic metabolites, rather than from an acute metabolic derangement. Furthermore, we speculate that the choice of anti-arrhythmic agent in this patient may paradoxically have contributed to his death.