RESUMO
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.
Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Doenças Mitocondriais , Doenças Musculares , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Humanos , Recém-Nascido , Japão/epidemiologia , Erros Inatos do Metabolismo Lipídico/epidemiologia , Doenças Mitocondriais/epidemiologia , Doenças Musculares/epidemiologia , Triagem Neonatal/métodosRESUMO
BACKGROUND: The clinical severity of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is difficult to predict using conventional diagnostic methods. METHODS: Peripheral blood mononuclear cells obtained from 14 VLCAD deficiency patients and 23 healthy adults were loaded with carbon-13-universally labeled (U-13C-) fatty acids. Differences in acylcarnitine ratios between the patients and healthy groups and correlations between acylcarnitine ratios and a newly established clinical severity score (CSS) in the patient group were statistically examined. RESULTS: There was a significant decrease in the 13C-C2/13C-C18 and 13C-C12/13C-C14 ratios in the U-13C-stearic acid loading test and in the 13C-C2/13C-C18:1 and 13C-C12:1/13C-C14:1 ratios in the U-13C-oleic acid loading test in the patient group. The values of each ratio were significantly correlated with the CSS, suggesting that they could predict disease severity. Additionally, patients with a higher 13C-C16/13C-C18 ratio than the 13C-C14/13C-C18 ratio in the U-13C-stearic acid loading test had a significantly higher CSS and were presumed to have more severe disease. CONCLUSIONS: Our data indicated that this method could be used to predict the clinical severity of VLCAD deficiency, and identify patients at a risk of severe disease. IMPACT: We established a novel method to predict the severity of VLCAD deficiency by performing a loading test with carbon-13-labeled fatty acids on peripheral blood mononuclear cells. The U-13C-oleic acid loading test was useful for comparing the patient group with the control group in terms of disease severity. The U-13C-stearic acid loading test was useful for identifying the more severely affected patients. These methods are relatively less invasive and enable rapid evaluation of the clinical severity.
Assuntos
Carnitina , Leucócitos Mononucleares , Adulto , Humanos , Ácidos Graxos , Ácidos Esteáricos , Ácidos OleicosRESUMO
OBJECTIVES: Mevalonate kinase deficiency (MKD), a rare autosomal recessive autoinflammatory syndrome, is caused by disease-causing variants of the mevalonate kinase (MVK) gene. A national survey was undertaken to investigate clinical and genetic features of MKD patients in Japan. METHODS: The survey identified ten patients with MKD. Clinical information and laboratory data were collected from medical records and by direct interviews with patients, their families, and their attending physicians. Genetic analysis and measurement of MVK activity and urinary excretion of mevalonic acid were performed. RESULTS: None of the 10 patients harbored MVK disease-causing variants that are common in European patients. However, overall symptoms were in line with previous European reports. Continuous fever was observed in half of the patients. Elevated transaminase was observed in four of the 10 patients, two of whom fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. About half of the patients responded to temporary administration of glucocorticoids and NSAIDs; the others required biologics such as anti-IL-1 drugs. CONCLUSION: This is the first national survey of MKD patients in a non-European country. Although clinical symptoms were similar to those reported in Europe, the incidence of continuous fever and elevated transaminase was higher, probably due to differences in disease-causing variants.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Glucocorticoides/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Deficiência de Mevalonato Quinase , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Anticorpos Monoclonais Humanizados , Feminino , Testes Genéticos/métodos , Humanos , Fatores Imunológicos/uso terapêutico , Lactente , Japão/epidemiologia , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/epidemiologia , Deficiência de Mevalonato Quinase/genética , Ácido Mevalônico/urina , Inquéritos e Questionários , Avaliação de SintomasRESUMO
Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.
