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Kononets V, Zharmakhanova G, Balmagambetova S, Syrlybayeva L, Berdesheva G, Zhussupova Z, Tautanova A, Kurmambayev Y. Tandem mass spectrometry in screening for inborn errors of metabolism: comprehensive bibliometric analysis. Front Pediatr 2025; 13:1463294. [PMID: 40051910 PMCID: PMC11882580 DOI: 10.3389/fped.2025.1463294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 01/28/2025] [Indexed: 03/09/2025] Open
Abstract
Tandem mass spectrometry (MS/MS) for detection of inborn errors of metabolism (IEM) is recognized as an ethical, safe, simple, and reliable screening test. Presented bibliometric analysis aims to describe the network structure of the scientific community in the study area at the level of countries, institutions, authors, papers, keywords, and sources; scientific productivity, directions, and collaboration efforts in a considered period (1991-2024, May). Using the PRISMA method, we conducted a systematic search for articles reporting using MS/MS to screen for inherited metabolic disorders and inborn errors of metabolism collected from the Web of Science Core Collection (WoSCC). A total of 677 articles out of 826, by 3,714 authors, published in 245 journals, with 21,193 citations in 11,295 citing articles, with an average citation of 31.3 per article, and an H-index of 69 were retrieved from the WoSCC. The research status of MS/MS in IEM screening was identified. The most relevant current research directions and future areas of interest were revealed: "selective screening for IEM," "new treatments for IEM," "new disorders considered for MS/MS testing," "ethical issues associated with newborn screening," "new technologies that may be used for newborn screening," and "use of a combination of MS/MS and gene sequencing".
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Affiliation(s)
- Victoria Kononets
- Department of Natural Sciences, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Gulmira Zharmakhanova
- Department of Natural Sciences, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Saule Balmagambetova
- Department of Oncology, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Lyazzat Syrlybayeva
- Department of Natural Sciences, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Gulshara Berdesheva
- Department of General Hygiene, West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
| | - Zhanna Zhussupova
- Department of Neonatal Pathology, Aktobe Regional Tertiary Care Center, Aktobe, Kazakhstan
| | - Aidana Tautanova
- Department of Microbiology and Virology, Named After Sh.I. Sarbasova, Astana Medical University, Astana, Kazakhstan
| | - Yergen Kurmambayev
- Consultative and Diagnostic Department, Medical Center of West Kazakhstan Marat Ospanov Medical University, Aktobe, Kazakhstan
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Nguyen KN, Dien TM, Can TBN, Thao BP, Do TS, Dang TKG, Nguyen NL, Tran VK, Nguyen TT, Trang TTQ, Phuong LT, Nguyen PL, Tran TH, Tu NH, Vu CD. Mitochondrial HMG-CoA Synthase Deficiency in Vietnamese Patients. Int J Mol Sci 2025; 26:1644. [PMID: 40004108 PMCID: PMC11855759 DOI: 10.3390/ijms26041644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/13/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare metabolic disorder that impairs the body's ability to produce ketone bodies and regulate energy metabolism. Diagnosing HMGCS2D is challenging because patients typically remain asymptomatic unless they experience fasting or illness. Due to the absence of reliable biochemical markers, genetic testing has become the definitive method for diagnosing HMGCS2D. This study included 19 patients from 14 unrelated families diagnosed with HMGCS2D in our department between October 2018 and October 2024. The clinical presentations, biochemical findings, molecular characteristics, and management strategies were systematically summarized and analyzed. Of the 19 cases studied, 16 were symptomatic, and 3 were asymptomatic. The onset of the first acute episode occurred between 10 days and 28 months of age. Triggers for the initial crisis in the symptomatic cases included poor feeding (93.8%), vomiting (56.3%), diarrhea (25.0%), and fever (18.8%). Clinical manifestations during the first episode were lethargy/coma (81.3%), rapid breathing (68.8%), hepatomegaly (56.3%), shock (37.5%), and seizures (18.8%). The biochemical abnormalities observed included elevated plasma transaminases (100%), metabolic acidosis (75%), hypoglycemia (56.3%), and elevated plasma ammonia levels (31.3%). Additionally, low free carnitine levels were found in seven cases, elevated C2 levels were found in one case, dicarboxylic aciduria was found in two cases, and ketonuria was found in two cases. Abnormal brain MRI findings were detected in three patients. Genetic analysis revealed seven HMGCS2 gene variants across the 19 cases. Notably, a novel variant, c.407A>T (p.D136V), was identified and has not been reported in any existing databases. Two common variants, c.559+1G>A and c.1090T>A (p.F364I), were present in 11 out of 19 cases (57.9%) and 10 out of 19 cases (55.5%), respectively. The implementation of a high glucose infusion and proactive management strategies-such as preventing prolonged fasting and providing enteral carbohydrate/glucose infusion during illness-effectively reduced the rate of acute relapses following accurate diagnosis. Currently, all 19 patients are alive, with ages ranging from 5 months to 14 years, and exhibit normal physical development. To the best of our knowledge, this study represents the first reported cases of HMGCS2D in Vietnamese patients. Our findings contribute to a broader understanding of the clinical phenotype and expand the known spectrum of HMGCS2 gene variants, enhancing current knowledge of this rare metabolic disorder.
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Affiliation(s)
- Khanh Ngoc Nguyen
- Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi 11512, Vietnam; (K.N.N.); (T.B.N.C.); (B.P.T.); (T.S.D.); (T.K.G.D.)
- Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam;
| | - Tran Minh Dien
- Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi 11512, Vietnam;
| | - Thi Bich Ngoc Can
- Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi 11512, Vietnam; (K.N.N.); (T.B.N.C.); (B.P.T.); (T.S.D.); (T.K.G.D.)
| | - Bui Phuong Thao
- Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi 11512, Vietnam; (K.N.N.); (T.B.N.C.); (B.P.T.); (T.S.D.); (T.K.G.D.)
| | - Tien Son Do
- Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi 11512, Vietnam; (K.N.N.); (T.B.N.C.); (B.P.T.); (T.S.D.); (T.K.G.D.)
| | - Thi Kim Giang Dang
- Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi 11512, Vietnam; (K.N.N.); (T.B.N.C.); (B.P.T.); (T.S.D.); (T.K.G.D.)
| | - Ngoc Lan Nguyen
- Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam; (N.L.N.); (V.K.T.); (T.T.N.); (T.T.Q.T.); (L.T.P.); (P.L.N.)
| | - Van Khanh Tran
- Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam; (N.L.N.); (V.K.T.); (T.T.N.); (T.T.Q.T.); (L.T.P.); (P.L.N.)
| | - Thuy Thu Nguyen
- Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam; (N.L.N.); (V.K.T.); (T.T.N.); (T.T.Q.T.); (L.T.P.); (P.L.N.)
| | - Tran Thi Quynh Trang
- Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam; (N.L.N.); (V.K.T.); (T.T.N.); (T.T.Q.T.); (L.T.P.); (P.L.N.)
| | - Le Thi Phuong
- Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam; (N.L.N.); (V.K.T.); (T.T.N.); (T.T.Q.T.); (L.T.P.); (P.L.N.)
| | - Phan Long Nguyen
- Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam; (N.L.N.); (V.K.T.); (T.T.N.); (T.T.Q.T.); (L.T.P.); (P.L.N.)
| | - Thinh Huy Tran
- Biochemistry Department, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam;
| | - Nguyen Huu Tu
- Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam;
| | - Chi Dung Vu
- Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi 11512, Vietnam; (K.N.N.); (T.B.N.C.); (B.P.T.); (T.S.D.); (T.K.G.D.)
- Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam;
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Kido J, Makris G, Santra S, Häberle J. Clinical landscape of citrin deficiency: A global perspective on a multifaceted condition. J Inherit Metab Dis 2024; 47:1144-1156. [PMID: 38503330 PMCID: PMC11586594 DOI: 10.1002/jimd.12722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/11/2024] [Accepted: 02/14/2024] [Indexed: 03/21/2024]
Abstract
Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in SLC25A13. The clinical manifestation is very variable and comprises three types: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD: OMIM 605814), post-NICCD including failure to thrive and dyslipidemia caused by citrin deficiency, and adult-onset type II citrullinemia (CTLN2: OMIM 603471). Frequently, NICCD can run with a mild clinical course and manifestations may resolve in the post-NICCD. However, a subset of patients may develop CTLN2 when they become more than 18 years old, and this condition is potentially life-threatening. Since a combination of diet with low-carbohydrate and high-fat content supplemented with medium-chain triglycerides is expected to ameliorate most manifestations and to prevent the progression to CTLN2, early detection and intervention are important and may improve long-term outcome in patients. Moreover, infusion of high sugar solution and/or glycerol may be life-threatening in patients with citrin deficiency, particularly CTLN2. The disease is highly prevalent in East Asian countries but is more and more recognized as a global entity. Since newborn screening for citrin deficiency has only been introduced in a few countries, the diagnosis still mainly relies on clinical suspicion followed by genetic testing or selective metabolic screening. This paper aims at describing (1) the different stages of the disease focusing on clinical aspects; (2) the current published clinical situation in East Asia, Europe, and North America; (3) current efforts in increasing awareness by establishing management guidelines and patient registries, hereby illustrating the ongoing development of a global network for this rare disease.
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Affiliation(s)
- Jun Kido
- University Children's Hospital Zurich and Children's Research CentreZurichSwitzerland
- Department of Pediatrics, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
- Department of PediatricsKumamoto University HospitalKumamotoJapan
| | - Georgios Makris
- University Children's Hospital Zurich and Children's Research CentreZurichSwitzerland
| | - Saikat Santra
- Department of Clinical Inherited Metabolic DisordersBirmingham Children's HospitalBirminghamUK
| | - Johannes Häberle
- University Children's Hospital Zurich and Children's Research CentreZurichSwitzerland
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Gupta N, Endrakanti M, Bhat M, Rao N, Kaur R, Kabra M. Clinical and Molecular Spectrum of Patients with Methylmalonic Acidemia. Indian J Pediatr 2024; 91:675-681. [PMID: 37420116 DOI: 10.1007/s12098-023-04651-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 03/17/2023] [Indexed: 07/09/2023]
Abstract
OBJECTIVES To study the clinical and molecular spectrum of Methylmalonic acidemia (MMA). METHODS In this retrospective study, the records of 30 MMA patients were evaluated for their phenotype, biochemical abnormalities, genotype, and outcomes. RESULTS Thirty patients with MMA (age range 0-21 y) from 27 unrelated families were enrolled. Family history and consanguinity were noted in 10/27 (37%) and 11/27 (41%) families respectively. Acute metabolic decompensation was more common (57%) than chronic presentation. Biochemical work-up was suggestive of isolated MMA (n = 18) and MMA with homocystinuria (n = 9) respectively. Molecular testing in 24 families showed 21 pathogenic or likely pathogenic variants with MMA cblC as the commonest molecular subtype (n = 8). B12 responsiveness, an important determinant of long-term outcome, was observed in eight patients [MMAA (n = 3) and MMACHC (n = 5)]. Mortality was 30% (n = 9/30) with a high proportion of early-onset severe disease and fatal outcome in isolated MMA mut0 (4/4) and MMA cblB (3/3), as compared to MMA cblA (1/5) and MMA cblC (1/10). CONCLUSIONS This study cohort had MMA cblC subtype as the most common type of MMA followed by the MMA mutase defect. Outcomes in MMA are influenced by the type of molecular defect, age, and severity of presentation. Early detection and management is likely to result in better outcomes.
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Affiliation(s)
- Neerja Gupta
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India.
| | - Mounika Endrakanti
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India
| | - Meenakshi Bhat
- Centre for Human Genetics, Bangalore, Karnataka, 560100, India
| | - Nivedita Rao
- Centre for Human Genetics, Bangalore, Karnataka, 560100, India
| | - Ravneet Kaur
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India
| | - Madhulika Kabra
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India
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Eriksson M. Insufficient evidence for the validity of the Language Development Survey and the MacArthur-Bates Communicative Development Inventories as screening tools: A critical review. INTERNATIONAL JOURNAL OF LANGUAGE & COMMUNICATION DISORDERS 2023; 58:555-575. [PMID: 36370048 DOI: 10.1111/1460-6984.12800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 09/23/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND The Language Development Survey (LDS) and the MacArthur-Bates Communicative Development Inventories (MB-CDI) are two parental report forms that have been productive in providing data on early child language during the past 30 years. The instruments have been used both in studies relating to typical developing children and in screening for language difficulties. AIM To review the evidence for the LDS and the MB-CDI utility as screening instruments. METHODS A literature search in PubMed and PsychInfo identified 16 articles based on LDS or MB-CDI that reported statistics pertinent to early screening for language difficulties. MAIN CONTRIBUTION It was found that most reviewed studies were explorative in nature and tried out different versions of the screening test, including different cut-off values, multiple reference tests, small sample sizes and rarely reported confidence intervals. Spectrum, verification and review biases were common. Moreover, no study could convincingly show that the actual diagnostic accuracy was sufficient for clinical use. CONCLUSIONS There is insufficient evidence that the LDS or any version of the MB-CDI is a valid tool for screening for language difficulties. Of course, this is not to say that sufficient evidence will not be achieved in future studies, or that the instruments do not work well for purposes other than screening. WHAT THIS PAPER ADDS What is already known on this subject The LDS and the MB-CDI are two often-used instruments assessing various aspects of early child language by parental reports. Both instruments have also been used in screening for early language difficulties. What this study adds This study reveals that most published studies in which the classification accuracy of LDS and the MB-CDI has been investigated contain serious methodological shortcomings limiting conclusions about their validity. Currently, there is no good evidence about the usefulness of the LDS and the MB-CDI as general screening tools for language difficulties. What are the potential or actual clinical implications of this work? The LDS and MB-CDI should not be used as screening tools for language difficulties until better evidence of their effectiveness has been demonstrated.
