Language：English   Publisher：Molecular Genetics and Genomic Medicine  

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

DOI： 10.1002/mgg3.2427

Web of Science

Scopus

PubMed

Language：English   Publisher：Journal of Clinical Endocrinology and Metabolism  

Context: Thyroglobulin (Tg), encoded by TG, is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS). Objective: We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period. Methods: We screened 1061 patients with CH for 13 CH-related genes and identified 30 patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into 2 groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the 7 missense variants using HEK293 cells. Results: Twenty-seven rare TG variants were detected, including 15 nonsense, 3 frameshift, 2 splice-site, and 7 missense variants. Patients were divided into 2 groups: 13 patients with biallelic truncating variants and 17 patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with thyrotropin stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the 7 missense variants was confirmed in vitro. Conclusion: To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement.

DOI： 10.1210/clinem/dgae098

Web of Science

Scopus

PubMed

Language：English   Publisher：International Journal of Molecular Sciences  

Severe obesity in young children prompts for a differential diagnosis that includes syndromic conditions. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) syndrome is a potentially fatal disorder characterized by rapid-onset obesity associated with hypoventilation, neural crest tumors, and endocrine and behavioral abnormalities. The etiology of ROHHAD syndrome remains to be established, but recent research has been focusing on autoimmunity. We report on a 2-year-old girl with rapid-onset obesity during the first year of life who progressed to hypoventilation and encephalitis in less than four months since the start of accelerated weight gain. The patient had a high titer of anti-ZSCAN1 antibodies (348; reference range < 40), and the increased values did not decline after acute phase treatment. Other encephalitis-related antibodies, such as the anti-NDMA antibody, were not detected. The rapid progression from obesity onset to central hypoventilation with encephalitis warns about the severe consequences of early-onset ROHHAD syndrome. These data indicate that serial measurements of anti-ZSCAN1 antibodies might be useful for the diagnosis and estimation of disease severity. Further research is needed to determine whether it can predict the clinical course of ROHHAD syndrome and whether there is any difference in antibody production between patients with and without tumors.

DOI： 10.3390/ijms25052820

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Early Human Development  

Introduction: To establish actionable neonatal screening during the first month of life, we investigated critical diseases in seemingly healthy newborns discharged from birth hospitals. Methods: This retrospective study enrolled previously healthy full-term infants who visited our hospital, a tertiary hospital in Japan, from home between 5 and 28 days after birth from 2009 to 2018. Infants with known perinatal or congenital diseases, positive newborn screening results, or accidental injuries were excluded. Data were collected from electronic medical records, including principal diagnosis, clinical details, and prognosis at 18 months of age. Results: Ninety-seven (58 %) of 168 eligible neonates were admitted to the hospital, and 71 (42 %) were not. The median admission rate in patients with disease onset at ≤14 days after birth (80 %) was significantly higher than that in patients with disease onset at ≥15 days (42 %). Among 45 patients who received intensive medical care, 5 died and 10 developed neurodevelopmental sequelae. Four of 5 patients died by 100 days. Among 25 diseases treated in intensive care unit, 17 (68 %) diseases had a prevalence of <1 per 2000 live births. The commonly used diagnostic methods were imaging (n = 58, 35 %) and physical examination (n = 34, 20 %). Conclusion: Critical diseases due to rare and heterogeneous causes in ostensibly healthy newborns occurred predominantly in the first two weeks of life. Optimal newborn screening and health check-up protocols may benefit from the wide spectrum of life-threatening diseases occurring in home after birth.

DOI： 10.1016/j.earlhumdev.2023.105869

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Pediatric Endocrinology  

<p>Purpose of developing the guidelines: Newborn screening (NBS) for congenital hypothyroidism (CH) was started in 1979 in Japan, and early diagnosis and treatment improved the intelligence prognosis of CH patients. The incidence of CH was once about one in 5,000–8,000 births, but has been increased with diagnosis of subclinical CH. The disease requires continuous treatment and specialized medical facilities should conduct differential diagnosis and treatment in patients who are positive by NBS to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, the guidelines were revised in 2014. Here, we have added minor revisions to the 2014 version to include the most recent findings. Target disease/conditions: Primary congenital hypothyroidism<b>.</b> Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.</p>

