Language：English   Publishing type：Research paper (scientific journal)  

DOI： org/10.3390/diagnostics11122195

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgmr.2021.100778

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgmr.2021.100724

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English  

DOI： 10.1002/mgg3.1175.

Language：Others  

Clinical course in a patient with myopathic VLCAD deficiency during pregnancy with an affected baby.

DOI： 10.1002/jmd2.12061

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1297/cpe.26.251.

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: We evaluated the effects of bezafibrate (BEZ) on beta-oxidation in fibroblasts obtained from patients with glutaric acidemia type II (GA2) of various clinical severities using an in vitro probe (IVP) assay.
Methods: Cultured fibroblasts from 12 patients with GA2, including cases of the neonatal-onset type both with and without congenital anomalies (the prenatal- and neonatal-onset forms, respectively), the infantile-onset, and the myopathic forms, were studied. The IVP assay was performed by measuring acylcarnitines (ACs) in the cell culture medium of fibroblasts incubated with palmitic acid for 96 h in the presence of 0-800 mu M BEZ using tandem mass spectrometry.
Results: The IVP assay showed that 100 mu M BEZ markedly reduced the level of palmitoylcarnitine (C16) in the neonatal-onset, infantile-onset, and myopathic forms of GA2, either increasing or maintaining a high level of acetylcarnitine (C2), which serves as an index of energy production via beta-oxidation. In the prenatal-onset form, although a small reduction of C16 was also observed in the presence of 100 mu M BEZ, the level of C2 remained low. At concentrations higher than 100 mu M, BEZ further decreased the level of ACs including C16, but a concentration over 400 mu M decreased the level of C2 in most cases.
Discussion: BEZ at 100 mu M was effective for all GA2 phenotypes except for the prenatal-onset form, as a reduction of C16 without deterioration of C2 is considered to indicate improvement of beta-oxidation. The effects of higher doses BEZ could not be estimated by the IVP assay but might be small or nonexistent. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2016.08.004

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Objective We examined the clinical and genetic features of hypophosphatasia (HPP) in Japanese patients. HPP is a rare metabolic bone disorder of bone mineralisation caused by mutations in the liver/bone/kidney alkaline phosphatase (ALPL) gene, which encodes tissue-non-specific alkaline phosphatase isoenzyme.
Methods We retrospectively investigate the incidence and clinical features of 52 patients with paediatric HPP who were born between 1999 and 2010. Mutations of the ALPL gene were analysed in 31 patients.
Results The annual incidence of perinatal lethal HPP (PLH) was estimated to be 2-3/1 000 000 births. The most frequent clinical type was PLH followed by prenatal benign. In addition to bone symptoms, cerebral manifestations were frequently observed including convulsion, mental retardation, deafness and short stature with growth hormone deficiency. Respiratory failure was the most significant predictor of a poor prognosis for PLH. The first and second most frequent mutations in the ALPL gene were c.1559delT and c. T979C (p.F327L), respectively. The c.1559delT homozygous mutation was lethal with respiratory failure. Patients with the p.F327L compound heterozygous mutation had the different non-lethal type with short stature and a gradual improvement in ALP level and bone mineralisation.
Conclusions The most frequent clinical type was the PLH type with prognosis related to respiratory failure, biochemical/radiological changes and ALPL mutations. Cerebral manifestations frequently occurred. Genotype-phenotype correlations were associated with specific outcomes in the PLH type, whereas different clinical features were associated with the same genotype in the non-lethal type.

DOI： 10.1136/archdischild-2013-305037

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1442-200X.2010.03260.x

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Mitochondrial trifunctional protein (MTP) deficiency is a rare inherited metabolic disorder of mitochondrial fatty acid oxidation. We newly characterized three novel mutations in 2 Japanese patients with MTP deficiency, and investigated the clinical and molecular aspects of 5 Japanese patients including 3 previously reported cases. Herein, we describe the characterization of four missense mutations, R214C, H346R, R411K, and V422G, in the HADHB gene, which have been identified in Japanese patients, employing a newly developed, sensitive transient expression analysis. Co-transfection of wild-type HADHA and HADHB cDNAs in SV40-transfected fibroblasts from a MTP-deficient patient yielded sufficient enzyme activity to evaluate low-level residual enzyme activity, using two incubation temperatures of 30 degrees C and 37 degrees C. At 30 degrees C, residual enzyme activity was higher than that at 37 degrees C in V422G, R214C, and 8411 K. However, H346R, which was seen in the most severe case, showed no enzyme activity at both temperatures. Our results demonstrate that a defect of HADHB in MTP deficiency is rather common in Japanese patients, and the mutational spectrum is heterogeneous. The present findings showed that all missense mutations in this study were disease-causing. Although the number of patients is still limited, it is suggested that the phenotype is correlated with the genotype and a combination of two mutant alleles of the HADHB gene in MTP deficiency. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ymgme.2009.07.011

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

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Event date： 2023.10

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Event date： 2020.2

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Venue：鹿児島   Country：Japan  

Event date： 2019.10 - 2019.11

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Venue：Boston   Country：United States  