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Affiliation(s)
- Mårten Eriksson
- Faculty of Health and Occupational Studies, Department of Occupational Health Science and Psychology, University of Gävle, Gävle, Sweden
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6
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Nguyen MHT, Nguyen AHP, Ngo DN, Nguyen PMT, Tang HS, Giang H, Lu YT, Nguyen HN, Tran MD. The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis. J Hum Genet 2023; 68:305-312. [PMID: 36599957 DOI: 10.1038/s10038-022-01112-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/29/2022] [Accepted: 12/19/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND Citrin deficiency (CD), a disorder caused by mutations in the SLC25A13 gene, may result in neonatal intrahepatic cholestasis. This study was purposely to explore the mutation spectrum of SLC25A13 gene in Vietnamese CD patients. METHODS The 292 unrelated CD patients were first screened for four high-frequency mutations by PCR/PCR-RFLP. Then, Sanger sequencing was performed directly for heterozygous or undetected patients. Novel mutations identified would need to be confirmed by their parents. RESULTS 12 pathogenic SLC25A13 mutations were identified in all probands, including three deletions c.851_854del (p.R284Rfs*3), c.70-63_133del (p.Y24_72Ifs*10), and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]), two splice-site mutations (IVS6+5G>A and IVS11+1G>A), one nonsense mutations c.1399C>T (p.R467*), one duplication mutation c.1638_1660dup (p.A554fs*570), one insertion IVSl6ins3kb (p.A584fs*585), and four missense mutation c.2T>C (p.M1T), c.1231G>A (p.V411M), c.1763G>A (p.R588Q), and c.135G>C (p.L45F). Among them, c.851_854del (mut I) was the most identified mutant allele (91.78%) with a total of 247 homozygous and 42 heterozygous genotypes of carriers. Interestingly, two novel mutations were identified: c.70-63_133del (p.Y24_72Ifs*10) and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]). CONCLUSION The SLC25A13 mutation spectrum related to intrahepatic cholestasis infants in Vietnam revealed a quite similar pattern to Asian countries' reports. This finding supports the use of targeted SLC25A13 mutation for CD screening in Vietnam and contributed to the SLC25A13 mutation spectra worldwide. It also helps emphasize the role of DNA analysis in treatment, genetic counseling, and prenatal diagnosis.
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Affiliation(s)
| | | | - Diem-Ngoc Ngo
- Human Genetics Department, National Children's Hospital, Hanoi, Vietnam
| | | | - Hung-Sang Tang
- Gene Solutions, Ho Chi Minh City, Vietnam.,Medical Genetics Institutes, Ho Chi Minh City, Vietnam
| | - Hoa Giang
- Gene Solutions, Ho Chi Minh City, Vietnam.,Medical Genetics Institutes, Ho Chi Minh City, Vietnam
| | - Y-Thanh Lu
- Medical Genetics Institutes, Ho Chi Minh City, Vietnam
| | - Hoai-Nghia Nguyen
- Medical Genetics Institutes, Ho Chi Minh City, Vietnam.,University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Minh-Dien Tran
- Human Genetics Department, National Children's Hospital, Hanoi, Vietnam.,Hepatology Department, National Children's Hospital, Hanoi, Vietnam
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Osawa Y, Kobayashi H, Tajima G, Hara K, Yamada K, Fukuda S, Hasegawa Y, Aisaki J, Yuasa M, Hata I, Okada S, Shigematsu Y, Sasai H, Fukao T, Takizawa T, Yamaguchi S, Taketani T. The frequencies of very long-chain acyl-CoA dehydrogenase deficiency genetic variants in Japan have changed since the implementation of expanded newborn screening. Mol Genet Metab 2022; 136:74-79. [PMID: 35400565 DOI: 10.1016/j.ymgme.2022.03.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 11/30/2022]
Abstract
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.
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Affiliation(s)
- Yoshimitsu Osawa
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan; Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
| | - Hironori Kobayashi
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan; Division of Laboratory, Shimane University Hospital, Izumo, Shimane, Japan.
| | - Go Tajima
- Division of Neonatal Screening, National Center for Child Health and Development, Setagaya, Tokyo, Japan.
| | - Keiichi Hara
- Department of Pediatrics, The NHO Kure Medical Center, Kure, Hiroshima, Japan.
| | - Kenji Yamada
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
| | - Seiji Fukuda
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
| | - Yuki Hasegawa
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
| | - Junko Aisaki
- Division of Neonatal Screening, National Center for Child Health and Development, Setagaya, Tokyo, Japan.
| | - Miori Yuasa
- Department of Pediatrics, University of Fukui, Eiheiji-cho, Fukui, Japan.
| | - Ikue Hata
- Department of Pediatrics, University of Fukui, Eiheiji-cho, Fukui, Japan.
| | - Satoshi Okada
- Department of Pediatrics, Hiroshima University Graduate School of Biochemical and Health Sciences, Hiroshima, Japan.
| | - Yosuke Shigematsu
- Department of Pediatrics, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan
| | - Hideo Sasai
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
| | - Toshiyuki Fukao
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Takumi Takizawa
- Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
| | - Seiji Yamaguchi
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
| | - Takeshi Taketani
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
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8
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Shimada Y, Kawano N, Goto M, Watanabe H, Ihara K. Stability of amino acids, free and acyl-carnitine in stored dried blood spots. Pediatr Int 2022; 64:e15072. [PMID: 34817917 PMCID: PMC9313883 DOI: 10.1111/ped.15072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 11/05/2021] [Accepted: 11/19/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Newborn screening of inborn errors of metabolism using tandem mass spectrometry has become a public health strategy in many developed countries. Retrospective analyses using stored dried blood specimens have been limited, mainly due to a lack of biochemical information on the long-term stability of acylcarnitines and amino acids in stored specimens. We studied the characteristic profiles of the stability of amino acid, free carnitine, and acyl carnitines in dried blood specimens stored in a refrigerator after newborn screening. METHODS Dried blood specimens from 198 healthy newborns, which had been stored in a refrigerator at 5 °C after newborn screening, were prospectively subjected to tandem mass spectrometry analyses after 1, 3, 6 months, 1 and 2 years of storage. We also retrospectively re-analyzed the stored samples from 90 newborns, which had been analyzed and stored at 5 °C for 4 years. RESULTS We found that proline (Pro) and tyrosine (Tyr) were stable for 2 years, and that alanine (Ala), arginine (Arg), and phenylalanine (Phe) decayed with linear regression. The C0 increased during the time-course of 2 years, whereas most acylcarnitines gradually decayed and some showed a linear correlation. The retrospective analysis of samples stored for 4 years revealed that Ala, Phe, Pro and Tyr were almost stable, leucine (Leu), valine (Val) decayed with linear regression, C0 increased, and C10, C12, C14, C14:1, C16, C18, C18:1 decreased, while maintaining a linear correlation. CONCLUSIONS These data suggested that some metabolic parameters from refrigerator-stored dried blood specimens were applicable for the detection of inborn errors of metabolism.
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Affiliation(s)
- Yumi Shimada
- Department of Pediatrics, Oita University Faculty of Medicine, Yufu City, Oita, Japan
| | - Nanae Kawano
- Department of Pediatrics, Oita University Faculty of Medicine, Yufu City, Oita, Japan
| | - Miho Goto
- Department of Clinical Laboratory, Almeida Memorial Hospital, Oita City, Oita, Japan
| | - Hiromi Watanabe
- Department of Clinical Laboratory, Almeida Memorial Hospital, Oita City, Oita, Japan
| | - Kenji Ihara
- Department of Pediatrics, Oita University Faculty of Medicine, Yufu City, Oita, Japan
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Jin L, Han X, He F, Zhang C. Prevalence of methylmalonic acidemia among newborns and the clinical-suspected population: a meta-analyse. J Matern Fetal Neonatal Med 2021; 35:8952-8967. [PMID: 34847798 DOI: 10.1080/14767058.2021.2008351] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
IMPORTANCE Knowing the scale of rare inborn errors is important for screening and resource allocation. Evidence on the prevalence of methylmalonic acidemia (MMA) among newborns and the clinical-suspected population from large-scale screening programs needs to be systematically synthesized. OBJECTIVE To estimate the worldwide prevalence of MMA for newborns and the clinical-suspected population and explore the differences in different regions, periods, and diagnostic technologies. DATA SOURCES MEDLINE, Embase, CRD, Cochrane Library, Scopus, CINAHL, and PROSPERO. Study Selection: All studies reporting the epidemiology characteristics of MMA were selected. DATA EXTRACTION AND SYNTHESIS Characteristics of study, subjects, and epidemiology were extracted, random-effect models were used for meta-analyses. MAIN OUTCOME AND MEASURE Pooled prevalence of MMA. RESULTS This study included 111 studies. The pooled prevalence of MMA worldwide was 1.14 per 100,000 newborns (1516/190,229,777 newborns, 95% CI: 0.99-1.29) and 652.11 per 100,000 clinical-suspected patients (1360/4,805,665 clinical-suspected individuals, CI: 544.14-760.07). Asia and Africa got a higher pooled prevalence of MMA. The prevalence of MMA in newborns increased through the years, while that in the clinical-suspected population decreased. Collecting blood ≥ 72 h after birth had a higher pooled prevalence of MMA than collecting during 24 h-72 h after birth. The combining-use of MS/MS and GC/MS had a higher pooled prevalence than the single-use of MS/MS or GC/MS. Prevalence of cbl C, mut, cbl B, cbl A, isolated MMA, combined MMA and homocystinuria, vitamin B12-responsive MMA was synthesized. CONCLUSIONS AND RELEVANCE Prevalence of MMA among newborns was extremely low, but considerably high in the clinical-suspected population, indicating the need for more efficient newborn screening strategies and closer monitoring of the high-risk population for the early signs of MMA. Asia and Africa should attach importance to the high prevalence of MMA. Further diagnostic tests were recommended for the combining-use vs single-use of MS/MS and GC/MS and for collecting blood after 72 h vs during 24-72 h after birth.
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Affiliation(s)
- Lizi Jin
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, P. R. China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Xueyan Han
- Department of Medical Statistics, Peking University First Hospital, Beijing, P. R. China
| | - Falin He
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, P. R. China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
| | - Chuanbao Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, P. R. China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China
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10
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Liu J, Liu Z, Yan H, Li Y. Dandy-Walker malformation in methylmalonic acidemia: a rare case report. BMC Pediatr 2021; 21:398. [PMID: 34511063 PMCID: PMC8436548 DOI: 10.1186/s12887-021-02874-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/02/2021] [Indexed: 11/23/2022] Open
Abstract
Background Methylmalonic acidemia is an organic acid metabolism disorder that usually has nonspecific clinical manifestations. Case presentation A 3-month-old female infant was admitted to the hospital for developmental retardation. Her prenatal and birth history was unremarkable. After admission, she developed dyspnea and severe anemia and was subsequently transferred to the intensive care unit. Magnetic resonance imaging of her brain showed a Dandy-Walker malformation, and metabolic screening indicated methylmalonic acidemia. Thus, she was diagnosed with methylmalonic acidemia and Dandy-Walker malformation. The patient underwent treatment including acidosis correction, blood transfusion, antibiotics, mechanical ventilation and heat preservation. Unfortunately, her condition progressively worsened and she died of metabolic crisis. Conclusions Dandy-Walker malformation may be a clinical manifestation of methylmalonic acidemia. Additionally, the co-existence of methylmalonic acidemia and Dandy-Walker malformation may be an uncharacterized syndrome which needs to be studied further.
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Affiliation(s)
- Jingwei Liu
- Department of Pediatric Intensive Care Unit, The First Hospital of Jilin University, Xin Min Street, 130021, Changchun, China
| | - Zhuohang Liu
- Department of Radiology, The First Hospital of Jilin University, Changchun, China
| | - Haibo Yan
- Department of Pediatric Intensive Care Unit, The First Hospital of Jilin University, Xin Min Street, 130021, Changchun, China
| | - Yumei Li
- Department of Pediatric Intensive Care Unit, The First Hospital of Jilin University, Xin Min Street, 130021, Changchun, China.