Assuntos
Carnitina O-Acetiltransferase/genética , Cromossomos Humanos Par 9/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Cadeias beta de HLA-DQ/genética , Polimorfismo de Nucleotídeo Único , Distúrbios do Sono por Sonolência Excessiva/enzimologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , MasculinoAssuntos
Tirosinemias , Humanos , Tirosinemias/complicações , Tirosinemias/diagnóstico , HeptanoatosRESUMO
BACKGROUND: Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder (FAOD). However, newborn screening (NBS) for this potentially fatal disease has not been established partly because reliable indices are not available. METHODS: We diagnosed CPT II deficiency in a 7-month-old boy presenting with hypoglycemic encephalopathy, which apparently had been missed in the NBS using C16 and C18:1 concentrations as indices. By referring to his acylcarnitine profile from the NBS, we adopted the (C16+C18:1)/C2 ratio (cutoff 0.62) and C16 concentration (cutoff 3.0nmol/mL) as alternative indices for CPT II deficiency such that an analysis of a dried blood specimen collected at postnatal day five retroactively yielded the correct diagnosis. Thereafter, positive cases were assessed by measuring (1) the fatty acid oxidation ability of intact lymphocytes and/or (2) CPT II activity in the lysates of lymphocytes. The diagnoses were then further confirmed by genetic analysis. RESULTS: The disease was diagnosed in seven of 21 newborns suspected of having CPT II deficiency based on NBS. We also analyzed the false-negative patient and five symptomatic patients for comparison. Values for the NBS indices of the false-negative, symptomatic patient were lower than those of the seven affected newborns. Although it was difficult to differentiate the false-negative patient from heterozygous carriers and false-positive subjects, the fatty acid oxidation ability of the lymphocytes and CPT II activity clearly confirmed the diagnosis. Among several other indices proposed previously, C14/C3 completely differentiated the seven NBS-positive patients and the false-negative patient from the heterozygous carriers and the false-positive subjects. Genetic analysis revealed 16 kinds of variant alleles. The most prevalent, detected in ten alleles in nine patients from eight families, was c.1148T>A (p.F383Y), a finding in line with those of several previous reports on Japanese patients. CONCLUSIONS: These findings suggested that CPT II deficiency can be screened by using (C16+C18:1)/C2 and C16 as indices. An appropriate cutoff level is required to achieve adequate sensitivity albeit at the cost of a considerable increase in the false-positive rate, which might be reduced by using additional indices such as C14/C3.
Assuntos
Carnitina O-Palmitoiltransferase/análise , Carnitina O-Palmitoiltransferase/deficiência , Erros Inatos do Metabolismo/diagnóstico , Triagem Neonatal , Palmitoilcarnitina/análise , Alelos , Carnitina O-Palmitoiltransferase/genética , Teste em Amostras de Sangue Seco/métodos , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Hipoglicemia/complicações , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/genética , Sensibilidade e Especificidade , Espectrometria de Massas em TandemRESUMO
Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder of mitochondrial fatty-acid oxidation. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is often reported in Caucasian countries due to a common mutation. However, the molecular and clinical basis of complete TFP deficiency has not been extensively reported. In this study, 14 Japanese cases (13 families) with complete TFP deficiency, including 9 previously reported cases, were analyzed to clarify the clinical and molecular characteristics of TFP deficiency. The clinical types of the 14 patients were as follows: 12 cases of neonatal (n=7) or myopathic (n=5) types and 2 cases of intermediate type. Peripheral neuropathy was found in four cases and hypocalcemia due to hypoparathyroidism, which is rarely reported in Caucasian patients, had developed in four cases. Maternal hemolysis, elevated liver enzymes and low platelet count syndrome and acute fatty liver of pregnancy were noted in two and one mothers, respectively. Fourteen mutations were identified in 26 alleles in Japanese patients, including two novel mutations (HADHA: c.361C>T, and HADHA-HADHB: g.26233880_ 26248855del), although no common mutations were found. This study suggests that the molecular and clinical aspects of Japanese patients with TFP deficiencies differ from those of Caucasian patients.
Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Rabdomiólise/diagnóstico , Rabdomiólise/genética , Adolescente , Povo Asiático/genética , Criança , Pré-Escolar , Ativação Enzimática , Família , Feminino , Testes Genéticos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Proteína Mitocondrial Trifuncional/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Subunidade beta da Proteína Mitocondrial Trifuncional/metabolismo , Mutação , População Branca/genéticaRESUMO
Tyrosinemia type I in Japan was reported for the first time in 1957 by Sakai et al. (Jikei Med J 2:1-10, 1957) and Kitagawa et al. (Proc Jpn Acad Ser B 88:192-200, 1957). Five cases of patients with tyrosinemia type I were reported to be definitively diagnosed in Japan. The first case was reported by Sakai et al. and Kitagawa et al. To the best of our knowledge, this was the first definite report in the world. The second and third cases were those of a brother and a sister who underwent liver transplantation and who were the children of a Japanese-descent migrant worker; the fourth case was that of a girl who underwent liver transplantation after 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) treatment, which was reported by Hata et al.; and the fifth case was that of a patient who was administered NTBC, which was reported by Ito et al. These were of the subacute type, wherein residual activity was considerably present. When combined therapy with a low phenylalanine and tyrosine diet and NTBC administration is started after early diagnosis, patients can survive without liver transplantation. Development of liver cancer is not found in the cases in Japan, but performing liver transplantation without delay is necessary when liver cancer is found.