DOI： 10.1297/cpe.2022-0063

Scopus

PubMed

CiNii Research

DOI： 10.1297/cpe.32.2022-0063

Web of Science

PubMed

Language：English   Publisher：Molecular Genetics and Metabolism Reports  

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disease caused by a defect in electron transfer flavoprotein alpha (ETFA), ETF beta (ETFB), or ETF dehydrogenase (ETFDH), and riboflavin metabolism disorders have recently been reported to present as mimicking MADD. MADD is roughly classified into neonatal (type 1 or 2) and later-onset (type 3) forms. To identify clinicogenetic characteristics in Japan, we investigated 37 Japanese patients with MADD diagnosed from 1997 to 2020. The causes of MADD were ETFDH deficiency in 26 patients, ETFA deficiency in four, ETFB deficiency in six, and riboflavin metabolism disorder in one. All 15 patients with the neonatal-onset type died by 2 years of age, while five of 22 patients with the later-onset form died by 3 years of age. Furthermore, 8 of 15 patients with the later-onset form of ETFDH deficiency treated with riboflavin were riboflavin non-responders. p.Y507D in ETFDH was identified as the most common variant (9 of 48 alleles, 18.8%). Of two patients with a homozygous p.Y507D variant, one experienced disease onset and died in the neonatal period, while the other experienced disease onset at two months of age and died at two years old, suggesting that the p.Y507D variant results in fatal outcomes. Our study concluded that more than half of Japanese patients with MADD died by three years old, and more than half of patients with the later-onset form had poor responsiveness to riboflavin, partly due to the unique Japanese p.Y507D variant in ETFDH.

DOI： 10.1016/j.ymgmr.2022.100940

Web of Science

Scopus

PubMed

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

DOI： 10.1016

Language：English   Publisher：Ja Clinical Reports  

Background: Carbamoyl phosphate synthetase deficiency (CPS1D) is a urea-cycle disorder (UCD). We report successful perioperative management of pediatric living donor liver transplantation (LDLT) in a CPS1D patient. Case presentation: A 10-year-old female patient with CPS1D underwent LDLT. Proper administration of dextrose 50% and 60 kcal/kg/day with l-arginine and l-carnitine resulted in the avoidance of intraoperative hyperammonemia induced by hypercatabolism. Serum ammonia level transiently increased to 61 mmol/L in the anhepatic phase and decreased to 44 mmol/L after reperfusion. Conclusions: We suggest anesthesia management with administration of dextrose to avoid hyperammonemia during LDLT in patients with CPS1D.

DOI： 10.1186/s40981-022-00558-9

Web of Science

Scopus

PubMed

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

DOI： 10.1186

Language：English   Publisher：Springer Berlin Heidelberg  

症例は10歳女児で、7歳時にカルバモイルリン酸合成酵素欠損症と診断され、9歳時に生体肝移植を受けていた。術前検査で特記すべき異常はなかった。肝機能はChild-Pugh分類クラスAであったが、血清アンモニア値は45μmol/Lであった。術中、60kcal/kg/日に相当するブドウ糖50%、L-アルギニン、L-カルニチンを投与して、高アンモニア血症を回避した。無肝期に血清アンモニア値が一時的に61mmol/Lまで上昇したが、再灌流後に44mmol/Lまで低下し、手術終了時は50mmol/Lであった。術後、ICUに入室し、L-カルニチンとブドウ糖の投与を継続した。血清アンモニア値は術後3日目に正常範囲に低下した。経過は良好で術後3日目に一般病棟に転棟し、27日目に退院した。

Language：English   Publisher：Journal of Human Genetics  

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.

DOI： 10.1038/s10038-021-00984-0

Web of Science

Scopus

PubMed

Language：English   Publisher：Nature Publishing Group  

症例1は3歳女児、症例2は生後10ヵ月男児で、いずれも原因不明のファンコーニ症候群と診断された。また、発達障害や軽度の肝酵素値上昇が認められた。全エクソームシーケンスの結果、症例1では既知のBCS1L遺伝子複合ヘテロ接合性ミスセンス変異およびフレームシフト変異(c.268C>T、p.[Arg90Cys]、c.821del、p.[Pro274Argfs*26])、症例2では新規BCS1L遺伝子複合ヘテロ接合性ミスセンス変異(c.167G>A、p.[Arg56Gln]、c.1195T>G、p.[Tyr399Asp])が同定された。また、BN-PAGE解析の結果、症例2において肝臓ライセート中のミトコンドリア呼吸鎖複合体IIIの発現低下が認められた。

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

DOI： 10.1111

Language：English   Publisher：Pediatrics International  

Background: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan. Methods: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene. Results: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT. Conclusions: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction.