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11
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Deng K, Zhu J, Yu E, Xiang L, Yuan X, Yao Y, Li X, Liu H. Incidence of inborn errors of metabolism detected by tandem mass spectrometry in China: A census of over seven million newborns between 2016 and 2017. J Med Screen 2021; 28:223-229. [PMID: 33241759 DOI: 10.1177/0969141320973690] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The incidence of inborn errors of metabolism varies widely across countries. Very few studies have analyzed the incidence of these disorders in Mainland China. We aimed to estimate the overall and disease-specific incidences of inborn errors of metabolism in Chinese newborns and investigate the geographical distribution of these disorders. METHODS A national cross-sectional survey was conducted to investigate newborn inborn errors of metabolism screening by tandem mass spectroscopy in Mainland China between 2016 and 2017. A total of 246 newborn screening centers were surveyed using a standardized questionnaire. We examined the cumulative and disease-specific incidences of inborn errors of metabolism in Mainland China as a whole and in different geographical locations. RESULTS Over 7 million newborns were screened and 2747 were diagnosed with inborn errors of metabolism, yielding an overall incidence of 38.69 per 100,000 births (95% confidence interval: 37.27-40.17). The most common disorders were amino acid disorders (17.14 per 100,000 births, 95% confidence interval: 16.21-18.13), followed by organic acid disorders (12.39 per 100,000 births, 95% confidence interval: 11.60-13.24) and fatty acid oxidation disorders (9.16 per 100,000 births, 95% confidence interval: 8.48-9.89). The overall and disease-specific incidence rates differed significantly across geographical locations (P < 0.001). CONCLUSIONS The overall incidence of inborn errors of metabolism in Chinese newborns is relatively high. It is urgent to establish the recommended uniform screening panel for inborn errors of metabolism to guide the national and regional tandem mass spectroscopy newborn screening programs.
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Affiliation(s)
- Kui Deng
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Jun Zhu
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Erling Yu
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Liangcheng Xiang
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xuelian Yuan
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yongna Yao
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xiaohong Li
- National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Hanmin Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education
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12
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Sugiyama M, Hazama T, Nakano K, Urae K, Moriyama T, Ariyoshi T, Kurokawa Y, Kodama G, Wada Y, Yano J, Otsubo Y, Iwatani R, Kinoshita Y, Kaida Y, Nasu M, Shibata R, Tashiro K, Fukami K. Effects of Reducing L-Carnitine Supplementation on Carnitine Kinetics and Cardiac Function in Hemodialysis Patients: A Multicenter, Single-Blind, Placebo-Controlled, Randomized Clinical Trial. Nutrients 2021; 13:nu13061900. [PMID: 34073024 PMCID: PMC8230272 DOI: 10.3390/nu13061900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/24/2021] [Accepted: 05/28/2021] [Indexed: 01/20/2023] Open
Abstract
L-carnitine (LC) supplementation improves cardiac function in hemodialysis (HD) patients. However, whether reducing LC supplementation affects carnitine kinetics and cardiac function in HD patients treated with LC remains unclear. Fifty-nine HD patients previously treated with intravenous LC 1000 mg per HD session (three times weekly) were allocated to three groups: LC injection three times weekly, once weekly, and placebo, and prospectively followed up for six months. Carnitine fractions were assessed by enzyme cycling methods. Plasma and red blood cell (RBC) acylcarnitines were profiled using tandem mass spectrometry. Cardiac function was evaluated using echocardiography and plasma B-type natriuretic peptide (BNP) levels. Reducing LC administration to once weekly significantly decreased plasma carnitine fractions and RBC-free carnitine levels during the study period, which were further decreased in the placebo group (p < 0.001). Plasma BNP levels were significantly elevated in the placebo group (p = 0.03). Furthermore, changes in RBC (C16 + C18:1)/C2 acylcarnitine ratio were positively correlated with changes in plasma BNP levels (β = 0.389, p = 0.005). Reducing LC administration for six months significantly decreased both plasma and RBC carnitine levels, while the full termination of LC increased plasma BNP levels; however, it did not influence cardiac function in HD patients.
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Affiliation(s)
- Miki Sugiyama
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
- Sugi Hospital, Omuta, Fukuoka 837-0916, Japan
| | - Takuma Hazama
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Kaoru Nakano
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Kengo Urae
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Tomofumi Moriyama
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Takuya Ariyoshi
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Yuka Kurokawa
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Goh Kodama
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | | | - Junko Yano
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
- Kurume Ekimae Clinic, Kurume, Fukuoka 830-0023, Japan
| | | | | | - Yukie Kinoshita
- Research Institute of Medical Mass Spectrometry, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (Y.K.); (K.T.)
| | - Yusuke Kaida
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Makoto Nasu
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Ryo Shibata
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
| | - Kyoko Tashiro
- Research Institute of Medical Mass Spectrometry, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (Y.K.); (K.T.)
| | - Kei Fukami
- Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; (M.S.); (T.H.); (K.N.); (K.U.); (T.M.); (T.A.); (Y.K.); (G.K.); (J.Y.); (Y.K.); (M.N.); (R.S.)
- Correspondence: ; Tel.: +81-942317002
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13
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Wang DD, Mao YZ, He SM, Yang Y, Chen X. Quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients. Expert Rev Clin Pharmacol 2021; 14:919-926. [PMID: 33861163 DOI: 10.1080/17512433.2021.1917381] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES This study aimed to explore the quantitative efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients using model-based meta-analysis (MBMA). METHODS Literatures were retrieved from the public database and data from these trials were extracted. The quantitative efficacy of L-carnitine on fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) in type 2 diabetes mellitus patients were evaluated by maximal effect (Emax) models with nonlinear mixed effects modeling (NONMEM). RESULTS In the model of FPG, Emax and treatment duration to reach half of the maximal effects (ET50) were -9.8% and 36.1 weeks, respectively. In the model of HbA1c, Emax and ET50 were -19.6% and 106 weeks, respectively. In addition, the durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on FPG were 13, 36.1, 118, 160, and 390 weeks, respectively. The durations for achieving 25%, 50%, 75%, 80%, and 90% Emax of L-carnitine on HbA1c were 38, 106, 334, 449, and 1058 weeks, respectively. CONCLUSIONS It was the first time to provide valuable quantitative information for efficacy of L-carnitine supplementation on glycemic control in type 2 diabetes mellitus patients.
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Affiliation(s)
- Dong-Dong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yi-Zhen Mao
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Su-Mei He
- Department of Pharmacy, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Yang Yang
- Department of Pharmacy, The Affiliated Changzhou Children's Hospital of Nantong University, Changzhou, China
| | - Xiao Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
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14
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Ma S, Guo Q, Zhang Z, He Z, Yue A, Song Z, Zhao Q, Wang X, Sun R. Expanded newborn screening for inborn errors of metabolism by tandem mass spectrometry in newborns from Xinxiang city in China. J Clin Lab Anal 2020; 34:e23159. [PMID: 31916308 PMCID: PMC7246475 DOI: 10.1002/jcla.23159] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/17/2019] [Accepted: 11/22/2019] [Indexed: 12/27/2022] Open
Abstract
Background Tandem mass spectrometry is a powerful technology available in China over the last 15 years. The development of tandem mass spectrometry had made it possible to rapidly screen newborns for inborn errors of metabolism. The aim of this study was to determine the birth incidence of inborn errors of metabolism through expanded screening of newborns by tandem mass spectrometry in Xinxiang area. Methods Dried blood spots from 50 112 newborns were assessed for inborn errors of metabolism by tandem mass spectrometry. The diagnoses were confirmed based on the clinical features, conventional laboratory tests, and the organic acid levels tested in urine by gas chromatography‐mass spectrometry. Results The study findings revealed that 31 newborns were diagnosed with inborn errors of metabolism. The total incidence rate of inborn errors of metabolism was 1/1617, and these included 16 cases of amino acid disorders (51.6%), nine cases of organic acid disorders (29.0%), and 6 (19.4%) cases of fatty acid beta‐oxidation disorders. Conclusions The screening for the incidence of inborn errors of metabolism in Xinxiang area showed that the rate was higher than previously reported. This study provides valuable data which may be useful in facilitating improvements in the expansion of screening to enable early diagnosis and treatment of inborn errors of metabolism before the onset of symptoms.
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Affiliation(s)
- Shujun Ma
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.,Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Qinghe Guo
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Zhongxin Zhang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Zhian He
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Aizhi Yue
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.,Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Zhishan Song
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Qingwei Zhao
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Xia Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Ruili Sun
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
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15
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Zhang W, Yang Y, Peng W, Chang J, Mei Y, Yan L, Chen Y, Wei X, Liu Y, Wang Y, Feng Z. A 7-Year Report of Spectrum of Inborn Errors of Metabolism on Full-Term and Premature Infants in a Chinese Neonatal Intensive Care Unit. Front Genet 2020; 10:1302. [PMID: 31998365 PMCID: PMC6967400 DOI: 10.3389/fgene.2019.01302] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 11/26/2019] [Indexed: 12/26/2022] Open
Abstract
Inborn errors of metabolism (IEMs) have great repercussions in neonatal intensive care units (NICUs). However, the integrative analysis of the incidence for full-term and premature neonates of IEMs in NICUs have not been reported. In this study, we aimed to estimate the incidence of IEMs in the NICU population so as to better evaluate the impact of IEMs on Chinese NICUs. A total of 42,257 newborns (proportion of premature as 36.7%) enrolled to the largest Chinese NICU center for a sequential 7 years screen, and 66 were diagnosed with IEMs. The prevalence of IEMs in total, full-term, and premature infants was 1:640, 1:446, and 1:2,584, respectively. In spectrum of our NICU, diseases that cause endogenous intoxication like methylmalonic acidemia accounted for 93.9% (62/66), and this ratio was higher in full-term infants with 98.3% (59/60), while the most prevalent disease in premature newborn was hyperphenylalaninemia (50%, 3/6), respectively. The genetic analysis of 49 cases revealed 62 potentially pathogenic mutations in 10 well-documented pathogenic genes of IEMs, among which 21 were novel. In conclusion, differences in incidence and spectrum of full-term and premature births we obtained in NICU will provide diagnostic guidelines and therapeutic clues of neonatal IEMs for pediatricians.
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Affiliation(s)
- Wanqiao Zhang
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Yao Yang
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Wei Peng
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Juan Chang
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Yabo Mei
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Lei Yan
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Yuhan Chen
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Xiujuan Wei
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Yabin Liu
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Yan Wang
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
| | - Zhichun Feng
- BaYi Children's Hospital, Seventh Medical Center of PLA General Hospital, Beijing, China.,National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China.,Beijing Key Laboratory of Pediatric Organ Failure, Beijing, China
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16
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Genetic Analysis of Peroxisomal Genes Required for Longevity in a Yeast Model of Citrin Deficiency. Diseases 2020; 8:diseases8010002. [PMID: 31936501 PMCID: PMC7151034 DOI: 10.3390/diseases8010002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/23/2019] [Accepted: 01/07/2020] [Indexed: 12/02/2022] Open
Abstract
Citrin is a liver-specific mitochondrial aspartate–glutamate carrier encoded by SLC25A13. Citrin deficiency caused by SLC25A13 mutation results in carbohydrate toxicity, citrullinemia type II, and fatty liver diseases, the mechanisms of some of which remain unknown. Citrin shows a functional homolog in yeast aspartate-glutamate carrier (Agc1p) and agc1Δ yeasts are used as a model organism of citrin deficiency. Here, we found that agc1Δ yeasts decreased fat utilization, impaired NADH balance in peroxisomes, and decreased chronological lifespan. The activation of GPD1-mediated NAD+ regeneration in peroxisomes by GPD1 over-expression or activation of the malate–oxaloacetate NADH peroxisomal shuttle, by increasing flux in this NADH shuttle and over-expression of MDH3, resulted in lifespan extension of agc1Δ yeasts. In addition, over-expression of PEX34 restored longevity of agc1Δ yeasts as well as wild-type cells. The effect of PEX34-mediated longevity required the presence of the GPD1-mediated NADH peroxisomal shuttle, which was independent of the presence of the peroxisomal malate–oxaloacetate NADH shuttle and PEX34-induced peroxisome proliferation. These data confirm that impaired NAD+ regeneration in peroxisomes is a key defect in the yeast model of citrin deficiency, and enhancing peroxisome function or inducing NAD+ regeneration in peroxisomes is suggested for further study in patients’ hepatocytes.
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Yamada K, Osawa Y, Kobayashi H, Hasegawa Y, Fukuda S, Yamaguchi S, Taketani T. Serum C14:1/C12:1 ratio is a useful marker for differentiating affected patients with very long-chain acyl-CoA dehydrogenase deficiency from heterozygous carriers. Mol Genet Metab Rep 2019; 21:100535. [PMID: 31844625 PMCID: PMC6895747 DOI: 10.1016/j.ymgmr.2019.100535] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/20/2019] [Indexed: 10/28/2022] Open
Abstract
Introduction Various markers, such as C14:1 and the C14:1/C2 ratio, are used as diagnostic markers of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). However, the levels of these markers in patients with VLCADD overlap with those in heterozygous carriers and even healthy subjects. Materials and methods In twenty-three affected patients and 15 heterozygous carriers with VLCADD, the accuracies of C14:1, C14:1/C12:1, C14:1/C2, and C14:1/C16 in dried blood spots (DBS) and serum were statistically estimated. Results Among the serum markers, the sensitivity, specificity, positive predictive value, negative predictive value, false-positive rate, false-negative rate, and validity of C14:1/C12:1 were superior to those of C14:1, C14:1/C2, and C14:1/C16, but C14:1/C2 demonstrated a statistical advantage compared with only C14:1 and C14:1/C16. Elevation in serum C14:1/C12:1 was observed in only one heterozygous carrier, whereas almost half of the carriers displayed false positive results for the other markers. Among the DBS markers, although the accuracy of C14:1/C2 was ostensibly the best, no statistical significance was observed. Discussion Serum C14:1/C12:1 might be useful for differentiating patients with VLCADD from heterozygous carriers. Although serum C14:1/C2 was significantly useful for the detection of VLCADD, this marker could not distinguish the affected patients from carriers. C14:1/C12:1 might be optimal compared with the other markers.
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Affiliation(s)
- Kenji Yamada
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan
| | - Yoshimitsu Osawa
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan.,Department of Pediatrics, Graduate School of Medicine, Gunma University, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
| | - Hironori Kobayashi
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan
| | - Yuki Hasegawa
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan
| | - Seiji Fukuda
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan
| | - Seiji Yamaguchi
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan
| | - Takeshi Taketani
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo, Shimane 693-8501, Japan
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Wang T, Ma J, Zhang Q, Gao A, Wang Q, Li H, Xiang J, Wang B. Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population. Front Genet 2019; 10:1052. [PMID: 31737040 PMCID: PMC6828960 DOI: 10.3389/fgene.2019.01052] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 10/01/2019] [Indexed: 12/30/2022] Open
Abstract
Expanded newborn screening for inborn errors of metabolism (IEMs) by tandem mass spectrometry (MS/MS) could simultaneously analyze more than 40 metabolites and identify about 50 kinds of IEMs. Next generation sequencing (NGS) targeting hundreds of IMEs-associated genes as a follow-up test in expanded newborn screening has been used for genetic analysis of patients. The spectrum, prevalence, and genetic characteristic of IEMs vary dramatically in different populations. To determine the spectrum, prevalence, and gene mutations of IEMs in newborns in Suzhou, China, 401,660 newborns were screened by MS/MS and 138 patients were referred to genetic analysis by NGS. The spectrum of 22 IEMs were observed in Suzhou population of newborns, and the overall incidence (excluding short chain acyl-CoA dehydrogenase deficiency (SCADD) and 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD)) was 1/3,163. The prevalence of each IEM ranged from 1/401,660 to 1/19,128, while phenylketonuria (PKU) (1/19,128) and Mild hyperphenylalaninemia (M-HPA) (1/19,128) were the most common IEMs, followed by primary carnitine uptake defect (PCUD) (1/26,777), SCADD (1/28,690), hypermethioninemia (H-MET) (1/30,893), 3-MCCD (1/33,412) and methylmalonic acidemia (MMA) (1/40,166). Moreover, 89 reported mutations and 51 novel mutations in 25 IMEs-associated genes were detected in 138 patients with one of 22 IEMs. Some hotspot mutations were observed for ten IEMs, including PAH gene c.728G > A, c.611A > G, and c.721C > T for Phenylketonuria, PAH gene c.158G > A, c.1238G > C, c.728G > A, and c.1315+6T > A for M-HPA, SLC22A5 gene c.1400C > G, c.51C > G, and c.760C > T for PCUD, ACADS gene c.1031A > G, c.164C > T, and c.1130C > T for SCAD deficiency, MAT1A gene c.791G > A for H-MET, MCCC1 gene c.639+2T > A and c.863A > G for 3-MCCD, MMUT gene c.1663G > A for MMA, SLC25A13 gene c.IVS16ins3Kb and c.852_855delTATG for cittrullinemia II, PTS gene c.259C > T and c.166G > A for Tetrahydrobiopterin deficiency, and ACAD8 gene c.1000C > T and c.286C > A for Isobutyryl coa dehydrogenase deficiency. All these hotspot mutations were reported to be pathogenic or likely pathogenic, except a novel mutation of ACAD8 gene c.286C > A. These mutational hotspots could be potential candidates for gene screening and these novel mutations expanded the mutational spectrum of IEMs. Therefore, our findings could be of value for genetic counseling and genetic diagnosis of IEMs.
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Affiliation(s)
- Ting Wang
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jun Ma
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Qin Zhang
- Genetic Clinic, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Ang Gao
- Genetic Clinic, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Qi Wang
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Hong Li
- Infertility Clinic, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jingjing Xiang
- Genetic Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Benjing Wang
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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Okano Y, Ohura T, Sakamoto O, Inui A. Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: Strategy to prevent CTLN2. Mol Genet Metab 2019; 127:175-183. [PMID: 31255436 DOI: 10.1016/j.ymgme.2019.06.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/14/2019] [Accepted: 06/14/2019] [Indexed: 11/26/2022]
Abstract
Identification of the genes responsible for adult-onset type II citrullinemia (CTLN2) and citrin protein function have enhanced our understanding of citrin deficiency. Citrin deficiency is characterized by 1) neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD); 2) adaptation/compensation stage with unique food preference from childhood to adulthood; and 3) CTLN2. The treatment of NICCD aims to prevent the progression of cholestasis, and it includes medium chain triglycerides (MCT) milk and lactose-free milk, in addition to medications (e.g., vitamin K2, lipid-soluble vitamins and ursodeoxycholic acid). Spontaneous remission around the age of one is common in NICCD, though prolonged cholestasis can lead to irreversible liver failure and may require liver transplantation. The adaptation/compensation stage (after one year of age) is characterized by the various signs and symptoms such as hypoglycemia, fatty liver, easy fatigability, weight loss, and neuropsychiatric symptoms. Some poorly-controlled patients show failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). Diet therapy is the key in the adaptation/compensation stage. Protein- and fat-rich diet with a protein: fat: carbohydrate ratio being 15-25%: 40-50%: 30-40% along with the appropriate energy intake is recommended. The use of MCT oil and sodium pyruvate is also effective. The toxicity of carbohydrate is well known in the progression to CTLN2 if the consumption is over a long term or intense. Alcohol can also trigger CTLN2. Continuous intravenous hyperalimentation with high glucose concentration needs to be avoided. Administration of Glyceol® (an osmotic agent containing glycerol and fructose) is contraindicated. Because the intense treatment such as liver transplantation may become necessary to cure CTLN2, the effective preventative treatment during the adaptation/compensation stage is very important. At present, there is no report of a case with patients reported having the onset of CTLN2 who are on the diet therapy and under the appropriate medical support during the adaptation/compensation stage.
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Affiliation(s)
- Yoshiyuki Okano
- Okano Children's Clinic, and Department of Pediatrics, Hyogo College of Medicine, 1-20-1 Izumifutyu, Izumi 594-0071, Japan.
| | - Toshihiro Ohura
- Division of Pediatrics, Sendai City Hospital, 1-1-1 Asutonagamachi, Taihaku-ku, Sendai 982-8502, Japan; Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574, Japan
| | - Osamu Sakamoto
- Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan
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20
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Lee T, Takami Y, Yamada K, Kobayashi H, Hasegawa Y, Sasai H, Otsuka H, Takeshima Y, Fukao T. A Japanese case of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency who presented with severe metabolic acidosis and fatty liver without hypoglycemia. JIMD Rep 2019; 48:19-25. [PMID: 31392109 PMCID: PMC6606983 DOI: 10.1002/jmd2.12051] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/15/2019] [Accepted: 05/15/2019] [Indexed: 11/17/2022] Open
Abstract
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mHS deficiency) is a rare autosomal recessive inborn error of ketogenesis caused by a mutation in the HMGCS2 gene, which is characterized by non-(hypo)-ketotic hypoglycemia, lethargy, and hepatomegaly during acute infection and/or prolonged fasting. Clinical presentations are similar to fatty acid oxidation defects; however, diagnosis of mHS deficiency is difficult because of poor biochemical markers. We report the case of a 12-month-old Japanese boy with mHS deficiency who presented with a coma, and hepatomegaly, but no hypoglycemia after a febrile episode and poor oral intake. Metabolic acidosis and severe fatty liver were observed. Serum acylcarnitine analysis revealed a slightly decreased free carnitine (C0) level and an increased acetylcarnitine (C2) level. Urinary organic acid analysis revealed hypoketotic dicarboxylic aciduria, and increased excretions of glutarate, and, retrospectively, 4-hydroxy-6-methyl-2-pyrone. Although the patient did not present with hypoglycemia, the severe fatty liver and elevated free fatty acids to total ketone bodies ratio strongly suggested an inborn error of ketogenesis. In the analysis of the HMGCS2 gene, compound heterozygous mutations of c.130_131ins C (L44PfsX29) and c.1156_1157insC (L386PfsX73) were identified, which led to the diagnosis of mHS deficiency. He had recovered without any complication by the therapy, including intravenous glucose infusion. Unlike the previously reported cases of mHS deficiency, our case did not present with hypoglycemia and the fatty liver lasted over several months. mHS deficiency should be taken into consideration when a patient has severe metabolic acidosis and fatty liver with no or subtle ketosis, even without hypoglycemia.
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Affiliation(s)
- Tomoko Lee
- Department of PediatricsHyogo College of MedicineNishinomiyaJapan
| | - Yuichi Takami
- Department of PediatricsJapanese Red Cross Society Himeji HospitalHimejiJapan
| | - Kenji Yamada
- Department of PediatricsShimane University Faculty of MedicineIzumoJapan
| | - Hironori Kobayashi
- Department of PediatricsShimane University Faculty of MedicineIzumoJapan
| | - Yuki Hasegawa
- Department of PediatricsShimane University Faculty of MedicineIzumoJapan
| | - Hideo Sasai
- Department of PediatricsGraduate School of Medicine, Gifu UniversityGifuJapan
| | - Hiroki Otsuka
- Department of PediatricsGraduate School of Medicine, Gifu UniversityGifuJapan
| | | | - Toshiyuki Fukao
- Department of PediatricsGraduate School of Medicine, Gifu UniversityGifuJapan
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21
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Almási T, Guey LT, Lukacs C, Csetneki K, Vokó Z, Zelei T. Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (mut) deficiency. Orphanet J Rare Dis 2019; 14:84. [PMID: 31023387 PMCID: PMC6485056 DOI: 10.1186/s13023-019-1063-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 04/08/2019] [Indexed: 12/13/2022] Open
Abstract
Methylmalonic acidemia/aciduria (MMA) is a genetically heterogeneous group of inherited metabolic disorders biochemically characterized by the accumulation of methylmalonic acid. Isolated MMA is primarily caused by the deficiency of methylmalonyl-CoA mutase (MMA mut; EC 5.4.99.2). A systematic literature review and a meta-analysis were undertaken to assess and compile published epidemiological data on MMA with a focus on the MMA mut subtype (OMIM #251000). Of the 1114 identified records, 227 papers were assessed for eligibility in full text, 48 articles reported on disease epidemiology, and 39 articles were included into the quantitative synthesis. Implementation of newborn screening in various countries has allowed for the estimation of birth prevalence of MMA and its isolated form. Meta-analysis pooled point estimates of MMA (all types) detection rates were 0.79, 1.12, 1.22 and 6.04 per 100,000 newborns in Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively. The detection rate of isolated MMA was < 1 per 100,000 newborns in all regions with the exception of MENA where it approached 6 per 100,000 newborns. Few studies published data on the epidemiology of MMA mut, therefore no meta-analysis could have been performed on this subtype. Most of the identified papers reported birth prevalence estimates below 1 per 100,000 newborns for MMA mut. The systematic literature review clearly demonstrates that MMA and its subtypes are ultra-rare disorders.
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Affiliation(s)
- Tímea Almási
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary.
| | | | | | - Kata Csetneki
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary
| | - Zoltán Vokó
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary.,Department of Health Policy & Health Economics, Eötvös Loránd University, Budapest, Hungary
| | - Tamás Zelei
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary
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22
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Almási T, Guey LT, Lukacs C, Csetneki K, Vokó Z, Zelei T. Systematic literature review and meta-analysis on the epidemiology of propionic acidemia. Orphanet J Rare Dis 2019; 14:40. [PMID: 30760309 PMCID: PMC6375193 DOI: 10.1186/s13023-018-0987-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 12/21/2018] [Indexed: 02/06/2023] Open
Abstract
Propionic acidemia (PA, OMIM #606054) is a serious, life-threatening, inherited, metabolic disorder caused by the deficiency of the mitochondrial enzyme propionyl-coenzyme A (CoA) carboxylase (EC 6.4.1.3). The primary objective of this study was to conduct a systematic literature review and meta-analysis on the epidemiology of PA. The literature search was performed covering Medline, Embase, Cochrane Database of Systematic Reviews, CRD Database, Academic Search Complete, CINAHL and PROSPERO databases. Websites of rare disease organizations were also searched for eligible studies. Of the 2338 identified records, 188 articles were assessed for eligibility in full text, 43 articles reported on disease epidemiology, and 31 studies were included into the quantitative synthesis. Due to the rarity of PA, broadly targeted population-based prevalence studies are not available. Nonetheless, implementation of newborn screening programs has allowed the estimation of the birth prevalence data of PA across multiple geographic regions. The pooled point estimates indicated detection rates of 0.29; 0.33; 0.33 and 4.24 in the Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively. Our systematic literature review and meta-analysis confirm that PA is an ultra-rare disorder, with similar detection rates across all regions with the exception of the MENA region where the disease, similar to other inherited metabolic disorders, is more frequent.
