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Kido J, Sugawara K, Tavoulari S, Makris G, Rüfenacht V, Nakamura K, Kunji ERS, Häberle J. Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review. Hum Mutat 2025; 2025:9326326. [PMID: 40309478 PMCID: PMC12041640 DOI: 10.1155/humu/9326326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/24/2024] [Accepted: 03/26/2025] [Indexed: 05/02/2025]
Abstract
Citrin deficiency (CD) is an autosomal recessive disorder caused by the absence or dysfunction of the mitochondrial transporter citrin, resulting from mutations in SLC25A13. The disease presents with age-dependent clinical manifestations: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia by CD (FTTDCD), and an adult-onset form (formerly called Type II citrullinemia, CTLN2, recently renamed to "adolescent and adult citrin deficiency," AACD). We performed this study to compile known genotypes found in CD patients and investigate their impact on the clinical course. Through a nationwide survey in Japan as well as a literature review, we collected information regarding 68 genetic variants of a total of 345 patients with CD (285 NICCD, 19 post-NICCD, and 41 AACD). In this cohort, the pathogenic variants, arising from nonsense, insertion/deletion, and splice site mutations, are expected to have severe functional or biogenesis defects. Of 82 alleles in patients with AACD, the two most common variants, c.852_855del and c.1177+1G>A, accounted for 25 alleles (30.5%) and 15 alleles (18.3%), respectively. The c.852_855del variant, even when present as part of compound heterozygosity, often presented with hyperammonemia (≥ 180 μmol/L), cognitive impairment, short stature (< -2SD), liver cirrhosis, and pancreatitis, with some patients requiring liver transplantation. In conclusion, certain SLC25A13 genotypes are particularly frequent, especially those that result in severely truncated citrin proteins with often a significant impact on the clinical outcome of the patient. The most prevalent variant is c.852_855del, which was found in 42% (128/304) of NICCD/post-NICCD cases and 49% (20/41) of AACD patients.
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Affiliation(s)
- Jun Kido
- University Children's Hospital Zurich and Children's Research Centre, University of Zurich, Zurich, Switzerland
- Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Keishin Sugawara
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Sotiria Tavoulari
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Georgios Makris
- University Children's Hospital Zurich and Children's Research Centre, University of Zurich, Zurich, Switzerland
| | - Véronique Rüfenacht
- University Children's Hospital Zurich and Children's Research Centre, University of Zurich, Zurich, Switzerland
| | - Kimitoshi Nakamura
- Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Edmund R. S. Kunji
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Johannes Häberle
- University Children's Hospital Zurich and Children's Research Centre, University of Zurich, Zurich, Switzerland
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Li J, Duan J, He S, Li Y, Wang M, Deng C. Biochemical characteristics, genetic variants and treatment outcomes of 55 Chinese cases with neonatal intrahepatic cholestasis caused by citrin deficiency. Front Pediatr 2025; 12:1293356. [PMID: 39872914 PMCID: PMC11769942 DOI: 10.3389/fped.2024.1293356] [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: 10/07/2023] [Accepted: 12/17/2024] [Indexed: 01/30/2025] Open
Abstract
Background The diagnostic criteria of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) have not been established due to non-specific clinical manifestations, and our understanding on the treatment outcome is still limited. We aim to investigate the biochemical characteristics, genetic variants, and treatment outcome of NICCD patients. Methods We compared the nutritional status and biochemical characteristics of 55 NICCD infants and 27 idiopathic neonatal cholestasis (INC) infants. SLC25A13 gene variant analysis was performed for definitive diagnosis of NICCD. NICCD infants received 12 months of lactose-free and/or medium-chain triglyceride-enriched (LF/MCT) formula treatment. The treatment efficacy was evaluated by comparing the outcome of NICCD with the 24 healthy infants that were selected as normal controls. All NICCD patients were followed up until death or at least 1 year of age. Results Compared to INC group, significant increase was found in levels of total bilirubin, indirect bilirubin, total bile acid, gamma-glutamyl transpeptidase, alkaline phosphatase, prothrombin time, thrombin time, international normalized ratio, alpha-fetoprotein (AFP), Vitamin D, and Vitamin E of NICCD group, while alanine aminotransferase, albumin, fibrinogen, glucose, and Vitamin A levels showed significant decrease in the NICCD group (P < 0.05). There were 7 novel variants among 19 SLC25A13 variant types. No significant differences were found between NICCD patients treated for 12 months and normal controls. In long term follow-up, 2 cases developed FTTDCD, 8 cases had special dietary habits, and 1 case died from cirrhosis. Conclusions NICCD showed more severe impairments in liver, coagulation, and metabolic function than INC. Significantly increased AFP levels could provide reference for the differential diagnosis of NICCD. The newly discovered variants may be meaningful for the individualized treatment of NICCD patients. LF/MCT formula was recommended for NICCD patients.