Event date： 2019.10

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Country：Japan  

Event date： 2019.4

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Venue：金沢   Country：Japan  

Event date： 2019.3

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Venue：New Orleans   Country：United States  

Event date： 2019.2

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Venue：北九州市   Country：Japan  

Event date： 2018.11

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Venue：Chiang Mai   Country：Thailand  

Event date： 2018.10

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Venue：東京   Country：Japan  

Event date： 2018.7

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Venue：大沼   Country：Japan  

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Venue：宮崎   Country：Japan  

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Venue：大分   Country：Japan  

Language：English  

Glutaric acidemia type 1 (GA1) is a metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Untreated patients mostly develop severe striatal degeneration. More than 200 mutations have been reported in the GCDH gene, and common R402W and IVS10-2A > C were found in Caucasian and Chinese/Taiwanese, respectively. However, in Japan, genetic mutations have only been reported in a few cases. Herein, we report the clinical and molecular basis of GA1 in 19 Japanese patients, including six previously reported patients. All cases showed high urinary glutaric acid excretion. Eleven patients were severely impaired (three patients died), three had mild impairment, and five showed normal development. Four of 5 patients that developed normally were detected in the presymptomatic stage by neonatal or sibling screening. Nineteen mutations in 26 alleles were identified, and eight of them (89 or 90delC, Y155C, IVS4+2T C, G244S, Q352X, G354A, K361E, and 1144-1145delGC) were novel. S305L (12.1%, 4/34 alleles) was found in several cases, suggesting that this mutation is a common mutation. In contrast, R402W was not identified and IVS10-2A>C was only found in one allele, suggesting that Japanese patients with GA1 show allelic heterogeneity and have a different genetic background to patients from other countries. One of a pair of sisters with the same mutations (M339V/S305L) lacking residual activity was severely retarded, whereas the older girl remains asymptomatic at 22 years of age, indicating that genotype does not necessarily predict GA1 phenotype. We consistently found that there was no association between genotype and phenotype. However, children with mild impairment were diagnosed and treated earlier than severely impaired cases (4.7 +/- 2.5 months (range: 2-8 months) vs. 11.6 +/- 12.7 months (range: 4-51 months)). Our results suggest that early detection and treatment but not genotype are associated with better patient outcome, reinforcing the importance of neonatal screening. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ymgme.2010.11.159

Language：Japanese  

Language：English  

Language：Japanese  

Language：English  

Glutaric aciduria type 2 (multiple acyl-CoA dehydrogenase deficiency. MAD) is a multiple defect of mitochondrial acyl-CoA dehydrogenases due to a deficiency of election transfer flavoprotein (ETF) cm ETF dehydrogenase The clinical spectrum are relatively wide from the neonatal onset, severe form (MAD-S) to the late-onset, milder form (MAD-M) In the present study, we determined whether the in vitro probe acylcarnitine assay using cultured fibroblasts and electrospray ionization tandem mass spectrometry (MS/MS) can evaluate then clinical severity or not Incubation of cells from MAD-S patients with palmitic acid showed large increase in palmitoylcarnitine (C16), whereas the downstream acylcarnitines, C14. C12, C10 or C8 as well as C2. were extremely low In contrast, accumulation of C16 was smaller while the amount of downstream metabolites was higher in fibroblasts from MAD-M compared to MAD-S The ratio of C16/C14. C16/C12, or C16/C10. in the culture medium was significantly higher in MAD-S compared with that in MAD-M Loading octanoic acid or myristic acid led to a significant elevation in C8 or C12, respectively in MAD-S. while their effects were less pronounced in MAD-M In conclusion, it is possible to distinguish MAD-S and MAD-M by in vitro probe acylcarnitine profiling assay with various fatty acids as substrates This strategy may be applicable for other metabolic disorders (C) 2010 Elsevier B V All rights reserved

DOI： 10.1016/j.jchromb.2010.03.029

Language：English  

Heat stress deteriorates mitochondrial beta-oxidation of long-chain fatty acids in cultured fibroblasts with fatty acid beta-oxidation disorders
Mitochondrial fatty acids beta-oxidation disorder (FAOD) has become popular with development of tandem mass spectrometry (MS/MS) and enzymatic evaluation techniques FAOD occasionally causes acute encephalopathy or even sudden death in children On the other hand, hyperpyrexia may also trigger severe seizures or encephalopathy, which might be caused by the defects of fatty acid beta-oxidation (FAO) We investigated the effect of heat stress on FAO to determine the relationship between serious febrile episodes and defect in beta-oxidation of fatty acid in children Fibroblasts from healthy control and children with various FAODs, were cultured in the medium loaded with unlabelled pain-arc acid for 96 h at 37 degrees C or 41 degrees C Acylcarnitine (AC) profiles in the medium were deter mined by MS/MS. and specific ratios of ACs were calculated Under heat stress (at 41 degrees C). long-chain ACs (C12. C14, or C16) were increased, while medium-chain ACs (C6, C8, or C10) were decreased in cells with carnitine palmitoyl transferase II deficiency, very-long-chain acyl-CoA dehydrogenase deficiency and mitochondrial trifunctional protein deficiency, whereas AC species from short-chain (C4) to long-chain (C16) were barely affected in medium-chain acyl-CoA dehydrogenase and control While long-chain ACs (C12-C16) were significantly elevated, short to medium-chain ACs (C4-C10) were reduced in multiple acyl-CoA dehydrogenase deficiency These data suggest that patients with long-chain FAODs may be more susceptible to heat stress compared to medium-chain FAOD or healthy control and that serious febrile episodes may deteriorate long-chain FAO in patients with long-chain FAODs (C) 2010 Elsevier B V All rights reserved