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Affiliation(s)
- Tímea Almási
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary.
| | | | | | - Kata Csetneki
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary
| | - Zoltán Vokó
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary.,Department of Health Policy & Health Economics, Eötvös Loránd University, Budapest, Hungary
| | - Tamás Zelei
- Syreon Research Institute, Mexikói str. 65/A, Budapest, H-1142, Hungary
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Abuduxikuer K, Chen R, Wang ZL, Wang JS. Risk factors associated with mortality in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and clinical implications. BMC Pediatr 2019; 19:18. [PMID: 30642297 PMCID: PMC6330752 DOI: 10.1186/s12887-018-1383-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 12/26/2018] [Indexed: 02/07/2023] Open
Abstract
Background Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) has high prevalence in East Asia, and has been reported in other parts of the world. NICCD is also the most common form of genetic cholestasis among East Asians. There has been reports of mortalities or liver transplants associated with NICCD, but risk factors associated with poor outcome were unknown. Our objective is to report NICCD mortalities in a tertiary pediatric hepatology center, and to explore associated risk factors along with implications to clinical practice. Method This is a retrospective analysis of NICCD cases collected from June 2003 until January 2017 in the Children’s Hospital of Fudan University. Clinical, biochemical, and genetic data were compared between deceased cases and survivors without liver transplant. Results Sixty-one confirmed NICCD cases, including 52 cases in the survival group, and 9 cases in the mortality group, were included in the analysis. Mean age at referral in the mortality group was significantly higher when compared to the survival group (9.58 ± 5.03 VS 3.96 ± 3.13 months, p < 0.000). The proportion with infection in the mortality group was significantly higher than the survival group (p = 0.023). 44.4% of patients in the mortality group did not receive lactose-free and/or medium chain triglycerides enriched (LF/MCT) formula, and this percentage was significantly higher than the survival group (9.6%, p = 0.021). Mean platelet (PLT) count in the mortality group was significantly lower than the survival group (p = 0.010). Mean serum gamma-glutamyl transpeptidase (GGT), and total cholesterol (TCH) levels were significantly lower in the mortality group when compared to the survival group with p values of 0.001, and 0.019, respectively. Those who died had higher serum ammonium levels than survivors (p = 0.016). Mean level of citrulline was significantly lower in the mortality group compared to the survival group (p = 0.010). On the other hand, mean level of tyrosine was significantly higher in the mortality group than that of the survival group (p = 0.015). Conclusion Late referral, presence of infection, delayed treatment with LF/MCT formula, lower platelet count, lower levels of GGT, total cholesterol, blood citrulline, and higher level of blood ammonia and tyrosine, were associated with poor prognosis in NICCD. Electronic supplementary material The online version of this article (10.1186/s12887-018-1383-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kuerbanjiang Abuduxikuer
- Department of Hepatology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Rui Chen
- Department of Hepatology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China
| | - Zhong-Lin Wang
- Department of Infectious Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
| | - Jian-She Wang
- Department of Hepatology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
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Age-Specific Cut-off Values of Amino Acids and Acylcarnitines for Diagnosis of Inborn Errors of Metabolism Using Liquid Chromatography Tandem Mass Spectrometry. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3460902. [PMID: 30723736 PMCID: PMC6339774 DOI: 10.1155/2019/3460902] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 11/28/2018] [Accepted: 12/12/2018] [Indexed: 12/30/2022]
Abstract
Liquid Chromatography tandem mass spectrometry (LC-MS/MS) is used for the diagnosis of more than 30 inborn errors of metabolisms (IEMs). Accurate and reliable diagnosis of IEMs by quantifying amino acids (AAs) and acylcarnitines (ACs) using LC-MS/MS systems depend on the establishment of age-specific cut-offs of the analytes. This study aimed to (1) determine the age-specific cut-off values of AAs and ACs in Bangladesh and (2) validate the LC-MS/MS method for diagnosis of the patients with IEMs. A total of 570 enrolled healthy participants were divided into 3 age groups, namely, (1) newborns (1-7 days), (2) 8 days–7 years, and (3) 8–17 years, to establish the age-specific cut-offs for AAs and ACs. Also, 273 suspected patients with IEMs were enrolled to evaluate the reliability of the established cut-off values. Quantitation of AAs and ACs was performed on an automated LC-MS/MS system using dried blood spot (DBS) cards. Then the specimens of the enrolled clinically suspected patients were analyzed by the established method. Nine patients came out as screening positive for different IEMs, including two borderline positive cases of medium-chain acyl-CoA dehydrogenase deficiency (MCAD). A second-tier test for confirmation of the screening positive cases was conducted by urinary metabolic profiling using gas chromatography- mass spectrometry (GC-MS). Out of 9 cases that came out as screening positive by LC-MS/MS, seven cases were confirmed by urinary GC-MS analysis including 3 cases with phenylketonuria, 1 with citrullinemia type II, 1 with methylmalonic acidemia, 1 with isovaleric acidemia and 1 with carnitine uptake defect. Two borderline positive cases with MCAD were found negative by urinary GC-MS analysis. In conclusion, along with establishment of a validated LC-MS/MS method for quantitation of AAs and ACs from the DBS cards, the study also demonstrates the presence of predominantly available IEMs in Bangladesh.
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Tong F, Jiang PP, Yang RL, Huang XL, Zhou XL, Hong F, Qian GL, Zhao ZY, Shu Q. [Medium-chain acyl-CoA dehydrogenase deficiency: neonatal screening and follow-uP]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2019; 21:52-57. [PMID: 30675864 PMCID: PMC7390178 DOI: 10.7499/j.issn.1008-8830.2019.01.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 11/14/2018] [Indexed: 06/09/2023]
Abstract
OBJECTIVE To investigate the epidemiological characteristics, phenotype, genotype, and prognosis of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in the Chinese population. METHODS A retrospective analysis was performed for the clinical data of the neonates who underwent screening with high-performance liquid chromatography-tandem mass spectrometry from January 2009 to June 2018 and were diagnosed with MCADD by gene detection. RESULTS A total of 2 674 835 neonates underwent neonatal screening, among whom 12 were diagnosed with MCADD. Gene detection was performed for 10 neonates with MCADD and found 13 mutation types at 16 mutation sites of the ACADM gene, among which there were 7 reported mutations (p.T150Rfs*4, p.M1V, p.R206C, p.R294T, p.G310R, p.M328V, and p.G362E), 5 novel mutations (p.N194D, p.A324P, p.N366S, c.118+3A>G, and c.387+1del G), and 1 exon 11 deletion; p.T150Rfs*4 was the most common mutation (4/16). The detection rate of mutation sites in the ACADM gene was 80%. No phenotype-genotype correlation was observed. Dietary guidance and symptomatic treatment were given after confirmed diagnosis. No acute metabolic imbalance was observed within 4-82 months of follow-up. All neonates had good prognosis except one who had brain dysplasia. CONCLUSIONS MCADD is relatively rare in southern China, and p.T150Rfs*4 is a common mutation in the Chinese population. Cases with positive screening results should be evaluated by octanoylcarnitine C8 value and gene detection.
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Affiliation(s)
- Fan Tong
- Department of Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China.
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Waters D, Adeloye D, Woolham D, Wastnedge E, Patel S, Rudan I. Global birth prevalence and mortality from inborn errors of metabolism: a systematic analysis of the evidence. J Glob Health 2018; 8:021102. [PMID: 30479748 PMCID: PMC6237105 DOI: 10.7189/jogh.08.021102] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background Inborn errors of metabolism (IEM) are a group of over 500 heterogeneous disorders resulting from a defect in functioning of an intermediate metabolic pathway. Individually rare, their cumulative incidence is thought to be high, but it has not yet been estimated globally. Although outcomes can often be good if recognised early, IEM carry a high fatality rate if not diagnosed. As a result, IEM may contribute significantly to the burden of non-communicable childhood morbidity. Methods We conducted a systematic literature review of birth prevalence and case fatality of IEM globally, with search dates set from 1980 to 2017. Using random-effects meta-analysis, we estimated birth prevalence of separate classes of IEM and all-cause IEM, split by geographical region. We also estimated levels of parental consanguinity in IEM cases and global case fatality rates and resultant child deaths from all-cause IEM. Findings 49 studies met our selection criteria. We estimate the global birth prevalence of all-cause IEM to be 50.9 per 100 000 live births (95% confidence intervals (CI) = 43.4-58.4). Regional pooled birth prevalence rates showed the highest rates of IEM to be in the Eastern Mediterranean region (75.7 per 100 000 live births, 95% CI = 50.0-101.4), correlating with a higher observed rate of parental consanguinity in studies from this area. We estimate case fatality rates to be 33% or higher in low- and middle-income countries (LMICs), resulting in a minimum of 23 529 deaths from IEM per year globally (95% CI = 20 382-27 427), accounting for 0.4% of all child deaths worldwide. Conclusions IEM represent a significant cause of global child morbidity and mortality, comprising a notable proportion of child deaths currently not delineated in global modelling efforts. Our data highlight the need for policy focus on enhanced laboratory capacity for screening and diagnosis, community interventions to tackle parental consanguinity, and increased awareness and knowledge regarding management of IEM, particularly in LMICs.
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Affiliation(s)
| | | | - Daisy Woolham
- Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh Scotland, UK.,These authors contributed equally
| | - Elizabeth Wastnedge
- Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh Scotland, UK.,These authors contributed equally
| | - Smruti Patel
- Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh Scotland, UK.,These authors contributed equally
| | - Igor Rudan
- Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh Scotland, UK.,These authors contributed equally
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Uemura Y, Kakuta N, Tanaka K, Tsutsumi YM. Anesthetic management of a patient with methylmalonic acidemia: a case report. JA Clin Rep 2018; 4:71. [PMID: 32025901 PMCID: PMC6966740 DOI: 10.1186/s40981-018-0209-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 09/24/2018] [Indexed: 11/28/2022] Open
Abstract
Background Methylmalonic acidemia (MMA) is a metabolic disorder of organic acids and is characterized by the accumulation of methylmalonic acids. Case presentation The patient was a 19-year-old female diagnosed with severe MMA at 3 days of age, who was scheduled for renal replacement therapy. Preoperatively, there was no evidence of metabolic acidosis or electrolyte abnormalities. Glucose was administered preoperatively following a 6-h fast. Anesthesia was administered using thiamylal, remifentanil, rocuronium, and sevoflurane. After tracheal intubation, the patient underwent an ultrasound-guided bilateral rectus sheath block with ropivacaine. A drop in blood sugar level was treated with 5% glucose. Extubation was performed after intravenous administration of sugammadex. Conclusions We report the anesthetic management of a patient with MMA using a combination of general anesthesia and rectus sheath block.
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Affiliation(s)
- Yuta Uemura
- Department of Anesthesiology, Tokushima University, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan
| | - Nami Kakuta
- Department of Anesthesiology, Tokushima University, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan
| | - Katsuya Tanaka
- Department of Anesthesiology, Tokushima University, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan
| | - Yasuo M Tsutsumi
- Department of Anesthesiology, Tokushima University, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan.
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Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening. Mol Genet Metab Rep 2018; 16:5-10. [PMID: 29946514 PMCID: PMC6014585 DOI: 10.1016/j.ymgmr.2018.05.003] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 05/08/2018] [Accepted: 05/08/2018] [Indexed: 12/14/2022] Open
Abstract
Background Expanded newborn screening (ENBS) utilizing tandem mass spectrometry (MS/MS) for inborn metabolic diseases (IMDs), such as organic acidemias (OAs), fatty acid oxidation disorders, (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in many Asian countries. This study aimed to determine the incidence rates of OAs, FAODs, and AAs in Asian countries and Germany using selective screening and ENBS records. Materials and methods Selective screening for IMDs using gas chromatography–mass spectrometry and MS/MS was performed among patients suspected to be afflicted in Asian countries (including Japan, Vietnam, China, and India) between 2000 and 2015, and the results from different countries were compared. Similarly, ENBS results from Japan, South Korea, Taiwan, and Germany were compared. Additionally, the results of selective screening and ENBS in Japan were compared. Results Among 39,270 patients who underwent selective screening, IMDs were detected in 1170. Methylmalonic acidemia was frequently identified in several countries, including Japan (81/377 diagnosed IMDs), China (94/216 IMDs), and India (72/293 IMDs). In Vietnam, however, β-ketothiolase deficiency was particularly frequent (33/250 IMDs). ENBS yielded differences in overall IMD rates by country: 1:8557 in Japan, 1:7030 in Taiwan, 1:13,205 in South Korea, and 1:2200 in Germany. Frequently discovered diseases included propionic acidemia (PPA) and phenylketonuria (PKU) in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I in South Korea, and PKU and medium-chain acyl-CoA dehydrogenase deficiency in Germany. Furthermore, in Japan, selective screening and ENBS yielded respective PPA frequencies of 14.7% and 49.4% among all organic acidemias. Conclusion The incidence rates of IMDs vary by country. Moreover, the disease spectra of IMDs detected via selective screening differ from those detected via ENBS.