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Affiliation(s)
- Juan Li
- Department of Gastroenterology, Kunming Children’s Hospital, Kunming, China
| | - Jintao Duan
- Department of Gastroenterology, Kunming Children’s Hospital, Kunming, China
| | - Shuli He
- Department of Gastroenterology, Kunming Children’s Hospital, Kunming, China
| | - Ying Li
- Department of Gastroenterology, Kunming Children’s Hospital, Kunming, China
| | - Meifen Wang
- Department of Infectious Diseases, Kunming Children’s Hospital, Kunming, China
| | - Chengjun Deng
- Department of Gastroenterology, Kunming Children’s Hospital, Kunming, China
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Wang P, Hu L, Chen Y, Zhou D, Zhu S, Zhang T, Cen Z, He Q, Wu B, Huang X. Enhancing newborn screening sensitivity and specificity for missed NICCD using selected amino acids and acylcarnitines. Orphanet J Rare Dis 2025; 20:17. [PMID: 39799340 PMCID: PMC11724517 DOI: 10.1186/s13023-025-03532-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 12/27/2024] [Indexed: 01/15/2025] Open
Abstract
PURPOSE To enhance the detection rate of Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) through newborn screening (NBS), we analyzed the metabolic profiles of missed patients and proposed a more reliable method for early diagnosis. METHODS In this retrospective study, NICCD patients were classified into "Newborn Screening" (64 individuals) and "Missed Screening" (52 individuals) groups. Metabolic profiles were analyzed using the non-derivatized MS/MS Kit, and genetic mutations were identified via next-generation sequencing and confirmed by Sanger sequencing. Receiver Operating Characteristic (ROC) analysis evaluated the predictive value of amino acids and acylcarnitines in dried blood spots (DBS) for identifying missed patients including 40 missed patients and 17,269 healthy individuals, with additional validation using 12 missed patients and 454 healthy controls. RESULTS The age of diagnosis was significantly higher in the "Missed Screening" group compared to the "Newborn Screening" group (74.50 vs. 18.00 days, P < 0.001). ROC analysis revealed that citrulline had excellent diagnostic accuracy for missed patients, with an AUC of 0.970 and a cut-off value of 17.57 µmol/L. Additionally, glycine, phenylalanine, ornithine, and C8 were significant markers, each with an AUC greater than 0.70. A combination of these markers achieved an AUC of 0.996 with a cut-off value of 0.00195. Validation demonstrated a true positive rate of 91.67% and a true negative rate of 96.48%. Common SLC25A13 mutations in both groups were c.852_855del, IVS16ins3kb, and c.615 + 5G > A. CONCLUSIONS Combining multiple metabolic markers during NBS significantly improves sensitivity and specificity for detecting missed NICCD cases. However, the relationship between genetic mutations and missed cases remains unclear.
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Affiliation(s)
- Peiyao Wang
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Lingwei Hu
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Yuhe Chen
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Duo Zhou
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Shasha Zhu
- Department of Pediatric Health, Taizhou Women and Children's Hospital, Taizhou, 318000, Zhejiang, China
| | - Ting Zhang
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Ziyan Cen
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Binjiang District, Hangzhou, 310053, Zhejiang, China
| | - Qimin He
- School of Geography Science and Geomatics Engineering, Suzhou University of Science and Technology, Suzhou, 215009, Jiangsu, China.
| | - Benqing Wu
- Children's Medical Center, University of the Chinese Academy of Sciences-Shenzhen Hospital, Shenzhen, 518106, Guangdong, China.
| | - Xinwen Huang
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Binjiang District, Hangzhou, 310053, Zhejiang, China.
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Häberle J. Citrin deficiency-The East-side story. J Inherit Metab Dis 2024; 47:1129-1133. [PMID: 38994653 PMCID: PMC11586598 DOI: 10.1002/jimd.12772] [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: 04/15/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 07/13/2024]
Abstract
Citrin deficiency (CD) is a complex metabolic condition due to defects in SLC25A13 encoding citrin, an aspartate/glutamate carrier located in the mitochondrial inner membrane. The condition was first described in Japan and other East Asian countries in patients who were thought to suffer from classical citrullinemia type 1, and was therefore classified as a urea cycle disorder. With an improved understanding of its molecular basis, it became apparent that a defect of citrin is primarily affecting the malate-aspartate shuttle with however multiple secondary effects on many central metabolic pathways including glycolysis, gluconeogenesis, de novo lipogenesis and ureagenesis. In the meantime, it became also clear that CD must be considered as a global disease with patients identified in many parts of the world and affected by SLC25A13 genotypes different from those known in East Asian populations. The present short review summarizes the (hi)story of this complex metabolic condition and tries to explain the relevance of including CD as a differential diagnosis in neonates and infants with cholestasis and in (not only adult) patients with hyperammonemia of unknown origin with subsequent impact on the emergency management.