DOI： 10.1016/j.jchromb.2010.01.046

Language：English  

Hyperpyrexia occasionally triggers acute life-threatening encephalopathy-like illnesses, including influenza-associated encephalopathy (IAE) in childhood, and can be responsible for impaired fatty acid beta-oxidation (FAO). In this regard, patients with impaired FAO may be more susceptible to febrile episodes. The effects of heat stress and a hypolipidemic drug, bezafibrate, on mitochondrial FAO were investigated using cultured cells from children with FAO disorders and from normal controls, using an in vitro probe acylcarnitine (AC) profiling assay. Fibroblasts were incubated in medium loaded with unlabelled palmitic acid for 96 h at 37 and 41 degrees C, with or without bezafibrate. AC profiles in culture medium were analyzed by electrospray ionization tandem mass spectrometry. Heat stress, introduced by 41 degrees C, significantly increased acetylcarnitine (C2) but slightly decreased the other acylcarnitines (ACs) in controls and medium-chain acyl-CoA dehydrogenase (MCAD)-deficient cells. On the other hand, in very long-chain acyl-CoA dehydrogenase (VLCAD)-deficient cells, accumulation of long-chain ACs were enhanced at 41 degrees C, compared with that at 37 degrees C. In contrast, bezafibrate decreased long-chain ACs with significant increase of C2 in both control and VLCAD-deficient cells at 37 degrees C. These data suggest that heat stress specifically inhibits long-chain FAO, whereas bezafibrate recovers the impaired FAO. Our approach is a simple and promising strategy to evaluate the effects of heat stress or therapeutic drugs on mitochondrial FAO. (c) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2009.06.001

Language：Japanese  

最近4年間に診断した中鎖アシルCoA脱水素酵素欠損症の日本人5症例における臨床像および発症形態について検討した。診断時年齢は1歳4ヵ月～8歳10ヵ月であった。2症例は同胞スクリーニングで診断されたが、うち1例は既に原因不明の脳症で発症していた。4症例は発症後に診断され、うち1例が死亡、3例が中等度から重度の障害を残していた。発症形態は繰り返すけいれんが1例、急性脳症様症状が2例、意識障害などの低血糖症状が1例であった。発症した4例は全例とも半日以上の絶食が発症の契機となっていた。また、長期間の飢餓となった理由は感染症罹患であった。

Language：English  

Glutaric acidemia type 1 (GA1) is usually diagnosed with an accumulation of glutaric acid (GA) or 3-hydroxyglutaric acid by GC/MS. In some cases, however, excretion of GA is low. We investigated enzymatic evaluation of GA1 using fibroblasts and MS/MS. After loading substrates, lysine, 2-aminoadipate (2AA), or GA, in fibroblasts, and incubating for 96 h, glutarylcarnitine (C5DC) levels in the media were measured. A significant increase of C5DC was observed in GA1 patients, irrespective of substrates added. 2AA showed the largest difference between patients and controls (p = 0.0004). Results suggested enzymatic evaluation of GA1 is useful under appropriate culture conditions. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jchromb.2009.04.043

Language：English  

DOI： 10.1016/j.ymgme.2009.07.011

Language：Japanese  

Language：Japanese  

我々は脂肪酸代謝異常症スクリーニングの補助診断として、線維芽細胞とタンデム質量分析法(MS/MS)を用い脂肪酸β酸化能を評価するin vitro probe assay法を導入してきた。今回、線維芽細胞の代わりに末梢血リンパ球を用いたβ酸化能評価方法を検討した。対象は遺伝子検査で診断が確定された中鎖アシルCoA脱水素酵素(MCAD)欠損症の3例。末梢血よりリンパ球を分離し、パルミチン酸を添加した培地で120時間培養後、MS/MSを用いて培養液中のアシルカルニチンを分析した。MCAD欠損症3症例では、C8-アシルカルニチンが0.96,0.49,0.58nmol/mlとコントロール(0.19±0.07nmol/ml)に比較して高値であった。アシルカルニチン間の比でみると、C8/C10比が対照と比べ差が最も大きかった(p<0.01)。リンパ球を用いたin vitro probe assayによって上記指標を用いればMCAD欠損症の診断が可能であることを確認した。(著者抄録)

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop