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1.
Int J Mol Sci ; 21(3)2020 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-32024277

RESUMO

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.

2.
Dis Markers ; 2019: 2984747, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881520

RESUMO

Because tandem mass spectrometry- (MS/MS-) based newborn screening identifies many suspicious cases of fatty acid oxidation and carnitine cycle disorders, a simple, noninvasive test is required to confirm the diagnosis. We have developed a novel method to evaluate the metabolic defects in peripheral blood mononuclear cells loaded with deuterium-labeled fatty acids directly using the ratios of acylcarnitines determined by flow injection MS/MS. We have identified diagnostic indices for the disorders as follows: decreased ratios of d27-C14-acylcarnitine/d31-C16-acylcarnitine and d23-C12-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-II (CPT-II) deficiency, decreased ratios of d23-C12-acylcarnitine/d27-C14-acylcarnitine for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and increased ratios of d29-C16-OH-acylcarnitine/d31-C16-acylcarnitine for trifunctional protein (TFP) deficiency, together with increased ratios of d7-C4-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-I deficiency. The decreased ratios of d1-acetylcarnitine/d31-C16-acylcarnitine could be indicative of ß-oxidation ability in patients with CPT-II, VLCAD, and TFP deficiencies. Overall, our data showed that the present method was valuable for establishing a rapid diagnosis of fatty acid oxidation disorders and carnitine cycle disorders and for complementing gene analysis because our diagnostic indices may overcome the weaknesses of conventional enzyme activity measurements using fibroblasts or mononuclear cells with assumedly uncertain viability.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Cardiomiopatias/sangue , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/sangue , Espectrometria de Massas/métodos , Doenças Mitocondriais/sangue , Miopatias Mitocondriais/sangue , Proteína Mitocondrial Trifuncional/deficiência , Técnicas de Diagnóstico Molecular/métodos , Monócitos/química , Doenças Musculares/sangue , Doenças do Sistema Nervoso/sangue , Rabdomiólise/sangue , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Adulto , Biomarcadores/sangue , Carnitina/análogos & derivados , Carnitina/química , Carnitina O-Palmitoiltransferase/deficiência , Deutério/química , Humanos , Lactente , Proteína Mitocondrial Trifuncional/sangue , Monócitos/metabolismo , Oxirredução
3.
J Hum Genet ; 64(2): 87-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30514913

RESUMO

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 , Prognóstico
4.
Mol Genet Metab ; 122(3): 67-75, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801073

RESUMO

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 Tandem
5.
Clin J Gastroenterol ; 10(4): 383-387, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28597413

RESUMO

The urea cycle converts ammonia and produces urea. One form of urea cycle abnormality is ornithine transcarbamylase (OTC) deficiency. This hereditary disorder is associated with hyperammonemia. OTC deficiency commonly appears during neonatal and early childhood life and is rare in adults. We report a 69-year-old man who presented at the local hospital with 3-day loss of appetite, early morning vomiting, and state of confusion. Blood ammonia was 293 µg/dl. At 2-3 h after admission, the patient went into a deep coma. He was intubated and admitted immediately to the intensive care unit. Treatment, including sustained hemodialysis, failed to lower blood ammonia level. His grandchild died of OTC deficiency at 6 year of age. Computed tomography, magnetic resonance imaging and esophagogastroduodenoscopy showed no abnormalities. On admission to our hospital, he complained of vomiting and disturbance of consciousness, hyperammonemia, and normal anion gap. Genetic analysis showed A208T mutation. The deceased grandchild with OTC deficiency also had the same mutation. Long-term hemodialysis coupled with administration of L-arginine and lactulose resulted in improvement of blood ammonia level. Early diagnosis and treatment of adult-onset OTC deficiency are essential to avoid serious complications.


Assuntos
Hiperamonemia/etiologia , Transtornos de Início Tardio/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Idoso , Diagnóstico Precoce , Humanos , Hiperamonemia/terapia , Transtornos de Início Tardio/complicações , Masculino , Doença da Deficiência de Ornitina Carbomoiltransferase/complicações , Resultado do Tratamento
6.
Pediatr Transplant ; 21(5)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28612395

RESUMO

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 , Imagem por Ressonância Magnética
7.
Mol Genet Metab Rep ; 11: 69-71, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28529889

RESUMO

The early-onset form of carnitine palmitoyltransferase (CPT) II deficiency has severe outcomes; patients typically die during the newborn period. We report a case of neonatal-onset CPT II deficiency with prolonged survival, exceeding 24 months. The patient was successfully treated by continuous hemodialysis (CHD), which enabled her to overcome repeated crises. We suggest that early intensive treatment, including CHD, is a key for prolonged survival in patients with neonatal-onset CPT II deficiency.

8.
Artigo em Inglês | MEDLINE | ID: mdl-28189105

RESUMO

Propionic acidemia (PA) is an inherited metabolic disease caused by low activity of propionyl coenzyme A (CoA) carboxylase (PCC), which metabolizes propionyl-CoA into methylmalonyl-CoA. Although many patients with PA have been identified by tandem mass spectrometry since the test was first included in neonatal mass screening in the 1990s, the disease severity varies. Thus, determining the specific level of PCC activity is considered to be helpful to grasp the severity of PA. We developed a new PCC assay method by the determination of methylmalonyl-CoA, which is formed by an enzyme reaction using peripheral lymphocytes, based on ultra high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). With methylmalonyl-CoA concentrations of 0.05, 0.5, and 5µmol/L, the intra-assay coefficients of variation (CVs) were 8.2%, 8.7%, and 5.1%, respectively, and the inter-assay CVs were 13.6%, 10.5%, and 5.9%, respectively. The PCC activities of 20 healthy individuals and 6 PA patients were investigated with this assay. Methylmalonyl-CoA was not detected in one PA patient with a severe form of the disease, but the remaining PA patients with mild disease showed residual activities (3.3-7.8%). These results demonstrate that determination of PCC activity with this assay would be useful to distinguish between mild and severe cases of PA to help choose an appropriate treatment plan.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Metilmalonil-CoA Descarboxilase/sangue , Metilmalonil-CoA Descarboxilase/metabolismo , Acidemia Propiônica/enzimologia , Espectrometria de Massas em Tandem/métodos , Adulto , Estudos de Casos e Controles , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Limite de Detecção , Modelos Lineares , Masculino , Acidemia Propiônica/sangue , Reprodutibilidade dos Testes , Adulto Jovem
9.
Mol Genet Metab ; 119(4): 322-328, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27856190

RESUMO

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/genética
10.
Mol Genet Metab ; 118(1): 9-14, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26947917

RESUMO

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 , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Japão , Erros Inatos do Metabolismo Lipídico/etnologia , Erros Inatos do Metabolismo Lipídico/genética , Masculino
11.
Anal Bioanal Chem ; 407(18): 5281-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26018627

RESUMO

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 Jovem
12.
Tohoku J Exp Med ; 235(4): 305-10, 2015 04.
Artigo em Inglês | MEDLINE | ID: mdl-25843429

RESUMO

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 , 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 , 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 Sequência
13.
J Obstet Gynaecol Res ; 41(7): 1126-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25655073

RESUMO

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 , 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 Termo
14.
Pediatr Int ; 56(1): 112-5, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24548198

RESUMO

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 Testes
15.
Neuropediatrics ; 45(1): 36-41, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24122274

RESUMO

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/classificação
16.
Pediatr Int ; 55(6): 775-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24330285

RESUMO

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 , Evolução Fatal , Humanos , Masculino
17.
Cell Biochem Biophys ; 67(1): 185-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23479330

RESUMO

We report herein a 1.5-year-old girl with methylmalonic acidemia (MMA) in whom two missense mutations were found: a novel I739T mutation located in exon 13 and the L494X mutation in exon 8. The results of organic acid test showed a pronounced increase in methylmalonate excretion with increased methylcitrate and 3-OH-propionate excretion, leading to a diagnosis of MMA, and Vitamin B12 administration was started. Analysis of the mut gene confirmed a T-to-A substitution at nucleotide position 1481 in exon 8 and a T-to-C substitution at nucleotide position 2216 in exon 13, leading to the amino acid isoleucine at position 739 being changed to threonine, resulting in c.2216T > C (p.I739T). The patient has now been on high-dose oral administration of Vitamin B12 and carnitine therapy (900 mg of levocarnitine chloride) for 5 years without experiencing further attacks, and her cognitive and motor development is normal. Further tests on residual enzyme activity, as well as experience with more cases, may shed light on the relationship between gene mutations and phenotypes in MMA.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Metilmalonil-CoA Mutase/genética , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Sequência de Bases , Carnitina/uso terapêutico , Citratos/metabolismo , Éxons , Feminino , Humanos , Lactente , Ácido Metilmalônico/metabolismo , Mutação de Sentido Incorreto , Propionatos/metabolismo , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico
18.
Mol Genet Metab ; 108(3): 172-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23375472