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Affiliation(s)
- Johannes Häberle
- University Children's Hospital Zurich and Children's Research CenterUniversity of ZurichZurichSwitzerland
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Kido J, Häberle J, Tanaka T, Nagao M, Wada Y, Numakura C, Bo R, Nyuzuki H, Dateki S, Maruyama S, Murayama K, Yoshida S, Nakamura K. Improved sensitivity and specificity for citrin deficiency using selected amino acids and acylcarnitines in the newborn screening. J Inherit Metab Dis 2024; 47:1134-1143. [PMID: 37681292 DOI: 10.1002/jimd.12673] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/27/2023] [Accepted: 08/18/2023] [Indexed: 09/09/2023]
Abstract
Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in the SLC25A13 gene. Intrahepatic cholestasis and various metabolic abnormalities, including hypoglycemia, galactosemia, citrullinemia, and hyperammonemia may be present in neonates or infants in the "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD) form of the disease. Because at present, newborn screening (NBS) for citrin deficiency using citrulline levels in dried blood spots (DBS) can only detect some of the patients, we tried to develop a new evaluation system to more reliably detect newborns with citrin deficiency utilizing parameters already in place in present NBS methods. To achieve this goal, we re-analyzed NBS profiles of amino acids and acylcarnitines in 96 NICCD patients, who were diagnosed through selective screening or positive family history. Hereby, we identified the combined evaluation of arginine (Arg), citrulline (Cit), isoleucine+leucine (Ile + Leu), tyrosine (Tyr), free carnitine (C0) / glutarylcarnitine (C5-DC) ratio in DBS as potentially sensitive to diagnose citrin deficiency in pre-symptomatic newborns. In particular, a scoring system using threshold levels for Arg (≥9 μmol/L), Cit (≥ 39 μmol/L), Ile + Leu (≥ 99 μmol/L), Tyr (≥ 96 μmol/L) and C0/C5-DC ratio (≥327) was significantly effective to detect newborns who later developed NICCD, and could thus be implemented in existing NBS programs at no extra analytical costs whenever citrin deficiency is considered to become a novel target disease.
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Affiliation(s)
- Jun Kido
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan
- University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Johannes Häberle
- University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Toju Tanaka
- Department of Pediatrics, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Masayoshi Nagao
- Department of Pediatrics, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Yoichi Wada
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Chikahiko Numakura
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Ryosuke Bo
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiromi Nyuzuki
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Sumito Dateki
- Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinsuke Maruyama
- Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kei Murayama
- Department of Metabolism, Center for Medical Genetics, Chiba Children's Hospital, Chiba, Japan
| | | | - Kimitoshi Nakamura
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan
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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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Hayasaka K. Pathogenesis and Management of Citrin Deficiency. Intern Med 2024; 63:1977-1986. [PMID: 37952953 PMCID: PMC11309867 DOI: 10.2169/internalmedicine.2595-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/22/2023] [Indexed: 11/14/2023] Open
Abstract
Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis.
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Affiliation(s)
- Kiyoshi Hayasaka
- Department of Pediatrics, Yamagata University School of Medicine, Japan
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Inui A, Ko JS, Chongsrisawat V, Sibal A, Hardikar W, Chang MH, Treepongkaruna S, Arai K, Kim KM, Chen HL. Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2024; 78:178-187. [PMID: 38374571 DOI: 10.1002/jpn3.12042] [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: 04/20/2023] [Revised: 08/31/2023] [Accepted: 09/14/2023] [Indexed: 02/21/2024]
Abstract
Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.
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Affiliation(s)
- Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamshi Tobu Hospital, Yokohama, Japan
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Voranush Chongsrisawat
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | | | - Winita Hardikar
- Department of Gastroenterology, Royal Children's Hospital, Melbourne, Australia
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Suporn Treepongkaruna
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Katsuhiro Arai
- Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
- Department and Graduate Institute of Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Kido J, Häberle J, Sugawara K, Tanaka T, Nagao M, Sawada T, Wada Y, Numakura C, Murayama K, Watanabe Y, Kojima-Ishii K, Sasai H, Kosugiyama K, Nakamura K. Clinical manifestation and long-term outcome of citrin deficiency: Report from a nationwide study in Japan. J Inherit Metab Dis 2022; 45:431-444. [PMID: 35142380 DOI: 10.1002/jimd.12483] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/08/2022] [Indexed: 11/05/2022]
Abstract
Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. The disease can present with age-dependent clinical manifestations: neonatal intrahepatic cholestasis by citrin deficiency (NICCD), failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD), and adult-onset type II citrullinemia (CTLN2). As a nationwide study to investigate the clinical manifestations, medical therapy, and long-term outcome in Japanese patients with citrin deficiency, we collected clinical data of 222 patients diagnosed and/or treated at various different institutions between January 2000 and December 2019. In the entire cohort, 218 patients were alive while 4 patients (1 FTTDCD and 3 CTLN2) had died. All patients <20 years were alive. Patients with citrin deficiency had an increased risk for low weight and length at birth, and CTLN2 patients had an increased risk for growth impairment during adolescence. Liver transplantation has been performed in only 4 patients (1 NICCD, 3 CTLN2) with a good response thereafter. This study reports the diagnosis and clinical course in a large cohort of patients with citrin deficiency and suggests that early intervention including a low carbohydrate diet and MCT supplementation can be associated with improved clinical course and long-term outcome.