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Key Words
- 2-OH-GA, 2-hydroxyglutaric acidemia
- 4-OH-BA, 4-hydroxybutyric acidemia
- AA, amino acid disorder
- ASA, argininosuccinic aciduria
- Amino acid disorder
- BKTD, β-ketothiolase deficiency
- CACT, carnitine-acylcarnitine translocase
- CPT1, carnitine palmitoyltransferase I
- CPT2, carnitine palmitoyltransferase II
- CTLN1, citrullinemia type I
- ENBS, expanded newborn screening
- Expanded newborn screening
- FAOD, fatty acid oxidation disorder
- Fatty acid oxidation disorder
- GA1, glutaric acidemia type I
- GA2, glutaric acidemia type II
- GC/MS, gas chromatography–mass spectrometry
- HAD, 3-hydoxyacyl-CoA dehydrogenase
- HCU, homocystinuria
- HMGL, 3-hydroxy-3-methylglutaryl-CoA lyase
- HMGS, 3-hydroxy-3-methylglutaryl-CoA synthetase
- IMD, inherited metabolic disease
- Incidence rate
- Inherited metabolic disease
- LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase
- MCAD, medium-chain acyl-CoA dehydrogenase
- MCCD, 3-methylcrotonyl-CoA carboxylase deficiency
- MCD, multiple carboxylase deficiency
- MGA, 3-methylglutaconic aciduria
- MMA, methylmalonic acidemia
- MS/MS, tandem mass spectrometry
- MSUD, maple syrup urine disease
- NBS, newborn screening
- OA, organic acidemia
- OXPA, 5-oxoprolinemia
- Organic acidemia
- PCD, primary carnitine deficiency
- PKU, phenylketonuria
- PPA, propionic acidemia
- SCAD, short-chain acyl-CoA dehydrogenase
- TFP, trifunctional protein
- UCD, urea cycle disorder
- VLCAD, very long-chain acyl-CoA dehydrogenase
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Abstract
Methylmalonic acidemia (MMA) is a lethal, severe heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism with poor prognosis. Two main forms of the disease have been identified, isolated methylmalonic acidurias and combined methylmalonic aciduria and homocystinuria, which is respectively caused by different gene mutations. Here, we review the improvement of pathogenesis, diagnosis and treatment in MMA. Importantly, the reported epidemiological data of MMA patients in China and the hot mutation sites in Chinese patients are listed, which will aid in improving healthcare of Chinese patients in the future. c.729_730insTT was the most common mutation in Chinese isolated MMA patients, while c.609G>A and c.658_660delAAG were in Chinese cblC type patients according to unrelated studies. The estimated newborn screening incidence was reported to be 1:26,000, 1:3,920, 1:11,160, 1:6,032 respectively in Beijing and Shanghai, Shandong province, Taian district, and Henan province of China. Alternatively, when patients with suspected inherited metabolic diseases were used as the screened sample, the relatively high incidence 0.3% and 1.32% were respectively obtained in southern China and throughout all the provinces of mainland China and Macao with the exception of five provinces (Hainan, Neimenggu, Tibet, Ningxia, and Hong Kong).
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Affiliation(s)
| | | | - Jinxiang Han
- Shandong Academy of Medical Science, Shandong Medical Biotechnological Center, Key Laboratory for Biotech Drugs of the Ministry of Health, Ji'nan, China
- Address correspondence to:Dr. Jinxiang Han, Shandong Academy of Medical Science, 18877 Jingshi Road, Ji'nan 250062, China. E-mail:
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Yang CJ, Wei N, Li M, Xie K, Li JQ, Huang CG, Xiao YS, Liu WH, Chen XG. Diagnosis and therapeutic monitoring of inborn errors of metabolism in 100,077 newborns from Jining city in China. BMC Pediatr 2018. [PMID: 29534692 PMCID: PMC5850921 DOI: 10.1186/s12887-018-1090-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mandatory newborn screening for metabolic disorders has not been implemented in most parts of China. Newborn mortality and morbidity could be markedly reduced by early diagnosis and treatment of inborn errors of metabolism (IEM). Methods of screening for IEM by tandem mass spectrometry (MS/MS) have been developed, and their advantages include rapid testing, high sensitivity, high specificity, high throughput, and low sample volume (a single dried blood spot). METHODS Dried blood spots of 100,077 newborns obtained from Jining city in 2014-2015 were screened by MS/MS. The screening results were further confirmed by clinical symptoms and biochemical analysis in combination with the detection of neonatal deficiency in organic acid, amino acid, or fatty acid metabolism and DNA analysis. RESULTS The percentages of males and females among the 100,077 infants were 54.1% and 45.9%, respectively. Cut-off values were established by utilizing the percentile method. The screening results showed that 98,764 newborns were healthy, and 56 out of the 1313 newborns with suspected IEM were ultimately diagnosed with IEM. Among these 56 newborns, 19 (1:5267) had amino acid metabolism disorders, 26 (1:3849) had organic acid metabolism disorders, and 11 (1:9098) had fatty acid oxidation disorders. In addition, 54 patients with IEM were found to carry mutations, and the other 2 patients had argininemia. CONCLUSIONS Fifty-six cases of metabolic disorders in Jining were confirmed via newborn screening (NBS) by MS/MS. Early diagnosis and treatment are crucial for the survival and well-being of affected children. A nationwide NBS program using MS/MS is recommended, especially in poor areas of China.
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Affiliation(s)
- Chi-Ju Yang
- Center of Neonatal Disease Screening, Maternal and Child Health Care Hospital, Number 12, Gongxiao Road, Jining, Shandong Province, People's Republic of China
| | - Na Wei
- Clinical Laboratory of Linyi People's Hospital, Linyi, Shandong Province, People's Republic of China
| | - Ming Li
- Center of Neonatal Disease Screening, Maternal and Child Health Care Hospital, Number 12, Gongxiao Road, Jining, Shandong Province, People's Republic of China
| | - Kun Xie
- Zhejiang Biosan Biochemical Technologies Co., Ltd., Hangzhou, Zhejiang Province, People's Republic of China
| | - Jian-Qiu Li
- Zhejiang Biosan Biochemical Technologies Co., Ltd., Hangzhou, Zhejiang Province, People's Republic of China
| | - Cheng-Gang Huang
- Zhejiang Biosan Biochemical Technologies Co., Ltd., Hangzhou, Zhejiang Province, People's Republic of China
| | - Yong-Sheng Xiao
- Zhejiang Biosan Biochemical Technologies Co., Ltd., Hangzhou, Zhejiang Province, People's Republic of China
| | - Wen-Hua Liu
- Zhejiang Biosan Biochemical Technologies Co., Ltd., Hangzhou, Zhejiang Province, People's Republic of China
| | - Xi-Gui Chen
- Center of Neonatal Disease Screening, Maternal and Child Health Care Hospital, Number 12, Gongxiao Road, Jining, Shandong Province, People's Republic of China.
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Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry. Int J Neonatal Screen 2018; 4:5. [PMID: 33072931 PMCID: PMC7548893 DOI: 10.3390/ijns4010005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 01/12/2018] [Indexed: 01/31/2023] Open
Abstract
Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial NBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although their citrulline values exceeded the mean of the normal neonates and 80% of them surpassed +3 SD (standard deviation), all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in patients with NICCD compared to the control. By evaluating two indicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an estimated index comprising citrulline values and citrulline to total amino acid ratios could assure NICCD detection by NBS.
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Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Maruyama S, Noguchi A, Awaya T, Ishige M, Ishige N, Musha I, Ajihara S, Ohtake A, Naito E, Hamada Y, Kono T, Asada T, Sasai H, Fukao T, Fujiki R, Ohara O, Bo R, Yamada K, Kobayashi H, Hasegawa Y, Yamaguchi S, Takayanagi M, Hata I, Shigematsu Y, Kobayashi M. Newborn screening for carnitine palmitoyltransferase II deficiency using (C16+C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity. Mol Genet Metab 2017; 122:67-75. [PMID: 28801073 DOI: 10.1016/j.ymgme.2017.07.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/27/2017] [Accepted: 07/28/2017] [Indexed: 11/21/2022]
Abstract
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.
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Affiliation(s)
- Go Tajima
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
| | - Keiichi Hara
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; Department of Pediatrics, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama-cho, Kure 737-0023, Japan.
| | - Miyuki Tsumura
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Reiko Kagawa
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Satoshi Okada
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Nobuo Sakura
- Nursing House for Severe Motor and Intellectual Severities Suzugamine, 104-27 Minaga, Itsukaichi-cho, Saeki-ku, Hiroshima 731-5122, Japan.
| | - Shinsuke Maruyama
- Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
| | - Atsuko Noguchi
- Department of Pediatrics, Akita University Graduate School of Medicine, 44-2 Hasunuma, Hiroomote, Akita 010-8543, Japan.
| | - Tomonari Awaya
- Department of Pediatrics, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
| | - Mika Ishige
- Department of Pediatrics and Child Health, Nihon University School of Medicine, 1-6 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8309, Japan.
| | - Nobuyuki Ishige
- Division of Newborn Screening, Tokyo Health Service Association, 1-2-59 Ichiga-Sadohara, Shinjuku-ku, Tokyo 162-8460, Japan.
| | - Ikuma Musha
- Department of Pediatrics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Saitama 350-0495, Japan.
| | - Sayaka Ajihara
- Department of Pediatrics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Saitama 350-0495, Japan.
| | - Akira Ohtake
- Department of Pediatrics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Saitama 350-0495, Japan.
| | - Etsuo Naito
- Department of Pediatrics, Japanese Red Cross Tokushima Hinomine Rehabilitation Center, 4-1 Shinbiraki, Chuden-cho, Komatsushima, Tokushima 773-0015, Japan.
| | - Yusuke Hamada
- Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
| | - Tomotaka Kono
- Division of Endocrinology and Metabolism, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama 330-8777, Japan.
| | - Tomoko Asada
- Department of Pediatrics, Faculty of Medicine, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan.
| | - Hideo Sasai
- Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
| | - Toshiyuki Fukao
- Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
| | - Ryoji Fujiki
- Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
| | - Osamu Ohara
- Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
| | - Ryosuke Bo
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo 693-8501, Japan; Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Kenji Yamada
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo 693-8501, Japan.
| | - Hironori Kobayashi
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo 693-8501, Japan.
| | - Yuki Hasegawa
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo 693-8501, Japan.
| | - Seiji Yamaguchi
- Department of Pediatrics, Shimane University Faculty of Medicine, 89-1 En-ya-cho, Izumo 693-8501, Japan.
| | - Masaki Takayanagi
- Department of Nursing, Faculty of Health Care and Medical Sport, Teikyo Heisei University, 6-19 Chiharadai-Nishi, Ichihara 290-0192, Japan.
| | - Ikue Hata
- Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Fukui 910-1193, Japan.
| | - Yosuke Shigematsu
- Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji-cho, Fukui 910-1193, Japan.
| | - Masao Kobayashi
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
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Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death. J Hum Genet 2017; 62:989-995. [DOI: 10.1038/jhg.2017.79] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 06/27/2017] [Accepted: 06/27/2017] [Indexed: 11/08/2022]
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Tashiro K, Kaida Y, Yamagishi SI, Tanaka H, Yokoro M, Yano J, Sakai K, Kurokawa Y, Taguchi K, Nakayama Y, Inokuchi T, Fukami K. L-Carnitine Supplementation Improves Self-Rating Depression Scale Scores in Uremic Male Patients Undergoing Hemodialysis. LETT DRUG DES DISCOV 2017; 14:737-742. [PMID: 28670223 PMCID: PMC5470074 DOI: 10.2174/1570180814666170216102632] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/05/2017] [Accepted: 02/17/2017] [Indexed: 11/25/2022]
Abstract
Background: Depression is highly prevalent in uremic patients undergoing hemodialysis (HD). We previously found that low free-carnitine levels are associated with depression severity in male patients undergoing HD. However, whether L-carnitine supplementation improves the depression state in male patients undergoing HD remains unclear. Methods: Sixteen male patients undergoing HD were orally administered 900 mg L-carnitine daily or intravenously administered 1000 mg L-carnitine immediately after undergoing HD for 3 months. The depression state and various types of carnitine levels were evaluated using the self-rating depression scale (SDS) and tandem mass spectrometry, respectively, at baseline and 3 months after treatment. Results: L-carnitine supplementation significantly increased serum levels of free and other acylcarnitine types, associated with improved SDS scores in male patients undergoing HD. Univariate analysis revealed that low baseline butyryl- and isovaleryl-/2-methylbutyryl-carnitine levels were significantly correlated with SDS scores after treatment. Multiple regression analysis revealed that butyryl-carnitine levels were a sole independent predictor of SDS scores after treatment (r2 = 0.533). Conclusion: L-carnitine supplementation for 3 months improved the depression state in uremic male patients undergoing HD. Thus, low butyryl-carnitine levels may predict the clinical response to L-carnitine supplementation in male patients undergoing HD and who have mild depression.