Assuntos
Tirosinemias/diagnóstico , Tirosinemias/patologia , Pré-Escolar , Cicloexanonas/uso terapêutico , Feminino , Humanos , Lactente , Japão , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Transplante de Fígado/métodos , Masculino , Nitrobenzoatos/uso terapêutico , Fenilalanina/metabolismo , Tirosina/metabolismo , Tirosinemias/tratamento farmacológico , Tirosinemias/metabolismoRESUMO
BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a representative disorder of fatty acid oxidation and is one of the most prevalent inborn errors of metabolism among Caucasian populations. In Japan, however, it was as late as 2000 when the first patient was found, and enzymatic and genetic evaluation of MCAD deficiency began. METHODS: We measured octanoyl-CoA dehydrogenase activity in lymphocytes of symptomatic children and newborn screening (NBS)-positive subjects who showed elevated levels of C8-acylcarnitine in blood. The results were further confirmed by direct sequencing of the ACADM gene. RESULTS: The disease was diagnosed in 9 out of 18 symptomatic children. The affected patients showed residual activities from 0% to 3% of the normal average value, except for one patient with 10% activity. Concerning 50 NBS-positive subjects, 18 with enzymatic activities around 10% or lower and 14 with activities ranging from 13% to 30% were judged to be affected patients, and biallelic variants were detected in most of the cases tested. Newborns with higher enzymatic activities were estimated to be heterozygous carriers or healthy subjects, though biallelic variants were detected in 5 of them. Genetic analysis detected 22 kinds of variant alleles. The most prevalent was c.449_452delCTGA (p.T150Rfs), which was followed by c.50G>A (p.R17H), c.1085G>A (p.G362E), c.157C>T (p.R53C), and c.843A>T (p.R281S); these five variants accounted for approximately 60% of all the alleles examined. CONCLUSION: Our study has revealed the unique genetic backgrounds of MCAD deficiency among Japanese, based on the largest series of non-Caucasian cases. A continuous spectrum of severity was also observed in our series of NBS-positive cases, suggesting that it is essential for every nation and ethnic group to accumulate its own information on gene variants, together with their enzymatic evaluation, in order to establish an efficient NBS system for MCAD deficiency.
Assuntos
Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Testes Genéticos , Hipoglicemia/genética , Erros Inatos do Metabolismo Lipídico/genética , Triagem Neonatal , Acil-CoA Desidrogenase/sangue , Alelos , Pré-Escolar , Feminino , Genótipo , Heterozigoto , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/epidemiologia , Hipoglicemia/fisiopatologia , Lactente , Recém-Nascido , Japão/epidemiologia , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/epidemiologia , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Masculino , Mutação , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Since the first case was detected in 2000, there has been a remarkable increase in Japanese patients diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Genetic analysis has revealed a spectrum of mutations that is quite different from those observed in Caucasian populations. In 2014, Japan initiated nationwide newborn screening (NBS) for MCAD using tandem mass spectrometry (MS/MS). It is an urgent issue to assess the risk of acute metabolic decompensation from the respective novel mutations found thus far. METHODS: To evaluate the pathogenic effect of each mutation, we established a eukaryotic cell expression system and prepared 11 mutant proteins identified in five symptomatic patients and eight MS/MS-NBS-positive newborns, as well as two common Caucasian mutations, p.K329E (c.985G>A) and p.Y67H (c.157C>T) for comparison. RESULTS: The expression of four mutant proteins (p.Q45R, p.P92L, p.P128X and p.Y397N) were severely impaired, whereas the others expressed normally, as did p.K329E and p.Y67H. Based on their dehydrogenase activities toward n-octanoyl-CoA, we determined three mutations (p.R53C, p.R281S and p.G362E) to be disease-causing, two mutations having (p.R17H and p.M274V) to be of marginal risk, and two mutations (p.K271E and p.I416T) as benign. Their allele-specific activities were as a whole in accordance with those estimated from the results of measurement in peripheral blood mononuclear cells. CONCLUSION: As most of the mutations detected in the Japanese population are unique, prudent genetic and enzymatic analysis is essential to precisely evaluate the latent risk of clinical onset for screening-positive newborns.