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Affiliation(s)
- Jun Kido
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan
| | - Johannes Häberle
- University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Keishin Sugawara
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Toju Tanaka
- Department of Pediatrics, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Masayoshi Nagao
- Department of Pediatrics, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan
| | - Takaaki Sawada
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan
| | - Yoichi Wada
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Chikahiko Numakura
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Kei Murayama
- Department of Metabolism, Center for Medical Genetics, Chiba Children's Hospital, Chiba, Japan
| | - Yoriko Watanabe
- Research Institute of Medical Mass Spectrometry, Kurume University School of Medicine, Kurume, Japan
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Kanako Kojima-Ishii
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideo Sasai
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
| | | | - Kimitoshi Nakamura
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Japan
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Arai-Ichinoi N, Kikuchi A, Wada Y, Sakamoto O, Kure S. Hypoglycemic attacks and growth failure are the most common manifestations of citrin deficiency after 1 year of age. J Inherit Metab Dis 2021; 44:838-846. [PMID: 33861477 DOI: 10.1002/jimd.12390] [Citation(s) in RCA: 9] [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: 12/19/2020] [Revised: 02/26/2021] [Accepted: 04/14/2021] [Indexed: 12/31/2022]
Abstract
Citrin deficiency develops in different symptomatic periods from the neonatal period to adulthood. Some infantile patients are diagnosed by newborn mass screening or symptoms of neonatal intrahepatic cholestasis caused by citrin deficiency, some patients in childhood may develop hepatopathy or dyslipidemia as failure to thrive and dyslipidemia caused by citrin deficiency, and some adults are diagnosed after developing adult-onset type 2 citrullinemia (CTLN2) with hyperammonemia or encephalopathy. A diagnosis is needed before the development of severe phenotypic CTLN2 but is often difficult to obtain because newborn mass screening cannot detect all patients with citrin deficiency, and undiagnosed patients often appear healthy in childhood. There are only a few reports that have described patients in childhood. To explore the clinical features of undiagnosed patients with citrin deficiency in childhood, we studied 20 patients who were diagnosed after the first year of life. Of these patients, 45% experienced hypoglycemic attacks in childhood. The acetoacetic acid level during hypoglycemic attacks was lower than expected. Growth failure at diagnosis (45%) was also noted. From the patients' history, fat- and protein-rich food preferences (80%), a low birth weight (70%), and prolonged jaundice or infantile hepatopathy (40%) were identified. To diagnose citrin deficiency in childhood, we should ask about food preferences and a history of infantile hepatopathy for all children with severe hypoglycemia or growth failure and consider the genetic test for citrin deficiency if the patient has characteristic food preferences or a history of infantile hepatopathy.
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Affiliation(s)
| | - Atsuo Kikuchi
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Yoichi Wada
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Osamu Sakamoto
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Shigeo Kure
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
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12
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Broeks MH, van Karnebeek CDM, Wanders RJA, Jans JJM, Verhoeven‐Duif NM. Inborn disorders of the malate aspartate shuttle. J Inherit Metab Dis 2021; 44:792-808. [PMID: 33990986 PMCID: PMC8362162 DOI: 10.1002/jimd.12402] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/08/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022]
Abstract
Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to the electron carrier NADH. By shuttling NADH across the mitochondrial membrane in the form of a reduced metabolite (malate), the MAS plays an important role in mitochondrial respiration. In addition, the MAS maintains the cytosolic NAD+ /NADH redox balance, by using redox reactions for the transfer of electrons. This explains why the MAS is also important in sustaining cytosolic redox-dependent metabolic pathways, such as glycolysis and serine biosynthesis. The current review provides insights into the clinical and biochemical characteristics of MAS deficiencies. To date, five out of seven potential MAS deficiencies have been reported. Most of them present with a clinical phenotype of infantile epileptic encephalopathy. Although not specific, biochemical characteristics include high lactate, high glycerol 3-phosphate, a disturbed redox balance, TCA abnormalities, high ammonia, and low serine, which may be helpful in reaching a diagnosis in patients with an infantile epileptic encephalopathy. Current implications for treatment include a ketogenic diet, as well as serine and vitamin B6 supplementation.