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Affiliation(s)
| | | | - Sho-Ichi Yamagishi
- Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
| | | | | | - Junko Yano
- Department of Medicine, Division of Nephrology
| | | | | | | | | | | | - Kei Fukami
- Department of Medicine, Division of Nephrology
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Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Hata I, Shigematsu Y, Kobayashi M. Screening of MCAD deficiency in Japan: 16years' experience of enzymatic and genetic evaluation. Mol Genet Metab 2016; 119:322-328. [PMID: 27856190 DOI: 10.1016/j.ymgme.2016.10.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 10/18/2016] [Accepted: 10/18/2016] [Indexed: 10/20/2022]
Abstract
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.
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Affiliation(s)
- Go Tajima
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
| | - Keiichi Hara
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan; Department of Pediatrics, National Hospital Organization Kure Medical Center, 3-1 Aoyama-cho, Kure 737-0023, Japan.
| | - Miyuki Tsumura
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Reiko Kagawa
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Satoshi Okada
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Nobuo Sakura
- Nursing House for Severe Motor and Intellectual Severities, Suzugamine, 104-27 Minaga, Itsukaichi-cho, Saeki-ku, Hiroshima 731-5122, Japan.
| | - Ikue Hata
- Department of Pediatrics, School of Medical Sciences, University of Fukui, 23 Shimogogetsu, Matsuoka, Eiheiji-cho, Fukui 910-1193, Japan.
| | - Yosuke Shigematsu
- Department of Pediatrics, School of Medical Sciences, University of Fukui, 23 Shimogogetsu, Matsuoka, Eiheiji-cho, Fukui 910-1193, Japan.
| | - Masao Kobayashi
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
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Purevsuren J, Bolormaa B, Narantsetseg C, Batsolongo R, Enkhchimeg O, Bayalag M, Hasegawa Y, Shintaku H, SeijiYamaguchi. The first Mongolian cases of phenylketonuria in selective screening of inborn errors of metabolism. Mol Genet Metab Rep 2016; 9:71-74. [PMID: 27830119 PMCID: PMC5094263 DOI: 10.1016/j.ymgmr.2016.10.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 10/21/2016] [Accepted: 10/21/2016] [Indexed: 12/01/2022] Open
Abstract
Background Inborn errors of metabolism (IEM) are rare genetic disorders in which a single gene defect causes a clinically significant block in a metabolic pathway. Clinical problems arise due to either accumulation of substrates that are toxic or interfere with normal function, or deficiency of the products that are used to synthesize essential compounds. There is no report of screening results or confirmed cases of IEM in Mongolia. Only pilot study of newborn screening for congenital hypothyroidism was implemented in Mongolia, where the incidence of congenital hypothyroidism is calculated to be 1:3057 in Mongolia. Methods Two hundred twenty-three Mongolian patients, who had developmental delay, psychomotor retardation with unknown cause, seizures, hypotonia or liver dysfunction, were studied. Urinary organic acid analysis was performed in all cases using gas chromatography mass spectrometric (GC/MS) analysis. Blood amino acids and acylcarnitines were checked in the patients who had abnormal GC/MS analyses. Mutation analysis was done in the patients, who were suspected having specific inborn errors of metabolism by mass spectrometric analysis. Results One hundred thirty-nine children had normal urinary organic acid analyses. Thirty one had metabolites of valproic acid, 17 had non- or hypoketotic dicarboxylic aciduria, 14 had tyrosiluria, 12 had ketosis, 4 had elevation of lactate and pyruvate, 3 had increased excretion of urinary glycerol or methylmalonic acids, respectively, and 2 had elevation of phenylacetate and phenyllactate. We checked blood amino acids and acylcarnitines in 38 patients, which revealed phenylketonuria (PKU) in 2 patients, and one with suspected citrin deficiency. Mutation analysis in PAH was done in 2 patients with PKU, and previously reported p.R243Q, p.Y356X, p.V399V, p.A403V mutations were detected. Discussion In conclusion, these were the first genetically confirmed cases of PKU in Mongolia, and the study suggested that the newborn screening program for PKU was significant because it enabled early treatment dietary restriction, specialized formulas and other medical management for prevention of neurological handicaps in these children.
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Affiliation(s)
- Jamiyan Purevsuren
- Chidlren's Hospital, National Center for Maternal and Child Health, Bayangol district, Ulaanbaatar 16060, Mongolia
| | - Baasandai Bolormaa
- Chidlren's Hospital, National Center for Maternal and Child Health, Bayangol district, Ulaanbaatar 16060, Mongolia
| | - Chogdon Narantsetseg
- Chidlren's Hospital, National Center for Maternal and Child Health, Bayangol district, Ulaanbaatar 16060, Mongolia
| | - Renchindorj Batsolongo
- Chidlren's Hospital, National Center for Maternal and Child Health, Bayangol district, Ulaanbaatar 16060, Mongolia
| | - Ochirbat Enkhchimeg
- Chidlren's Hospital, National Center for Maternal and Child Health, Bayangol district, Ulaanbaatar 16060, Mongolia
| | - Munkhuu Bayalag
- Chidlren's Hospital, National Center for Maternal and Child Health, Bayangol district, Ulaanbaatar 16060, Mongolia
| | - Yuki Hasegawa
- Department of Pediatrics, Shimane University School of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan
| | - Haruo Shintaku
- Department of Pediatrics, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
| | - SeijiYamaguchi
- Department of Pediatrics, Shimane University School of Medicine, 89-1 Enya, Izumo, Shimane 693-8501, Japan
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Disruption of Slc52a3 gene causes neonatal lethality with riboflavin deficiency in mice. Sci Rep 2016; 6:27557. [PMID: 27272163 PMCID: PMC4897618 DOI: 10.1038/srep27557] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 05/18/2016] [Indexed: 12/03/2022] Open
Abstract
Homeostasis of riboflavin should be maintained by transporters. Previous in vitro studies have elucidated basic information about riboflavin transporter RFVT3 encoded by SLC52A3 gene. However, the contribution of RFVT3 to the maintenance of riboflavin homeostasis and the significance in vivo remain unclear. Here, we investigated the physiological role of RFVT3 using Slc52a3 knockout (Slc52a3−/−) mice. Most Slc52a3−/− mice died with hyperlipidemia and hypoglycemia within 48 hr after birth. The plasma and tissue riboflavin concentrations in Slc52a3−/− mice at postnatal day 0 were dramatically lower than those in wild-type (WT) littermates. Slc52a3−/− fetuses showed a lower capacity of placental riboflavin transport compared with WT fetuses. Riboflavin supplement during pregnancy and after birth reduced neonatal death and metabolic disorders. To our knowledge, this is the first report to indicate that Rfvt3 contributes to placental riboflavin transport, and that disruption of Slc52a3 gene caused neonatal mortality with hyperlipidemia and hypoglycemia owing to riboflavin deficiency.
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Kobayashi H, Fukuda S, Yamada K, Hasegawa Y, Takahashi T, Purevsuren J, Yamaguchi S. Clinical Features of Carnitine Deficiency Secondary to Pivalate-Conjugated Antibiotic Therapy. J Pediatr 2016; 173:183-7. [PMID: 27059912 DOI: 10.1016/j.jpeds.2016.02.080] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 01/11/2016] [Accepted: 02/29/2016] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To examine the clinical features and risk factors of secondary carnitine deficiency due to long-term use of pivalate-conjugated antibiotics (PCAs). STUDY DESIGN We retrospectively investigated the age, clinical manifestations, PCA administration period, and background of 22 patients who showed a decrease in free carnitine (C0; ≤20 μmol/L) concomitant with an increase in pivaloyl carnitine (detected as C5-acylcarnitine) on acylcarnitine analysis with tandem mass spectrometry. Administration of PCAs was confirmed in all cases. RESULTS The patients ranged in age from 2 months to 42 years (median, 1 year, 11 months). One patient was aged <1 year, 10 patients were aged 1 year, 1 patient was aged 2 years, and 10 patients were aged ≥3 years. Nine patients had known underlying disease. Fourteen patients developed acute encephalopathy, 13 with accompanying hypoglycemia. Four patients presented with hypoglycemia without signs of encephalopathy. C0 values ranged from 0.25 to 19.66 μmol/L (median, 1.31 μmol/L); C5-acylcarnitine values, from 0.43 to 11.92 μmol/L (median, 3.23 μmol/L). There was no correlation between the PCA administration period and C0 level. Ten patients developed the symptoms after PCA administration for ≥14 days, whereas 6 patients showed symptoms after PCA administration for <14 days. CONCLUSION Carnitine deficiency resulting from PCA treatment was most frequently observed in 1-year-old infants. Most patients manifested acute encephalopathy and/or hypoglycemia. Some patients developed carnitine deficiency after PCA administration for <14 days.
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Affiliation(s)
- Hironori Kobayashi
- Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan.
| | - Seiji Fukuda
- Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
| | - Kenji Yamada
- Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
| | - Yuki Hasegawa
- Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
| | - Tomoo Takahashi
- Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
| | - Jamiyan Purevsuren
- Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
| | - Seiji Yamaguchi
- Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
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Hara K, Tajima G, Okada S, Tsumura M, Kagawa R, Shirao K, Ohno Y, Yasunaga S, Ohtsubo M, Hata I, Sakura N, Shigematsu Y, Takihara Y, Kobayashi M. Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan. Mol Genet Metab 2016; 118:9-14. [PMID: 26947917 DOI: 10.1016/j.ymgme.2015.12.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 12/25/2015] [Accepted: 12/25/2015] [Indexed: 12/30/2022]
Abstract
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.
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Affiliation(s)
- Keiichi Hara
- Department of Pediatrics, National Hospital Organization Kure Medical Center, Kure 737-0023, Japan; Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Go Tajima
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Satoshi Okada
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Miyuki Tsumura
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Reiko Kagawa
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Kenichiro Shirao
- Shirao Clinic of Pediatrics and Pediatric Allergy, Department of Pediatrics, Hiroshima 734-0023, Japan
| | - Yoshinori Ohno
- Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
| | - Shin'ichiro Yasunaga
- Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
| | - Motoaki Ohtsubo
- Department of Food and Nutrition, Beppu University, Ooita 874-0501, Japan
| | - Ikue Hata
- Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Nobuo Sakura
- Nursing House for Severe Motor and Intellectual Disabilities SUZUGAMINE, Hiroshima 731-5122, Japan
| | - Yosuke Shigematsu
- Department of Health Science, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Yoshihiro Takihara
- Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
| | - Masao Kobayashi
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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Ding Y, Li X, Liu Y, Hua Y, Song J, Wang L, Li M, Qin Y, Yang Y. Seven novel mutations of the SMPD1 gene in four Chinese patients with Niemann-Pick disease type A and prenatal diagnosis for four fetuses. Eur J Med Genet 2016; 59:263-8. [DOI: 10.1016/j.ejmg.2015.11.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/12/2015] [Accepted: 11/26/2015] [Indexed: 12/16/2022]
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Yamada K, Kobayashi H, Bo R, Takahashi T, Purevsuren J, Hasegawa Y, Taketani T, Fukuda S, Ohkubo T, Yokota T, Watanabe M, Tsunemi T, Mizusawa H, Takuma H, Shioya A, Ishii A, Tamaoka A, Shigematsu Y, Sugie H, Yamaguchi S. Clinical, biochemical and molecular investigation of adult-onset glutaric acidemia type II: Characteristics in comparison with pediatric cases. Brain Dev 2016; 38:293-301. [PMID: 26403312 DOI: 10.1016/j.braindev.2015.08.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 08/06/2015] [Accepted: 08/13/2015] [Indexed: 01/14/2023]
Abstract
INTRODUCTION An increasing number of adult patients have been diagnosed with fatty acid β-oxidation disorders with the rising use of diagnostic technologies. In this study, clinical, biochemical, and molecular characteristics of 2 Japanese patients with adult-onset glutaric acidemia type II (GA2) were investigated and compared with those of pediatric cases. METHODS The patients were a 58-year-old male and a 31-year-old male. In both cases, episodes of myopathic symptoms, including myalgia, muscle weakness, and liver dysfunction of unknown cause, had been noted for the past several years. Muscle biopsy, urinary organic acid analysis (OA), acylcarnitine (AC) analysis in dried blood spots (DBS) and serum, immunoblotting, genetic analysis, and an in vitro probe acylcarnitine (IVP) assay were used for diagnosis and investigation. RESULTS In both cases, there was no obvious abnormality of AC in DBS or urinary OA, although there was a increase in medium- and long-chain ACs in serum; also, fat deposits were observed in the muscle biopsy. Immunoblotting and gene analysis revealed that both patients had GA2 due to a defect in electron transfer flavoprotein dehydrogenase (ETFDH). The IVP assay indicated no special abnormalities in either case. CONCLUSION Late-onset GA2 is separated into the intermediate and myopathic forms. In the myopathic form, episodic muscular symptoms or liver dysfunction are primarily exhibited after later childhood. Muscle biopsy and serum (or plasma) AC analysis allow accurate diagnosis in contrast with other biochemical tests, such as analysis of AC in DBS, urinary OA, or the IVP assay, which show fewer abnormalities in the myopathic form compared to intermediate form.
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Affiliation(s)
- Kenji Yamada
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
| | - Hironori Kobayashi
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Ryosuke Bo
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Tomoo Takahashi
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Jamiyan Purevsuren
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Yuki Hasegawa
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Takeshi Taketani
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Seiji Fukuda
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | - Takuya Ohkubo
- Department of Neurology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Takanori Yokota
- Department of Neurology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Mutsufusa Watanabe
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Sumida-ku, Tokyo, Japan
| | - Taiji Tsunemi
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - Hiroshi Takuma
- Department of Neurology, University of Tsukuba Faculty of Medicine, Tsukuba, Ibaraki, Japan
| | - Ayako Shioya
- Department of Neurology, University of Tsukuba Faculty of Medicine, Tsukuba, Ibaraki, Japan
| | - Akiko Ishii
- Department of Neurology, University of Tsukuba Faculty of Medicine, Tsukuba, Ibaraki, Japan
| | - Akira Tamaoka
- Department of Neurology, University of Tsukuba Faculty of Medicine, Tsukuba, Ibaraki, Japan
| | - Yosuke Shigematsu
- Department of Pediatrics, University of Fukui Faculty of Medical Sciences, Yoshida-gun, Fukui, Japan
| | - Hideo Sugie
- Faculty of Health and Medical Sciences, Tokoha University, Hamamatsu, Shizuoka, Japan
| | - Seiji Yamaguchi
- Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
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Abstract
Defects in the human gene encoding methylmalonyl-CoA mutase enzyme (MCM) give rise to a rare autosomal recessive inherited disorder of propionate metabolism termed mut methylmalonic acidemia (MMA). Patients with mut MMA have been divided into two subgroups: mut0 with complete loss of MCM activity and mut- with residual activity in the presence of adenosylcobalamin (AdoCbl). The disease typically presents in the first weeks or months of life and is clinically characterized by recurrent vomiting, metabolic acidosis, hyperammonemia, lethargy, poor feeding, failure to thrive and neurological deficit. To better elucidate the spectrum of mutations causing mut MMA in Saudi patients, we screened a cohort of 60 Saudi patients affected by either forms of the disease for mutations in the MUT gene. A total of 13 different mutations, including seven previously reported missense changes and six novel mutations, were detected in a homozygous state except for two compound heterozygous cases. The six novel mutations identified herein consist of three nonsense, two missense and one frameshift, distributed throughout the whole protein. This study describes for the first time the clinical and mutational spectrum of mut MMA in Saudi Arabian patients.
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Assay for methylmalonyl coenzyme A mutase activity based on determination of succinyl coenzyme A by ultrahigh-performance liquid chromatography tandem mass spectrometry. Anal Bioanal Chem 2015; 407:5281-6. [PMID: 26018627 DOI: 10.1007/s00216-015-8753-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 04/28/2015] [Accepted: 04/29/2015] [Indexed: 10/23/2022]
Abstract
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.
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van der Hooft JJJ, Ridder L, Barrett MP, Burgess KEV. Enhanced acylcarnitine annotation in high-resolution mass spectrometry data: fragmentation analysis for the classification and annotation of acylcarnitines. Front Bioeng Biotechnol 2015; 3:26. [PMID: 25806366 PMCID: PMC4353373 DOI: 10.3389/fbioe.2015.00026] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 02/19/2015] [Indexed: 11/24/2022] Open
Abstract
Metabolite annotation and identification are primary challenges in untargeted metabolomics experiments. Rigorous workflows for reliable annotation of mass features with chemical structures or compound classes are needed to enhance the power of untargeted mass spectrometry. High-resolution mass spectrometry considerably improves the confidence in assigning elemental formulas to mass features in comparison to nominal mass spectrometry, and embedding of fragmentation methods enables more reliable metabolite annotations and facilitates metabolite classification. However, the analysis of mass fragmentation spectra can be a time-consuming step and requires expert knowledge. This study demonstrates how characteristic fragmentations, specific to compound classes, can be used to systematically analyze their presence in complex biological extracts like urine that have undergone untargeted mass spectrometry combined with data dependent or targeted fragmentation. Human urine extracts were analyzed using normal phase liquid chromatography (hydrophilic interaction chromatography) coupled to an Ion Trap-Orbitrap hybrid instrument. Subsequently, mass chromatograms and collision-induced dissociation and higher-energy collisional dissociation (HCD) fragments were annotated using the freely available MAGMa software1. Acylcarnitines play a central role in energy metabolism by transporting fatty acids into the mitochondrial matrix. By filtering on a combination of a mass fragment and neutral loss designed based on the MAGMa fragment annotations, we were able to classify and annotate 50 acylcarnitines in human urine extracts, based on high-resolution mass spectrometry HCD fragmentation spectra at different energies for all of them. Of these annotated acylcarnitines, 31 are not described in HMDB yet and for only 4 annotated acylcarnitines the fragmentation spectra could be matched to reference spectra. Therefore, we conclude that the use of mass fragmentation filters within the context of untargeted metabolomics experiments is a valuable tool to enhance the annotation of small metabolites.
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Affiliation(s)
| | - Lars Ridder
- Laboratory of Biochemistry, Wageningen University and Research Centre , Wageningen , Netherlands
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Hisahara S, Matsushita T, Furuyama H, Tajima G, Shigematsu Y, Imai T, Shimohama S. A Heterozygous Missense Mutation in Adolescent-Onset Very Long-Chain Acyl-CoA Dehydrogenase Deficiency with Exercise-Induced Rhabdomyolysis. TOHOKU J EXP MED 2015; 235:305-10. [DOI: 10.1620/tjem.235.305] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Shin Hisahara
- Department of Neurology, School of Medicine, Sapporo Medical University
| | | | | | - Go Tajima
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences & Health Sciences
| | - Yosuke Shigematsu
- Department of Health Science, Faculty of Medical Sciences, University of Fukui
| | - Tomihiro Imai
- Department of Occupational Therapy, School of Health Sciences, Sapporo Medical University
- Department of Neurology, School of Medicine, Sapporo Medical University
| | - Shun Shimohama
- Department of Neurology, School of Medicine, Sapporo Medical University
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Estrella J, Wilcken B, Carpenter K, Bhattacharya K, Tchan M, Wiley V. Expanded newborn screening in New South Wales: missed cases. J Inherit Metab Dis 2014; 37:881-7. [PMID: 24970580 DOI: 10.1007/s10545-014-9727-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 04/10/2014] [Accepted: 05/19/2014] [Indexed: 10/25/2022]
Abstract
There have been few reports of cases missed by expanded newborn screening. Tandem mass spectrometry was introduced in New South Wales, Australia in 1998 to screen for selected disorders of amino acid, organic acid and fatty acid metabolism. Of 1,500,000 babies screened by 2012, 1:2700 were diagnosed with a target disorder. Fifteen affected babies were missed by testing, and presented clinically or in family studies. In three cases (cobalamin C defect, very-long-chain acyl-CoA dehydrogenase deficiency and glutaric aciduria type 1), this led to modification of analyte cut-off values or protocols during the first 3 years. Two patients with intermittent MSUD, two with β-ketothiolase deficiency, two with citrin deficiency, two siblings with arginosuccinic aciduria, two siblings with homocystinuria, and one with cobalamin C defect had analyte values and ratios below the action limits which could not have been detected without unacceptable false-positive rates. A laboratory interpretation error led to missing one case of cobalamin C defect. Reference ranges, regularly reviewed, were not altered. For citrin deficiency, while relevant metabolites are detectable by tandem mass spectrometry, our cut-off values do not specifically screen for that disorder. Most of the missed cases are doing well and with no acute presentations although eight of 15 are likely to have been somewhat adversely affected by a late diagnosis. Analyte ratio and cut-off value optimisations are important, but for some disorders occasional missed cases may have to be tolerated to maintain an acceptable specificity, and avoid harm from screening.
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Affiliation(s)
- Jane Estrella
- Department of Medical Genetics Westmead Hospital, Sydney, Australia
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Mak CM, Lee HCH, Chan AYW, Lam CW. Inborn errors of metabolism and expanded newborn screening: review and update. Crit Rev Clin Lab Sci 2014; 50:142-62. [PMID: 24295058 DOI: 10.3109/10408363.2013.847896] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.
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Affiliation(s)
- Chloe Miu Mak
- Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital , Hong Kong, SAR , China and
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Han L, Han F, Ye J, Qiu W, Zhang H, Gao X, Wang Y, Ji W, Gu X. Spectrum analysis of common inherited metabolic diseases in Chinese patients screened and diagnosed by tandem mass spectrometry. J Clin Lab Anal 2014; 29:162-8. [PMID: 24797655 DOI: 10.1002/jcla.21745] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 01/10/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Information concerning inherited metabolic diseases in China is scarce. We investigated the prevalence and age distributions of amino acid, organic acid, and fatty acid oxidation disorders in Chinese patients. METHODS Blood levels of amino acids and acylcarnitines (tandem mass spectrometry) were measured in 18,303 patients with suspected inherited metabolic diseases. Diagnosis was based on clinical features, blood levels of amino acids or acylcarnitines, urinary organic acid levels (gas chromatography-mass spectrometry), and (in some) gene mutation tests. RESULTS Inherited metabolic diseases were confirmed in 1,135 patients (739 males, 396 females). Median age was 12 months (1 day to 59 years). There were 28 diseases: 12 amino acid disorders (580 patients, 51.1%), with hyperphenylalaninemia (HPA) being the most common; nine organic acidemias (408 patients, 35.9%), with methylmalonic acidemia (MMA) as the most common; and seven fatty acid oxidation defects (147 patients, 13.0%), with multiple acyl-coenzyme A dehydrogenase deficiency (MADD) being the most common. Onset was mainly at 1-6 months for citrin deficiency, 0-6 months for MMA, and in newborns for ornithine transcarbamylase deficiency (OTCD). HPA was common in patients aged 1-3 years, and MADD was common in patients >18 years. CONCLUSIONS In China, HPA, citrin deficiency, MMA, and MADD are the most common inherited disorders, particularly in newborns/infants.
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Affiliation(s)
- Lianshu Han
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Isabel IG, Cynthia FL, Diana RG, Leticia BM, Sara GL, Susana MS, Marcela VA. Inborn Errors of Intermediary Metabolism in Critically Ill Mexican Newborns. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2014. [DOI: 10.1177/2326409814529649] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Ibarra-González Isabel
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Fernández-Lainez Cynthia
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Reyes-González Diana
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Belmont-Martínez Leticia
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Guillén-López Sara
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Monroy-Santoyo Susana
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
| | - Vela-Amieva Marcela
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Secretaría de Salud, México
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Kuhara T. [Present status of expanded newborn screening project for inborn errors of metabolism by tandem mass spectrometry]. Nihon Eiseigaku Zasshi 2014; 69:60-74. [PMID: 24476596 DOI: 10.1265/jjh.69.60] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In Japan, screening for six diseases including four inborn errors of metabolism has been performed since 1977 for all neonates to prevent severe mental handicaps or death. A rapid screening procedure for analysis of several amino acids and acylcarnitines in blood spots by tandem mass spectrometry was developed by Millington DS et al. in the early 1990s. Although it is called expanded (or extended) newborn screening, the procedure is insufficiently sensitive to or specific for several diseases. Screening for all diseases that can be screened using this procedure is suggested to be cost-ineffective. Many European countries target only two diseases: medium-chain acyl-CoA dehydrogenase deficiency and phenylketonuria; their prevalence in Caucasian populations is very high, but some countries target more than twenty diseases and others an intermediate number. A pilot study targeting 22 diseases suggests that the combined incidence is one per 9,000 (0.01%) in Japan. This primary screening requires secondary screening to confirm the disease using urine, and either organic acids with solvent extraction or metabolome without fractionation are analyzed by gas chromatography-mass spectrometry. There is no need for primary or secondary screening tests to be performed at the same laboratory because the skills required are quite different. Understanding of the methodological problems of tandem mass screening and amelioration of variation and false positivity rate of this screening method among laboratories are critical to the success of the screening system in Japan. GC/MS-based urine metabolomics is expected to become one of the primary screening methodologies for neonates/infants who are already ill.
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