Assuntos
Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Erros Inatos do Metabolismo Lipídico/diagnóstico , Mutação , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem/métodos , Povo Asiático/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Japão , Erros Inatos do Metabolismo Lipídico/etnologia , Erros Inatos do Metabolismo Lipídico/genética , Masculino , População Branca/genéticaRESUMO
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency and mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase or T2) deficiency are classified as autosomal recessive disorders of ketone body utilization characterized by intermittent ketoacidosis. Patients with mutations retaining no residual activity on analysis of expression of mutant cDNA are designated as severe genotype, and patients with at least one mutation retaining significant residual activity, as mild genotype. Permanent ketosis is a pathognomonic characteristic of SCOT-deficient patients with severe genotype. Patients with mild genotype, however, may not have permanent ketosis, although they may develop severe ketoacidotic episodes similar to patients with severe genotype. Permanent ketosis has not been reported in T2 deficiency. In T2-deficient patients with severe genotype, biochemical diagnosis is done on urinary organic acid analysis and blood acylcarnitine analysis to observe characteristic findings during both ketoacidosis and non-episodic conditions. In Japan, however, it was found that T2-deficient patients with mild genotype are common, and typical profiles were not identified on these analyses. Based on a clinical study of ketone body utilization disorders both in Japan and worldwide, we have developed guidelines for disease diagnosis and treatment. These diseases are treatable by avoiding fasting and by providing early infusion of glucose, which enable the patients to grow without sequelae.
Assuntos
Acidose , Coenzima A-Transferases/deficiência , DNA Complementar/genética , Corpos Cetônicos/metabolismo , Erros Inatos do Metabolismo , Mutação , Acidose/congênito , Acidose/genética , Acidose/metabolismo , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Análise Mutacional de DNA , Genótipo , Humanos , Recém-NascidoRESUMO
Fructose-1,6-bisphosphatase (FBPase), an enzyme involved in gluconeogenesis, catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate. FBPase deficiency is an autosomal recessive inherited disorder, characterized by episodic attacks of hypoglycemia, ketosis, and lactic acidosis during fasting. In general, urinary organic acid analysis using gas chromatography-mass spectrometry (GC/MS) is very useful for the diagnosis of FBPase deficiency, because the appearance of glycerol or glycerol-3-phosphate in the urine is characteristic of this disease. Here, we report a case of FBPase deficiency in a girl with a history of several severe lactic acidosis events, both as a neonate and after the age of 12 months. The patient was identified as a compound heterozygote with two mutations in the FBPase 1 gene: c.841G>A (p.Glu281Lys) and c.960_961insG (p.Ser321fs). The c.841G>A is a newly identified pathogenic mutation. An abnormal level of glycerol-3-phosphate was not detected in the conventional urinary organic acid analysis using GC/MS after solvent extraction. This method, which is a widely used diagnostic standard, could not detect increased levels of glycerol or glycerol-3-phosphate in the patient's urine, which was sampled during the episode. However, glycerol and glycerol-3-phosphate were detected in the same sample, when it was analyzed using GC/MS with the urease pretreatment non-extraction method. Patients with FBPase deficiency have good glycemic control after correct treatment. Therefore, accurate and early diagnosis is essential for a good prognosis. Accordingly, when a patient presents with hypoglycemia and lactic acidosis, it is important to select the appropriate method of urinalysis for organic acids by GC/MS.
Assuntos
Deficiência de Frutose-1,6-Difosfatase/diagnóstico , Deficiência de Frutose-1,6-Difosfatase/urina , Glicerofosfatos/urina , Solventes/química , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Glicerol/metabolismo , Humanos , Recém-NascidoRESUMO
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial ß-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial ß-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and myoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial ß-oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Exercício Físico , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/complicações , Doenças Mitocondriais/genética , Doenças Musculares/complicações , Doenças Musculares/genética , Mutação de Sentido Incorreto/genética , Rabdomiólise/complicações , Rabdomiólise/etiologia , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Acil-CoA Desidrogenase de Cadeia Longa/química , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Carnitina/análogos & derivados , Carnitina/sangue , Síndrome Congênita de Insuficiência da Medula Óssea , Heterozigoto , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/enzimologia , Masculino , Doenças Mitocondriais/sangue , Doenças Mitocondriais/enzimologia , Modelos Moleculares , Dados de Sequência Molecular , Doenças Musculares/sangue , Doenças Musculares/enzimologia , Estrutura Terciária de Proteína , Alinhamento de SequênciaRESUMO
Very-long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is a rare and life-threatening disease characterized by an enzymatic defect in the fatty acid ß-oxidation pathway. A nulliparous woman with VLCADD showed improvements in serum levels of the long-chain acylcarnitine moiety (C14:1) during pregnancy and successfully delivered a healthy infant vaginally. Pregnancy and vaginal delivery can be successfully completed in patients with VLCADD with careful management.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico/terapia , Doenças Mitocondriais/terapia , Doenças Musculares/terapia , Complicações na Gravidez/terapia , Gravidez de Alto Risco , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Repouso em Cama , Criança , Terapia Combinada , Síndrome Congênita de Insuficiência da Medula Óssea , Diagnóstico Tardio , Ácidos Graxos Monoinsaturados/sangue , Feminino , Hospitalização , Humanos , Recém-Nascido , Japão , Trabalho de Parto Induzido , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/fisiopatologia , Doenças Musculares/sangue , Doenças Musculares/diagnóstico , Doenças Musculares/fisiopatologia , Mialgia/etiologia , Mialgia/prevenção & controle , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/fisiopatologia , Gravidez de Alto Risco/sangue , Diagnóstico Pré-Natal , Nascimento a TermoRESUMO
Citrin deficiency is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. The disorder manifests either as neonatal intra-hepatic cholestasis or occurs in adulthood with recurrent hyperammonemia and neuropsychiatric disturbances. It has a high prevalence in the East Asian population, but is actually pan-ethnic. We report the case of a 26-year-old male patient presenting with episodes of abnormal neuro-psychiatric behavior associated with hyperammonemia, who was diagnosed to be having citrin deficiency. Sequencing of the SLC25A13 gene revealed two novel mutations, a single base pair deletion, c. 650delT (p.Phe217SerfsFNx0133) in exon 7, and a missense mutation, c. 869T>C (p.Ile290Thr) in exon 9. Confirmation of the diagnosis allowed establishment of the appropriate management. The latter is an essential pre-requisite for obtaining a good prognosis as well as for family counseling.
RESUMO
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (2M3HBD) deficiency (HSD10 disease) is a rare inborn error of metabolism, and <30 cases have been reported worldwide. This disorder is typically characterized by progressive neurodegenerative disease from 6 to 18 months of age. Here, we report the first patient with this disorder in Asia, with atypical clinical presentation. A 6-year-old boy, who had been well, presented with severe ketoacidosis following a 5-day history of gastroenteritis. Urinary organic acid analysis showed elevated excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine. He was tentatively diagnosed with ß-ketothiolase (T2) deficiency. However, repeated enzyme assays using lymphocytes showed normal T2 activity and no T2 mutation was found. Instead, a hemizygous c.460G>A (p.A154T) mutation was identified in the HSD17B10 gene. This mutation was not found in 258 alleles from Japanese subjects (controls). A normal level of the HSD17B10 protein was found by immunoblot analysis but no 2M3HBD enzyme activity was detected in enzyme assays using the patient's fibroblasts. These data confirmed that this patient was affected with HSD10 disease. He has had no neurological regression until now. His fibroblasts showed punctate and fragmented mitochondrial organization by MitoTracker staining and had relatively low respiratory chain complex IV activity to those of other complexes.
Assuntos
Acetil-CoA C-Acetiltransferase/deficiência , Erros Inatos do Metabolismo Lipídico/genética , Mutação Puntual , 3-Hidroxiacil-CoA Desidrogenases/química , 3-Hidroxiacil-CoA Desidrogenases/genética , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Acetil-CoA C-Acetiltransferase/genética , Sequência de Bases , Carnitina/análogos & derivados , Carnitina/sangue , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Discinesias , Fibroblastos/metabolismo , Glicina/análogos & derivados , Glicina/urina , Humanos , Hidroxibutiratos/urina , Immunoblotting , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Deficiência Intelectual Ligada ao Cromossomo X , Mitocôndrias/metabolismo , Modelos Moleculares , Estrutura Terciária de ProteínaRESUMO
Amino acid formulas and hydrolyzed formulas given to infants in Japan with milk allergies theoretically contain little, if any, biotin and carnitine. We assessed biotin and carnitine insufficiency in six infants with milk allergy who were fed amino acid formulas and/or hydrolyzed formulas, by measuring urine 3-hydroxyisovaleric acid (3-HIA) and serum free carnitine (C0), respectively. All patients presented with elevated urine 3-HIA and lowered serum C0 compared with post-menstrual age-matched infants who were fed breast milk or standard infant formulas. Supplementation with biotin and L-carnitine immediately improved the insufficiency. Care should be taken to avoid biotin and carnitine deficiency in allergic infants fed amino acid or hydrolyzed formulas.
Assuntos
Biotina/deficiência , Carnitina/deficiência , Deficiências Nutricionais/etiologia , Fórmulas Infantis , Hipersensibilidade a Leite , Feminino , Humanos , Lactente , Masculino , Hipersensibilidade a Leite/dietoterapiaRESUMO
Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a long-chain fatty acid oxidation disorder that manifests as either a severe phenotype associated with cardiomyopathy, a hypoglycemic phenotype, or a myopathic phenotype. As the hypoglycemic phenotype can cause sudden infant death, VLCAD deficiency is included in newborn screening (NBS) panels in many countries. The tetradecenoylcarnitine (C14:1) level in dried blood specimens is commonly used as a primary marker for VLCAD deficiency in NBS panels. Its ratio to acetylcarnitine (C2) and various other acylcarnitines is used as secondary markers. In Japan, tandem mass spectrometry-based NBS, initially launched as a pilot study in 1997, was introduced to the nationwide NBS program in 2013. In the present study, we evaluated levels of acylcarnitine with various chain lengths (C18 to C2), free carnitine, and their ratios in 175 infants who tested positive for VLCAD deficiency with C14:1 and C14:1/C2 ratios. Our analyses indicated that the ratios of C14:1 to medium-chain acylcarnitines (C10, C8, and C6) were the most effective markers in reducing false-positive rates. Their use with appropriate cutoffs is expected to improve NBS performance for VLCAD deficiency.
RESUMO
Many reports have been published on the long-term outcome and treatment of hepatic glycogen storage diseases (GSDs) overseas; however, none have been published from Japan. We investigated the clinical manifestations, treatment, and prognosis of 127 hepatic GSD patients who were evaluated and treated between January 1999 and December 2009. A characteristic genetic pattern was noted in the Japanese GSD patients: most GSD Ia patients had the g727t mutation, and many GSD Ib patients had the W118R mutation. Forty-one percent (14/34) of GSD Ia patients and 18% (2/11) of GSD Ib patients of ages î¶13 years 4 months had liver adenoma. Among subjects aged 10 years, 19% (7/36) of the GSD Ia patients and none of the GSD Ib patients had renal dysfunction. The mean height of male GSD Ia patients aged î¶18 years was 160.8±10.6 cm (n=14), and that of their female counterparts was 147.8±3.80 cm (n=9). Patients with hepatic GSDs develop a variety of symptoms but can survive in the long term by diet therapy, corn starch treatment and supportive care. Liver transplantation for hepatic GSDs is an important treatment strategy and can help improve the patients'quality of life.
Assuntos
Doença de Depósito de Glicogênio/epidemiologia , Adolescente , Adulto , Fatores Etários , Idade de Início , Estatura , Criança , Pré-Escolar , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/terapia , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Transplante de Fígado , Masculino , Prognóstico , Adulto JovemRESUMO
Organic acidemias (OAs) are rare inborn errors of metabolism. The clinical presentations of methylmalonic acidemia (MMA) and propionic acidemia (PA) in Japan have not yet been examined in detail. We aimed to investigate the clinical presentations of OAs in Japan and evaluate current therapies for improving long-term outcomes, especially in MMA and PA cases. Questionnaires were sent to 928 institutions in 2009 inquiring about OAs, and secondary questionnaires were sent to those who confirmed that they had diagnosed and/or treated such cases; 119 cases were eventually included for analysis. In Japan, the majority of OAs was MMA, which was associated with a high mortality rate. The survival rates at 20 years of age in vitamin B12-unresponsive MMA, vitamin B12-responsive MMA and PA patients were 69.8%, 94.4% and 95.8%, respectively. Factors associated with mortality in MMA were failure to thrive, hypoglycemia and pancreatitis. Factors associated with mental retardation in vitamin B12-unresponsive MMA, vitamin B12-responsive MMA, and PA were seizure and liver dysfunction, seizure and failure to thrive, and failure to thrive, respectively. We advocated that avoiding failure to thrive due to too restricted protein diet, hypoglycemia and pancreatitis associated with mortality lead to improve outcome, especially in vitamin B12-unresponsive MMA patients.