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 , Irmãos
19.
Eur J Endocrinol ; 166(2): 235-40, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22048973

RESUMO

OBJECTIVE: Ghrelin requires a fatty acid modification for binding to the GH secretagogue receptor. Acylation of the Ser3 residue of ghrelin is essential for its biological activities. We hypothesized that acyl-CoA is the fatty acid substrate for ghrelin acylation. Because serum octanoyl-CoA levels are altered by fatty acid oxidation disorders, we examined circulating ghrelin levels in affected patients. MATERIALS AND METHODS: Blood levels of acyl (A) and des-acyl (D) forms of ghrelin and acylcarnitine of patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and glutaric aciduria type II (GA2) were measured. RESULTS: Plasma acyl ghrelin levels and A/D ratios increased in patients with MCAD deficiency or GA2 when compared with normal subjects. Reverse-phase HPLC confirmed that n-octanoylated ghrelin levels were elevated in these patients. CONCLUSION: Changing serum medium-chain acylcarnitine levels may affect circulating acyl ghrelin levels, suggesting that acyl-CoA is the substrate for ghrelin acylation.


Assuntos
Grelina/sangue , Erros Inatos do Metabolismo Lipídico/sangue , Deficiência Múltipla de Acil Coenzima A Desidrogenase/sangue , Acil-CoA Desidrogenase/sangue , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/metabolismo , Adulto , Análise Química do Sangue/métodos , Carnitina/análogos & derivados , Carnitina/análise , Carnitina/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Grelina/análise , Grelina/metabolismo , Humanos , Erros Inatos do Metabolismo Lipídico/metabolismo , Deficiência Múltipla de Acil Coenzima A Desidrogenase/metabolismo , Processamento de Proteína Pós-Traducional , Adulto Jovem
20.
Mol Genet Metab ; 104(4): 556-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22000755

RESUMO

Mitochondrial trifunctional protein (MTP) is a multienzyme complex involved in the metabolism of long-chain hydroxyacyl-CoA, a product of the fatty acid ß-oxidation cycle. MTP is an α4ß4 hetero-octomer encoded by two different genes: HADHA (OMIM 600890) and HADHB (OMIM 143450). MTP deficiency induces three different types of presentation: (1) a lethal phenotype with neonatal onset (severe); (2) a hepatic phenotype with infant onset (intermediate); and (3) a neuromyopathic phenotype with late-adolescent onset (mild). While acylcarnitine analysis has revealed increased levels of long-chain hydroxyacylcarnitine in blood when an MTP deficiency exists, the neuromyopathic type is usually asymptomatic and does not always result in an abnormality in acylcarnitine analysis results. We report here the case of a 13-year-old girl with recurrences of intermittent myalgia since her early childhood, for whom the disorder had not been definitely diagnosed. Since she was referred to our hospital because of rhabdomyolysis, we have repeatedly performed blood acylcarnitine analysis and found slight increases in long-chain 3-OH-acylcarnitine levels, on the basis of which we made a chemical diagnosis of MTP deficiency. Immunoblot analysis of skin fibroblasts revealed loss of α- and ß-subunits of MTP. In addition, analysis of the HADHB gene, which encodes long-chain 3-ketoacyl-CoA thiolase, one of the enzymes constituting MTP, identified compound heterozygous mutations of c.520C>T (p.R141C) and c.1331G>A (p.R411K). MTP deficiency is considered an extremely rare disorder, as only five cases (lethal phenotype, two patients; hepatic phenotype, two patients; and neuromyopathic phenotype, one patient) have thus far been reported in Japan. However, it is likely that the neuromyopathic phenotype of MTP deficiency has not yet been diagnosed among patients with recurrences of intermittent myalgia and rhabdomyolysis, as in our patient reported here.


Assuntos
Substituição de Aminoácidos , Doenças Genéticas Inatas/diagnóstico , Complexos Multienzimáticos/deficiência , Complexos Multienzimáticos/genética , Adolescente , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Proteína Mitocondrial Trifuncional , Subunidade alfa da Proteína Mitocondrial Trifuncional , Subunidade beta da Proteína Mitocondrial Trifuncional
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