RESUMO
BACKGROUND: Multiple acyl-coA dehydrogenase deficiency (MADD) is a rare, inherited, autosomal-recessive disorder leading to the accumulation of acylcarnitine of all chain lengths. Acute decompensation with cardiac, respiratory or hepatic failure and metabolic abnormalities may be life-threatening. CASE PRESENTATION: A 29-year-old woman presented with severe lactic acidosis associated with intense myalgia and muscle weakness. The clinical examination revealed symmetric upper and lower limb motor impairment (rated at 2 or 3 out of 5 on the Medical Research Council scale) and clear amyotrophy. Laboratory tests had revealed severe rhabdomyolysis, with a serum creatine phosphokinase level of 8,700 IU/L and asymptomatic hypoglycemia in the absence of ketosis. Electromyography revealed myotonic bursts in all four limbs. The absence of myositis-specific autoantibodies ruled out a diagnosis of autoimmune myositis. Finally, Acylcarnitine profile and gas chromatography-mass spectrometry analysis of organic acids led to the diagnosis of MADD. A treatment based on the intravenous infusion of glucose solutes, administration of riboflavin, and supplementation with coenzyme Q10 and carnitine was effective. Lipid consumption was strictly prohibited in the early stages of treatment. The clinical and biochemical parameters rapidly improved and we noticed a complete disappearance of the motor deficit, without sequelae. CONCLUSION: A diagnosis of MADD must be considered whenever acute or chronic muscle involvement is associated with metabolic disorders. Acute heart, respiratory or hepatic failure and metabolic abnormalities caused by MADD may be life-threatening, and will require intensive care.
Assuntos
Encefalopatias/diagnóstico , Corpo Caloso/patologia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/tratamento farmacológico , Riboflavina/uso terapêutico , Adulto , Encefalopatias/etiologia , Corpo Caloso/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genéticaAssuntos
DNA Polimerase Dirigida por DNA/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação de Sentido Incorreto , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , DNA Polimerase gama , Europa (Continente) , Feminino , Estudos de Associação Genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/classificação , Doenças Mitocondriais/fisiopatologia , Músculos/patologia , Fenótipo , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto JovemRESUMO
INTRODUCTION: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. METHODS AND RESULTS: Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. CONCLUSION: Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.
Assuntos
Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/terapia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Doenças Neuromusculares/enzimologia , Doenças Neuromusculares/terapia , Adulto , Idade de Início , Biópsia , Carnitina/análogos & derivados , Carnitina/metabolismo , Eletromiografia , Flavoproteínas Transferidoras de Elétrons/genética , Exercício Físico , Feminino , França , Humanos , Proteínas Ferro-Enxofre/genética , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Mutação/genética , Doenças Neuromusculares/genética , Oxirredução , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Rabdomiólise/etiologia , Adulto JovemRESUMO
INTRODUCTION: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare genetic disease involving fatty acid oxidation. It is due to the deficiency of one of the two electron transporters: electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxydoreductase (ETF-QO). Symptoms begin more often in childhood or in young adulthood with a multisystemic disease with encephalopathy or muscular weakness. CASE REPORTS: We report here two adult cases with ETF-QO deficiency, confirmed by mutation analysis (ETFDH gene), revealed by a muscular weakness associated with muscle lipidosis. One of our patients presented an acute encephalopathy with vomiting ten years before the onset of muscular symptoms. The second patient exhibited a slowly progressive pelvic girdle muscle weakness. Diagnosis was established by characteristic abnormalities of acylcarnitine profile by tandem mass spectrometry. For both patients, a dramatic clinical improvement was observed under treatment with riboflavine and L-carnitine. CONCLUSION: Since it is a treatable disorder, this diagnosis must be considered by performing an acylcarnitine profile in all patients presenting with an unexplained muscular weakness.
Assuntos
Acil-CoA Desidrogenases/deficiência , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Lipidoses/tratamento farmacológico , Lipidoses/genética , Adulto , Biópsia , Encefalopatias Metabólicas/genética , Carnitina/análogos & derivados , Carnitina/análise , Carnitina/metabolismo , Corantes , Análise Mutacional de DNA , Transporte de Elétrons/genética , Flavoproteínas Transferidoras de Elétrons/genética , Flavoproteínas Transferidoras de Elétrons/metabolismo , Feminino , Humanos , Erros Inatos do Metabolismo Lipídico/patologia , Lipidoses/patologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Debilidade Muscular/genética , Músculo Esquelético/patologia , Riboflavina/metabolismo , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
We report a newborn with progressive leukoencephalopathy and lactic acidaemia, diagnosed with isolated sulfite oxidase deficiency. We show that low plasma total homocysteine (PTHcy) is a valuable early indicator of sulfite oxidase dysfunction, providing a crucial first-line screen, whereas plasma cystine is not always informative in the first few days of life.
Assuntos
Acidose Láctica/diagnóstico , Encefalopatias/diagnóstico , Ácido Láctico/sangue , Sulfito Oxidase/deficiência , Acidose Láctica/sangue , Acidose Láctica/etiologia , Encefalopatias/sangue , Encefalopatias/etiologia , Homocisteína/sangue , Humanos , Recém-Nascido , MasculinoRESUMO
Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and isovaleryl-CoA dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicine.
Assuntos
Acil-CoA Desidrogenase/deficiência , Doenças dos Cavalos/enzimologia , Rabdomiólise/veterinária , Acil-CoA Desidrogenase/genética , Animais , Feminino , Doenças dos Cavalos/patologia , Cavalos , Masculino , Rabdomiólise/enzimologia , Rabdomiólise/patologiaAssuntos
Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/enzimologia , Encéfalo/enzimologia , Creatina/deficiência , Predisposição Genética para Doença/genética , Deficiência Intelectual/enzimologia , Deficiência Intelectual/etiologia , Adolescente , Amidinotransferases/genética , Encéfalo/patologia , Encéfalo/fisiopatologia , Encefalopatias Metabólicas Congênitas/genética , Criança , Pré-Escolar , Transtornos Cromossômicos/enzimologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Creatina/genética , Creatinina/metabolismo , Análise Mutacional de DNA , Feminino , Genes Recessivos/genética , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Testes Genéticos , Guanidinoacetato N-Metiltransferase/genética , Humanos , Deficiência Intelectual/genética , Espectroscopia de Ressonância Magnética , Masculino , Proteínas de Membrana Transportadoras/genética , Estudos Prospectivos , Fatores SexuaisRESUMO
Seventy-six compounds of biological interest for the diagnosis of inherited disorders of amino acids (AA) metabolism have previously been demonstrated to be detectable in positive mode electrospray ionisation tandem mass spectrometry (ESI-MS/MS), after separation by ion-pairing reversed-phase liquid chromatography (RPLC). The separation method used tridecafluoroheptanoic acid as ion-pairing agent, and a gradient of acetonitrile for the elution of the most retained compounds. This method had previously been demonstrated to be suitable for the qualitative diagnosis of many AA disorders, and for the quantitative measurement of 16 AA in biological fluids, using their stable isotope labelled (SIL) AA as internal standard. For quantification of the other AA, an internal standard was chosen among the available SIL-AA, as close as possible to the analyte to be measured, in terms of structural analogy, and of retention time in the chromatographic system. The performances of the quantitative analysis of the other AA to be measured are reported here. They show validated results for several AA, allowing their accurate quantification, with another SIL-AA as internal standard. For some other AA, quantitative results were not accurate, allowing only semi-quantitative or qualitative determination for these parameters.