DOI： 10.1111/ped.15286

Web of Science

Scopus

PubMed

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

新生児スクリーニングで同定された日本人初の小児発症Pompe病症例および新生児スクリーニング以前に診断された別症例を対象として、早期酵素補充療法を速やかに開始することの問題点について検討した。症例1は女児で、妊娠36週4日に帝王切開により娩出された。6日目に実施された新生児スクリーニングで酸性アルファグルコシダーゼ(GAA)低値であったため、28日目に当院に紹介された。新生児スクリーニング結果および臨床所見から乳児発症Pompe病が疑われた。GAA遺伝子の次世代シーケンシングの結果、新規アウトフレーム変異(p.F181Dfs*6)および既知変異(p.R600C)が同定され、乳児発症Pompe病と診断された。58日目にERTが開始された。生後58日目にクレアチンキナーゼ血清中濃度が上昇し、心筋肥大がみられたため、酵素補充療法が開始された。その後、臨床的・生化学的マーカーは速やかに改善した。生後14ヵ月で発達遅滞もなく、健常であった。症例2は12歳男児で、NBS時代の前に生後5ヵ月齢で乳児発症Pompe病と診断されていた。GAAホモ接合性変異(p.R608X)が同定された。12年間にわたる酵素補充療法により、心筋肥大は克服された。

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  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Event date： 2023.10

Language：Japanese  

Country：Japan  

Event date： 2023.10

Language：Japanese  

Country：Japan  

Event date： 2023.10

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.5

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2022.12

Language：Japanese  

Country：Japan  

Event date： 2022.11

Language：Japanese  

Country：Japan  

Event date： 2022.11

Language：Japanese  

Country：Japan  

Event date： 2022.11

Language：Japanese  

Country：Japan  

Event date： 2022.11

Language：Japanese  

Country：Japan  

Event date： 2022.10

Language：Japanese  

Country：Japan  

Event date： 2022.9

Language：Japanese  

Country：Japan  

Event date： 2022.5

Language：Japanese  

Country：Japan  

Event date： 2022.2

Language：Japanese  

Country：Japan  

Event date： 2021.12

Language：Japanese  

Country：Japan  

Event date： 2021.11

Language：Japanese  

Country：Japan  

Event date： 2021.11

Language：Japanese  

Country：Japan  

Event date： 2021.11

Language：Japanese  

Country：Japan  

Event date： 2021.10

Language：Japanese  

Country：Japan  

Event date： 2021.10

Language：Japanese  

Country：Japan  

Event date： 2021.10

Language：Japanese  

Country：Japan  

Event date： 2021.10

Language：Japanese  

Country：Japan  

Event date： 2021.10

Language：English  

Country：Japan  

Event date： 2021.10

Language：Japanese  

Country：Japan  

Event date： 2021.10

Language：Japanese  

Country：Japan  

Event date： 2021.4

Language：Japanese  

Country：Japan  

Event date： 2021.2

Language：Japanese  

Country：Japan  

Event date： 2020.2

Language：Japanese  

Venue：鹿児島   Country：Japan  

Event date： 2019.10 - 2019.11

Language：Japanese  

Venue：Boston   Country：United States  

Event date： 2019.10

Language：Japanese  

Country：Japan  

Event date： 2019.4

Language：Japanese  

Venue：金沢   Country：Japan  

Event date： 2019.3

Language：Japanese  

Venue：New Orleans   Country：United States  

Event date： 2019.2

Language：Japanese  

Venue：北九州市   Country：Japan  

Event date： 2018.11

Language：Japanese  

Venue：Chiang Mai   Country：Thailand  

Event date： 2018.10

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2018.7

Language：Japanese  

Venue：大沼   Country：Japan  

Event date： 2018.6

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2018.5

Language：Japanese  

Country：Japan  

Event date： 2018.4

Language：Japanese  

Venue：宮崎   Country：Japan  

Event date： 2018.4

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2018.2

Language：Japanese  

Venue：大分   Country：Japan  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

DOI： 10.1530/EJE-11-0812e

Language：Japanese  

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&#37;, 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)

researchmap