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
BACKGROUND: Morquio A syndrome, mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disorder caused by the deficient activity of N-acetylgalactosamine-6-sulfatase (GalNac6S), due to alterations in the GALNS gene. This disorder results in marked abnormalities in bones and connective tissues, and affects multiple organs. Here, we describe the clinical course of a Japanese boy with MPS IVA who began enzyme replacement therapy (ERT) at the age of 24 months. PATIENT: the patient presented for kyphosis treatment at 22 months of age. An X-ray examination revealed dysostosis multiplex. Uronic acids were elevated in the urine and the keratan sulfate (KS) fraction was predominant. The leukocyte GalNac6S enzyme activity was extremely low. The patient exhibited the c.463G > A (p.Gly155Arg) mutation in GALNS. Based on these findings, his disease was diagnosed as classical (severe) Morquio A syndrome. An elosulfase alfa infusion was initiated at the age of 24 months. The patient's body height improved from -2.5 standard deviation (SD) to -2 SD and his physical activity increased during the first 9 months on ERT. However, he gradually developed paralysis in the lower legs with declining growth velocity, which required cervical decompression surgery in the second year of the ERT. The mild mitral regurgitation, serous otitis media, and mild hearing loss did not progress during treatment. CONCLUSION: early initiation of the elosulfase alfa to our patient showed good effects on the visceral system and muscle strength, while its effect on bones appeared limited. Careful observation is necessary to ensure timely surgical intervention for skeletal disorders associated with neurological symptoms. Centralized and multidisciplinary management is essential to improve the prognosis of pediatric patients with MPS IVA.
Assuntos
Condroitina Sulfatases/administração & dosagem , Terapia de Reposição de Enzimas/métodos , Mucopolissacaridose IV/terapia , Pré-Escolar , Condroitina Sulfatases/deficiência , Condroitina Sulfatases/genética , Humanos , Masculino , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/genética , Mutação , PrognósticoRESUMO
Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder. Its clinical phenotypes are classified into the muscle, severe infantile, and lethal neonatal forms. Among Caucasians, the muscle form predominates, and the c.338C > T (p.S113L) variant is detected in most cases, whereas among the Japanese, c.1148T > A (p.F383Y) is the variant allele occurring with the highest frequency and can apparently cause symptoms of the severe infantile form. Newborn screening (NBS) for this potentially fatal disease has not been established. We encountered an infantile case of CPT II deficiency not detected in NBS using C16 and C18:1 concentrations as indices, and therefore we adopted the (C16 + C18:1)/C2 ratio as an alternative primary index. As a result, the disease was diagnosed in nine of 31 NBS-positive subjects. The values for (C16 + C18:1)/C2 in the affected newborns partly overlapped with those in unaffected ones. Among several other indices proposed previously, C14/C3 has emerged as a more promising index. Based on these findings, nationwide NBS for CPT II deficiency using both (C16 + C18:1)/C2 and C14/C3 as indices was officially approved and started in April 2018. We diagnosed the disease in four young children presenting with symptoms of the muscle form, whose values for the new indices were not elevated. Although it is still difficult to detect all cases of the muscle form of CPT II deficiency in NBS, our system is expected to save many affected children in Japan with the severe infantile form predominating.
Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Erros Inatos do Metabolismo/diagnóstico , Triagem Neonatal/métodos , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/enzimologia , PrognósticoRESUMO
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
Classical MSUD is often fatal without appropriate medical interventions because of metabolic crisis. There are numerous reports suggesting the therapeutic potential of deceased donor liver transplantation for MSUD. However, the usefulness of LDLT for MSUD is unknown. We report a case of classical MSUD, which was successfully managed by LDLT from the patient's father at 1 year of age. Abnormal brain findings, which were cured with effective treatment, gradually disappeared after LDLT. The patient then developed normally. Findings from this case suggest the importance of LDLT for maintaining low leucine levels and subsequent normal neurological development. Although LDLT involves a modest surgical insult, LDLT with a related donor achieves acceptable leucine levels for life.
Assuntos
Transplante de Fígado/métodos , Doadores Vivos , Doença da Urina de Xarope de Bordo/diagnóstico por imagem , Doença da Urina de Xarope de Bordo/cirurgia , Pré-Escolar , Feminino , Humanos , Imageamento por Ressonância MagnéticaRESUMO
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
Methylmalonic acidemia (MMA) is an inherited metabolic disease. In this condition, metabolism from methylmalonyl coenzyme A (CoA) to succinyl-CoA is inhibited because of either low methylmalonyl-CoA mutase (MCM) activity or adenosylcobalamin deficiency owing to altered vitamin B12 metabolism. A high-precision assay for detecting MCM activity would facilitate not only MMA diagnosis but also the ability to determine the severity of MMA. We developed an MCM assay method based on ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) that involves the determination of succinyl-CoA, which is formed in an enzyme reaction, using peripheral lymphocytes. Using 0.05, 0.5, and 5 µmol/L succinyl-CoA, the intra-assay coefficient of variation (CV) was less than 5.2% and the inter-assay CV was less than 8.7%. The MCM activities of five healthy individuals and four patients were investigated with this assay. The MCM activities of the patients were very low in relation to those of healthy individuals. Together, these results show that the UPLC-MS/MS method is useful for a detailed MCM activity assay.
Assuntos
Acil Coenzima A/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Enzimáticos/métodos , Metilmalonil-CoA Mutase/metabolismo , Espectrometria de Massas em Tandem/métodos , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Feminino , Humanos , Masculino , Sensibilidade e Especificidade , Adulto JovemRESUMO
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
AIM: Recently, epilepsy with late-onset epileptic spasms (ES) has been reported to be distinct from West syndrome and Lennox-Gastaut syndrome. We identified the characteristics of this clinical entity by analyzing clinical data, including ictal electroencephalography (EEG) and electromyography (EMG) in symptomatic patients. METHODS: We evaluated retrospectively eight symptomatic patients with epilepsy with late-onset ES. All patients underwent video-EEG analysis for more than 24 hours and have been followed up for at least 1 year. Interictal EEG, ictal EEG, ictal EMG, coexistence seizures, response to treatment, and intellectual or daily activity level were assessed. Ictal EMG was evaluated by spectral analysis. RESULTS: All patients exhibited neurological deterioration and had multiple seizure types; seven of them had intractable seizures. Interictal EEG showed no typical hypsarrhythmia in any case. Ictal EMG analysis revealed that the predominant seizure types presenting with the tonic component were distributed among ES, spasms followed by tonic seizures (SFT), and tonic seizures. CONCLUSIONS: The clinical characteristics of our patients were identical to infantile epileptic encephalopathy with late-onset spasms. Our patients had ES, SFT, and tonic seizures as the core seizure types, developed ES beyond the age of 1 year, and showed neurological deterioration. These may be essential symptoms of this clinical entity.
Assuntos
Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , Espasmos Infantis/fisiopatologia , Idade de Início , Pré-Escolar , Eletroencefalografia , Eletromiografia , Epilepsia/classificação , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Espasmos Infantis/classificaçãoRESUMO
We describe a male neonate with classic maple syrup urine disease (MSUD) in metabolic crisis. On day 7 of life, he was referred to hospital because of coma and metabolic acidosis with maple syrup odor. On day 4 after admission, brain magnetic resonance imaging findings were consistent with encephalopathy due to MSUD. Proton magnetic resonance spectroscopy ((1) H-MRS) showed a large methyl resonance peak at 0.9 p.p.m. The diagnosis of MSUD was confirmed on low branched-chain α-keto acid dehydrogenase complex activity in lymphocyte. (1) H-MR spectra were obtained in 10 min, while it took at least several days to obtain the results of other diagnostic examinations. In convalescence, the peak at 0.9 p.p.m. decreased. The large methyl resonance peak at 0.9 p.p.m. in brain (1) H-MRS would be one of the earliest clues to the diagnosis of classic MSUD in the neonatal period, especially in metabolic crisis.
Assuntos
Ácido Aspártico/análogos & derivados , Diagnóstico Precoce , Linfócitos/química , Doença da Urina de Xarope de Bordo/diagnóstico , Espectroscopia de Prótons por Ressonância Magnética/métodos , Ácido Aspártico/análise , Diagnóstico Diferencial , Humanos , Recém-Nascido , Masculino , Reprodutibilidade dos TestesRESUMO
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
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that is progressive and involves multiple organs and tissues. While enzyme replacement therapy (ERT) with idursulfase has been shown to improve many somatic features of the disease, some such as dysostosis multiplex and cardiac valve disease appear irreversible once established, and little is known about the preventative effects of ERT in pre-symptomatic patients. We report on two siblings with severe MPS II caused by an inversion mutation with recombination breakpoints located within the IDS gene and its adjacent pseudogene, IDS-2. The siblings initiated treatment with idursulfase at 3.0 years (older brother) and 4 months (younger brother) of age, and we compared their outcomes following 2 years of treatment. At the start of treatment, the older brother showed typical features of MPS II, including intellectual disability. After 34 months of ERT, his somatic disease was stable or improved, but he continued to decline cognitively. By comparison, after 32 months of ERT his younger brother remained free from most of the somatic features that had already appeared in his brother at the same age, manifesting only exudative otitis media. Skeletal X-rays revealed characteristic signs of dysostosis multiplex in the older brother at the initiation of treatment that were unchanged two years later, whereas the younger brother showed only slight findings of dysostosis multiplex throughout the treatment period. The younger brother's developmental quotient trended downward over time to just below the normal range. These findings suggest that pre-symptomatic initiation of ERT may prevent or attenuate progression of the somatic features of MPS II. Follow-up in a larger number of patients is required to confirm the additive long-term benefits of ERT in pre-symptomatic patients.
Assuntos
Glicoproteínas/genética , Iduronato Sulfatase/uso terapêutico , Mucopolissacaridose II/tratamento farmacológico , Mucopolissacaridose II/genética , Mutação , Tempo para o Tratamento , Pré-Escolar , Cognição/efeitos dos fármacos , Progressão da Doença , Terapia de Reposição de Enzimas , Glicoproteínas/deficiência , Humanos , Iduronato Sulfatase/farmacologia , Masculino , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/fisiopatologia , IrmãosRESUMO
VLCAD deficiency is an autosomal recessive disorder caused by a defect of fatty acid oxidation. The phenotype is classified into three clinical forms on the basis of the onset of symptoms: a severe form with neonatal onset; a milder form with childhood onset; and a late-onset form. The neonatal form is the most common, and has a higher mortality rate than the others. We report the case of a newborn infant with VLCAD deficiency who developed ventricular fibrillation, which was successfully treated by intensive care, but who suddenly died after a respiratory syncytial virus infection. Early institution of i.v. glucose treatment and active immunization with vaccine, such as palivizumab (anti-RSV mAb), may be important to reduce the frequency and severity of life-threatening episodes.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico/complicações , Doenças Mitocondriais/complicações , Doenças Musculares/complicações , Infecções por Vírus Respiratório Sincicial/complicações , Fibrilação Ventricular/etiologia , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Evolução Fatal , Humanos , MasculinoRESUMO
A 25-year-old Japanese woman with a history of repeated episodes of rhabdomyolysis since the age of 12 presented with rhabdomyolysis caused by hyperemesis gravidarum. Blood tests showed an elevated serum CK level (11,755â |IU/l; normal: 30-180â |IU/l). Carnitine fractionation analysis revealed low levels of total carnitine (18.3â |µmol/l; normal: 45-91â |µmol/l), free carnitine (13.1â |µmol/l; normal: 36-74â |µmol/l), and acylcarnitine (5.2â |µmol/l; normal: 6-23â |µmol/l). Tandem mass spectrometry showed high levels of C14:1 acylcarnitine (0.84â |nmol/ml: normal: <0.4â |nmol/ml) and a high C14:1/C2 ratio of 0.253 (normal: <0.013), indicating a potential diagnosis of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Enzyme activity measurement in the patient's peripheral blood lymphocytes confirmed the diagnosis of VLCAD deficiency, with low palmitoyl-CoA dehydrogenase levels (6.5% of normal control value). With the patient's informed consent, acyl-CoA dehydrogenase very long-chain (ACADVL) gene analysis revealed compound heterozygous mutations of c.1332G>A in exon 13 and c.1349G>A (p.R450H) in exon 14. In Japan, neonatal mass screening is performed to detect congenital metabolic diseases. With the introduction of tandem mass screening in 2014, fatty acid metabolism disorders, including VLCAD deficiency, are being detected before the onset of symptoms. However, it is important to note that mass screening cannot detect all cases of this disease. For patients with recurrent rhabdomyolysis, it is essential to consider congenital diseases, including fatty acid metabolism disorders, as a potential diagnosis.
Assuntos
Hiperêmese Gravídica , Erros Inatos do Metabolismo Lipídico , Rabdomiólise , Recém-Nascido , Feminino , Gravidez , Humanos , Adulto , Hiperêmese Gravídica/complicações , Hiperêmese Gravídica/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/genética , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Rabdomiólise/diagnóstico , Rabdomiólise/etiologia , Carnitina , Ácidos GraxosRESUMO
Whether or not conditions should be included in publicly funded newborn screening (NBS) programs should be discussed according to objective and transparent criteria. Certain criteria have been developed for the introduction of NBS programs in the context of individual countries; however, there are no standard selection criteria for NBS programs in Japan. This study aimed to develop a quantitative scoring model to assess newborn screening that incorporates the views of a variety of stakeholders in Japan. The five recommended eligibility criteria for NBS were stratified based on previous studies and expert opinions, using the analytic hierarchy process. We conducted a cross-sectional, web-based questionnaire targeting a wide range of people involved in NBS to investigate pairwise comparisons of the evaluation items between February and April of 2022. There were 143 respondents. Most of our respondents (44.1%) were physicians. Fifty-eight respondents (40.6%) had been engaged in NBS-related research or work for more than 10 years. The distribution of allocation points was the highest for 'intervention', 'screening test', 'follow-up setting', 'economic evaluation', and 'disease/condition', in that order. The algorithm in this study will guide decision makers in collecting and evaluating objective data, thus enabling transparent discussions to occur.
RESUMO
Mutations in transport and Golgi organization 2 homolog (TANGO2) have recently been described as a cause of an autosomal recessive syndrome characterized by episodes of metabolic crisis associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration. Herein, we report a case of a one-and-a-half-year-old Japanese girl, born to nonconsanguineous parents, who presented with metabolic crisis characterized by hypoglycemia with hypoketonemia, rhabdomyolysis, lactic acidosis, and prolonged corrected QT interval (QTc) at the age of 6 months. Acylcarnitine analysis during the episode of crisis showed prominent elevation of C14:1, suggesting very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. In addition, worsening rhabdomyolysis was observed after intravenous administration of L-carnitine. VLCAD deficiency was initially suspected; however, the enzyme activity in lymphocytes was only mildly decreased at the gene carrier level, and no mutation in the VLCAD gene (ADADVL) was detected. Subsequently, acylcarnitine analysis was nonspecific at 17-h fasting and almost normal during the stable phase. Eventually, a trio whole-exome sequencing revealed a compound heterozygous variant of two novel variants in the TANGO2 gene, a missense variant, and a deletion of exon 7. This is the first case of TANGO2 deficiency in Asians. Our case suggests that elevated C14:1 may be seen in severe metabolic crises and that the use of L-carnitine should be avoided during metabolic crises.
RESUMO
Carnitine palmitoyltransferase (CPT) II deficiency is a long-chain fatty acid oxidation disorder. It manifests as (1) a lethal neonatal form, (2) a hypoglycemic form, or (3) a myopathic form. The second form can cause sudden infant death and is more common among Japanese people than in other ethnic groups. Our study group had earlier used (C16 + C18:1)/C2 to conduct a pilot newborn screening (NBS) study, and found that the use of C14/C3 for screening yielded lower rates of false positivity; in 2018, as a result, nationwide NBS for CPT II deficiency started. In this study, we evaluated the utility of these ratios in 71 NBS-positive infants and found that the levels of both C14/C3 and (C16 + C18:1)/C2 in patients overlapped greatly with those of infants without the disease. Among the levels of acylcarnitines with various chain lengths (C18 to C2) and levels of free carnitine (C0) as well as their ratios of various patterns, C12/C0 appeared to be a promising index that could reduce false-positive results without missing true-positive cases detected by current indices. Although some cases of the myopathic form may go undetected even with C12/C0, its use will help prevent life-threatening onset of the hypoglycemic form of CPT II deficiency.