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Affiliation(s)
- Melissa H. Broeks
- Department of Genetics, Section Metabolic DiagnosticsUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Clara D. M. van Karnebeek
- Departments of PediatricsAmsterdam University Medical CenterAmsterdamThe Netherlands
- Department of Pediatrics, Amalia Children's Hospital, Radboud Center for Mitochondrial DiseasesRadboud University Medical CenterNijmegenThe Netherlands
- On behalf of “United for Metabolic Diseases”The Netherlands
| | - Ronald J. A. Wanders
- Departments of Pediatrics and Laboratory Medicine, Laboratory Genetic Metabolic DiseasesAmsterdam University Medical Center, University of AmsterdamAmsterdamThe Netherlands
| | - Judith J. M. Jans
- Department of Genetics, Section Metabolic DiagnosticsUniversity Medical Center UtrechtUtrechtThe Netherlands
- On behalf of “United for Metabolic Diseases”The Netherlands
| | - Nanda M. Verhoeven‐Duif
- Department of Genetics, Section Metabolic DiagnosticsUniversity Medical Center UtrechtUtrechtThe Netherlands
- On behalf of “United for Metabolic Diseases”The Netherlands
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Okano Y, Okamoto M, Yazaki M, Inui A, Ohura T, Murayama K, Watanabe Y, Tokuhara D, Takeshima Y. Analysis of daily energy, protein, fat, and carbohydrate intake in citrin-deficient patients: Towards prevention of adult-onset type II citrullinemia. Mol Genet Metab 2021; 133:63-70. [PMID: 33741270 DOI: 10.1016/j.ymgme.2021.03.004] [Citation(s) in RCA: 4] [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: 12/06/2020] [Revised: 03/05/2021] [Accepted: 03/06/2021] [Indexed: 10/21/2022]
Abstract
Patients with citrin deficiency during the adaptation/compensation period exhibit diverse clinical features and have characteristic diet of high protein, high fat, and low carbohydrate. Japanese cuisine typically contains high carbohydrate but evaluation of diet of citrin-deficient patients in 2008 showed a low energy intake and a protein:fat:carbohydrate (PFC) ratio of 19:44:37, which indicates low carbohydrate consumption rate. These findings prompted the need for diet intervention to prevent the adult onset of type II citrullinemia (CTLN2). Since the publication of the report about 10 years ago, patients are generally advised to eat what they wish under active dietary consultation and intervention. In this study, citrin-deficient patients and control subjects living in the same household provided answers to a questionnaire, filled-up a maximum 6-day food diary, and supplied physical data and information on medications if any. To study the effects of the current diet, the survey collected data from 62 patients and 45 controls comparing daily intakes of energy, protein, fat, and carbohydrate. Food analysis showed that patient's energy intake was 115% compared to the Japanese standard. The confidence interval of the PFC ratio of patients was 20-22:47-51:28-32, indicating higher protein, higher fat and lower carbohydrate relative to previous reports. The mean PFC ratio of female patients (22:53:25) was significantly different from that of male patients (20:46:34), which may explain the lower frequency of CTLN2 in females. Comparison of the present data to those published 10 years ago, energy, protein, and fat intakes were significantly higher but the amount of carbohydrate consumption remained the same. Regardless of age, most patients (except for adolescents) consumed 100-200 g/day of carbohydrates, which met the estimated average requirement of 100 g/day for healthy individuals. Finally, patients were generally not overweight and some CTLN2 patients were underweight although their energy intake was higher compared with the control subjects. We speculate that high-energy of a low carbohydrate diet under dietary intervention may help citrin-deficient patients attain normal growth and prevent the onset of CTLN2.
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Affiliation(s)
- Yoshiyuki Okano
- Department of Pediatrics, Hyogo College of Medicine, Nishinomiya 663-8501, Japan; Okano Children's Clinic, Izumi 594-0071, Japan.
| | | | - Masahide Yazaki
- Department of Biological Sciences for Intractable Neurological Disorders, Institute for Biomedical Sciences, Shinshu University, Nagano 390-8621, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama 230-0012, Japan
| | - Toshihiro Ohura
- Division of Clinical Laboratory, Sendai City Hospital, Sendai 982-8502, Japan
| | - Kei Murayama
- Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan
| | - Yoriko Watanabe
- Research Institute of Medical Mass Spectrometry and Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Daisuke Tokuhara
- Department of Pediatrics, Osaka City University Hospital, Osaka 545-0051, Japan
| | - Yasuhiro Takeshima
- Department of Pediatrics, Hyogo College of Medicine, Nishinomiya 663-8501, Japan
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Pasquadibisceglie A, Polticelli F. Computational studies of the mitochondrial carrier family SLC25. Present status and future perspectives. BIO-ALGORITHMS AND MED-SYSTEMS 2021. [DOI: 10.1515/bams-2021-0018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Abstract
The members of the mitochondrial carrier family, also known as solute carrier family 25 (SLC25), are transmembrane proteins involved in the translocation of a plethora of small molecules between the mitochondrial intermembrane space and the matrix. These transporters are characterized by three homologous domains structure and a transport mechanism that involves the transition between different conformations. Mutations in regions critical for these transporters’ function often cause several diseases, given the crucial role of these proteins in the mitochondrial homeostasis. Experimental studies can be problematic in the case of membrane proteins, in particular concerning the characterization of the structure–function relationships. For this reason, computational methods are often applied in order to develop new hypotheses or to support/explain experimental evidence. Here the computational analyses carried out on the SLC25 members are reviewed, describing the main techniques used and the outcome in terms of improved knowledge of the transport mechanism. Potential future applications on this protein family of more recent and advanced in silico methods are also suggested.
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Affiliation(s)
| | - Fabio Polticelli
- Department of Sciences , Roma Tre University , Rome , Italy
- National Institute of Nuclear Physics, Roma Tre Section , Rome , Italy
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AGC2 (Citrin) Deficiency-From Recognition of the Disease till Construction of Therapeutic Procedures. Biomolecules 2020; 10:biom10081100. [PMID: 32722104 PMCID: PMC7465890 DOI: 10.3390/biom10081100] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/16/2022] Open
Abstract
Can you imagine a disease in which intake of an excess amount of sugars or carbohydrates causes hyperammonemia? It is hard to imagine the intake causing hyperammonemia. AGC2 or citrin deficiency shows their symptoms following sugar/carbohydrates intake excess and this disease is now known as a pan-ethnic disease. AGC2 (aspartate glutamate carrier 2) or citrin is a mitochondrial transporter which transports aspartate (Asp) from mitochondria to cytosol in exchange with glutamate (Glu) and H+. Asp is originally supplied from mitochondria to cytosol where it is necessary for synthesis of proteins, nucleotides, and urea. In cytosol, Asp can be synthesized from oxaloacetate and Glu by cytosolic Asp aminotransferase, but oxaloacetate formation is limited by the amount of NAD+. This means an increase in NADH causes suppression of Asp formation in the cytosol. Metabolism of carbohydrates and other substances which produce cytosolic NADH such as alcohol and glycerol suppress oxaloacetate formation. It is forced under citrin deficiency since citrin is a member of malate/Asp shuttle. In this review, we will describe history of identification of the SLC25A13 gene as the causative gene for adult-onset type II citrullinemia (CTLN2), a type of citrin deficiency, pathophysiology of citrin deficiency together with animal models and possible treatments for citrin deficiency newly developing.
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Lin Y, Liu Y, Zhu L, Le K, Shen Y, Yang C, Chen X, Hu H, Ma Q, Shi X, Hu Z, Yang J, Shen Y, Lin CH, Huang C, Huang X. Combining newborn metabolic and genetic screening for neonatal intrahepatic cholestasis caused by citrin deficiency. J Inherit Metab Dis 2020; 43:467-477. [PMID: 31845334 DOI: 10.1002/jimd.12206] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 12/08/2019] [Accepted: 12/12/2019] [Indexed: 12/19/2022]
Abstract
To evaluate the feasibility of incorporating genetic screening for neonatal intrahepatic cholestasis, caused by citrin deficiency (NICCD), into the current newborn screening (NBS) program. We designed a high-throughput iPLEX genotyping assay to detect 28 SLC25A13 mutations in the Chinese population. From March 2018 to June 2018, 237 630 newborns were screened by tandem mass spectrometry at six hospitals. Newborns with citrulline levels between 1/2 cutoff and cutoff values of the upper limit were recruited for genetic screening using the newly developed assay. The sensitivity and specificity of the iPLEX genotyping assay both reached 100% in clinical practice. Overall, 29 364 (12.4%) newborns received further genetic screening. Five patients with conclusive genotypes were successfully identified. The most common SLC25A13 mutation was c.851_854del, with an allele frequency of 60%. In total, 658 individuals with one mutant allele were identified as carriers. Eighteen different mutations were observed, yielding a carrier rate of 1/45. Notably, Quanzhou in southern China had a carrier rate of up to 1/28, whereas Jining in northern China had a carrier rate higher than that of other southern and border cities. The high throughput iPLEX genotyping assay is an effective and reliable approach for NICCD genotyping. The combined genetic screening could identify an additional subgroup of patients with NICCD, undetectable by conventional NBS. Therefore, this study demonstrates the viability of incorporating genetic screening for NICCD into the current NBS program.
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Affiliation(s)
- Yiming Lin
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
- Neonatal Disease Screening Center, Quanzhou Maternity and Children's Hospital, Quanzhou, China
| | - Yaru Liu
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Lin Zhu
- Department of Translational Medicine, Hangzhou Genuine Clinical Laboratory Co. Ltd, Hangzhou, China
| | - Kaixing Le
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Yuyan Shen
- Neonatal Disease Screening Center, Huaihua Maternal and Child Health Hospital, Huaihua, China
| | - Chiju Yang
- Neonatal Disease Screening Center, Jining Maternal and Child Health Family Service Center, Jining, China
| | - Xigui Chen
- Neonatal Disease Screening Center, Jining Maternal and Child Health Family Service Center, Jining, China
| | - Haili Hu
- Neonatal Disease Screening Center, Hefei Women and Children's Health Care Hospital, Hefei, China
| | - Qingqing Ma
- Neonatal Disease Screening Center, Hefei Women and Children's Health Care Hospital, Hefei, China
| | - Xueqin Shi
- Department of Pediatrics, Yancheng Maternity and Child Health Care Hospital, Yancheng, China
| | - Zhenzhen Hu
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Jianbin Yang
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yaping Shen
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Chien-Hsing Lin
- Department of Research and Development, Feng Chi Biotech Corp, Taipei, Taiwan
| | - Chenggang Huang
- Research and Development Center, Zhejiang Biosan Biochemical Technologies Co., Ltd, Hangzhou, China
| | - Xinwen Huang
- Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
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Schumann T, König J, Henke C, Willmes DM, Bornstein SR, Jordan J, Fromm MF, Birkenfeld AL. Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease. Pharmacol Rev 2020; 72:343-379. [PMID: 31882442 DOI: 10.1124/pr.118.015735] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The solute carrier (SLC) superfamily comprises more than 400 transport proteins mediating the influx and efflux of substances such as ions, nucleotides, and sugars across biological membranes. Over 80 SLC transporters have been linked to human diseases, including obesity and type 2 diabetes (T2D). This observation highlights the importance of SLCs for human (patho)physiology. Yet, only a small number of SLC proteins are validated drug targets. The most recent drug class approved for the treatment of T2D targets sodium-glucose cotransporter 2, product of the SLC5A2 gene. There is great interest in identifying other SLC transporters as potential targets for the treatment of metabolic diseases. Finding better treatments will prove essential in future years, given the enormous personal and socioeconomic burden posed by more than 500 million patients with T2D by 2040 worldwide. In this review, we summarize the evidence for SLC transporters as target structures in metabolic disease. To this end, we identified SLC13A5/sodium-coupled citrate transporter, and recent proof-of-concept studies confirm its therapeutic potential in T2D and nonalcoholic fatty liver disease. Further SLC transporters were linked in multiple genome-wide association studies to T2D or related metabolic disorders. In addition to presenting better-characterized potential therapeutic targets, we discuss the likely unnoticed link between other SLC transporters and metabolic disease. Recognition of their potential may promote research on these proteins for future medical management of human metabolic diseases such as obesity, fatty liver disease, and T2D. SIGNIFICANCE STATEMENT: Given the fact that the prevalence of human metabolic diseases such as obesity and type 2 diabetes has dramatically risen, pharmacological intervention will be a key future approach to managing their burden and reducing mortality. In this review, we present the evidence for solute carrier (SLC) genes associated with human metabolic diseases and discuss the potential of SLC transporters as therapeutic target structures.
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Affiliation(s)
- Tina Schumann
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
| | - Jörg König
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
| | - Christine Henke
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
| | - Diana M Willmes
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
| | - Stefan R Bornstein
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
| | - Jens Jordan
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
| | - Martin F Fromm
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
| | - Andreas L Birkenfeld
- Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine (T.S., C.H., D.M.W., S.R.B.), and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine (T.S., C.H., D.M.W.), Technische Universität Dresden, Dresden, Germany; Deutsches Zentrum für Diabetesforschung e.V., Neuherberg, Germany (T.S., C.H., D.M.W., A.L.B.); Clinical Pharmacology and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (J.K., M.F.F.); Institute for Aerospace Medicine, German Aerospace Center and Chair for Aerospace Medicine, University of Cologne, Cologne, Germany (J.J.); Diabetes and Nutritional Sciences, King's College London, London, United Kingdom (S.R.B., A.L.B.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany (A.L.B.); and Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany (A.L.B.)
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18
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Yahyaoui R, Pérez-Frías J. Amino Acid Transport Defects in Human Inherited Metabolic Disorders. Int J Mol Sci 2019; 21:ijms21010119. [PMID: 31878022 PMCID: PMC6981491 DOI: 10.3390/ijms21010119] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/12/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023] Open
Abstract
Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future.
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Affiliation(s)
- Raquel Yahyaoui
- Laboratory of Metabolic Disorders and Newborn Screening Center of Eastern Andalusia, Málaga Regional University Hospital, 29011 Málaga, Spain
- Grupo Endocrinología y Nutrición, Diabetes y Obesidad, Instituto de Investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain
- Correspondence:
| | - Javier Pérez-Frías
- Grupo Multidisciplinar de Investigación Pediátrica, Instituto de Investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain;
- Departamento de Farmacología y Pediatría, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
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19
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Lin H, Qiu JW, Rauf YM, Lin GZ, Liu R, Deng LJ, Deng M, Song YZ. Sodium Taurocholate Cotransporting Polypeptide (NTCP) Deficiency Hidden Behind Citrin Deficiency in Early Infancy: A Report of Three Cases. Front Genet 2019; 10:1108. [PMID: 31788003 PMCID: PMC6856633 DOI: 10.3389/fgene.2019.01108] [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: 02/12/2019] [Accepted: 10/16/2019] [Indexed: 12/14/2022] Open
Abstract
Sodium taurocholate cotransporting polypeptide (NTCP), a carrier protein encoded by the gene SLC10A1, is expressed in the basolateral membrane of the hepatocyte to uptake bile acids from plasma. As a new inborn error of bile acid metabolism, NTCP deficiency remains far from being well understood in terms of the clinical and molecular features. Citrin deficiency is a well-known autosomal recessive disease arising from SLC25A13 mutations, and in neonates or infants, this condition presents as transient intrahepatic cholestasis which usually resolves before 1 year of age. All the three patients in this paper exhibited cholestatic jaundice and elevated total bile acids in their early infancy, which were attributed to citrin deficiency by SLC25A13 genetic analysis. In response to feeding with lactose-free and medium-chain triglycerides-enrich formula, their clinical and laboratory presentations disappeared gradually while the hypercholanemia persisted, even beyond 1 year of age. On subsequent SLC10A1 analysis, they were all homozygous for the well-known pathogenic variant c.800C > T (p.Ser267Phe), and NTCP deficiency was thus definitely diagnosed. The findings in this paper indicated that NTCP deficiency could be covered up by citrin deficiency during early infancy; however, in citrin-deficient patients with intractable hypercholanemia following resolved cholestatic jaundice, NTCP deficiency should be taken into consideration.
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Affiliation(s)
- Hui Lin
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Jian-Wu Qiu
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Yaqub-Muhammad Rauf
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Gui-Zhi Lin
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Rui Liu
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Li-Jing Deng
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Mei Deng
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Yuan-Zong Song
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
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20
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Zhang L, Li Y, Shi W, Gao J, Tian Y, Li Y, Guo Y, Cui S, Zhang X. Identification of a novel splicing mutation in the SLC25A13 gene from a patient with NICCD: a case report. BMC Pediatr 2019; 19:348. [PMID: 31607264 PMCID: PMC6790242 DOI: 10.1186/s12887-019-1751-9] [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: 05/31/2019] [Accepted: 09/27/2019] [Indexed: 11/30/2022] Open
Abstract
Background Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder and one of the most common inherent causes of cholestatic jaundice in Asian infants. Mutations in the SLC25A13 gene, which encodes citrin protein expressed in the liver, have been identified as the genetic cause for NICCD. Case presentation Here, we report a 4-month-old female with clinical features including jaundice, hyperbilirubinemia, hyperlactacidemia, and abnormal liver function. The patient was diagnosed with NICCD by differential diagnosis using genetic analysis. Mutations in 60 jaundice-related genes were tested by using amplicon sequencing, which was performed on an Ion S5XL genetic analyzer. A compound heterozygous mutation in the SLC25A13 gene was identified, consisting of a known deletion SLC25A13:c.852_855delTATG and a novel splicing mutation SLC25A13:c.1841 + 3_1841 + 4delAA. Sanger sequencing for the proband and her parents was performed to validate the result and reveal the source of mutations. Conclusion A compound heterozygous mutation in the SLC25A13 gene was identified in a 4-month-old female patient with NICCD. Our data suggest that amplicon sequencing is a helpful tool for the differential diagnosis of inherited diseases with similar symptoms. Further studies of the mutation spectrum of neonatal jaundice in China are warranted.
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Affiliation(s)
- Linlin Zhang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.,International Joint Research Laboratory for US-China Prenatal Medicine Of Henan, Zhengzhou, China
| | - Yingying Li
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Wenli Shi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China
| | - Jinshuang Gao
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.,International Joint Research Laboratory for US-China Prenatal Medicine Of Henan, Zhengzhou, China
| | - Yuan Tian
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.,International Joint Research Laboratory for US-China Prenatal Medicine Of Henan, Zhengzhou, China
| | - Ying Li
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.,International Joint Research Laboratory for US-China Prenatal Medicine Of Henan, Zhengzhou, China
| | - Yaqing Guo
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.,International Joint Research Laboratory for US-China Prenatal Medicine Of Henan, Zhengzhou, China
| | - Shihong Cui
- International Joint Research Laboratory for US-China Prenatal Medicine Of Henan, Zhengzhou, China. .,Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China.
| | - Xiaoan Zhang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, China. .,International Joint Research Laboratory for US-China Prenatal Medicine Of Henan, Zhengzhou, China.
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21
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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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22
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Cao J, An D, Galduroz M, Zhuo J, Liang S, Eybye M, Frassetto A, Kuroda E, Funahashi A, Santana J, Mihai C, Benenato KE, Kumarasinghe ES, Sabnis S, Salerno T, Coughlan K, Miracco EJ, Levy B, Besin G, Schultz J, Lukacs C, Guey L, Finn P, Furukawa T, Giangrande PH, Saheki T, Martini PGV. mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency. Mol Ther 2019; 27:1242-1251. [PMID: 31056400 DOI: 10.1016/j.ymthe.2019.04.017] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 04/14/2019] [Accepted: 04/19/2019] [Indexed: 02/08/2023] Open
Abstract
Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.
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Affiliation(s)
| | - Ding An
- Moderna, Inc., Cambridge, MA, USA
| | | | | | | | | | | | - Eishi Kuroda
- Department of Molecular Oncology, Kagoshima University, Kagoshima, Japan
| | - Aki Funahashi
- Department of Molecular Oncology, Kagoshima University, Kagoshima, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | - Lin Guey
- Moderna, Inc., Cambridge, MA, USA
| | | | - Tatsuhiko Furukawa
- Department of Molecular Oncology, Kagoshima University, Kagoshima, Japan
| | | | - Takeyori Saheki
- Department of Molecular Oncology, Kagoshima University, Kagoshima, Japan
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23
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Ogunbona OB, Claypool SM. Emerging Roles in the Biogenesis of Cytochrome c Oxidase for Members of the Mitochondrial Carrier Family. Front Cell Dev Biol 2019; 7:3. [PMID: 30766870 PMCID: PMC6365663 DOI: 10.3389/fcell.2019.00003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 01/10/2019] [Indexed: 12/11/2022] Open
Abstract
The mitochondrial carrier family (MCF) is a group of transport proteins that are mostly localized to the inner mitochondrial membrane where they facilitate the movement of various solutes across the membrane. Although these carriers represent potential targets for therapeutic application and are repeatedly associated with human disease, research on the MCF has not progressed commensurate to their physiologic and pathophysiologic importance. Many of the 53 MCF members in humans are orphans and lack known transport substrates. Even for the relatively well-studied members of this family, such as the ADP/ATP carrier and the uncoupling protein, there exist fundamental gaps in our understanding of their biological roles including a clear rationale for the existence of multiple isoforms. Here, we briefly review this important family of mitochondrial carriers, provide a few salient examples of their diverse metabolic roles and disease associations, and then focus on an emerging link between several distinct MCF members, including the ADP/ATP carrier, and cytochrome c oxidase biogenesis. As the ADP/ATP carrier is regarded as the paradigm of the entire MCF, its newly established role in regulating translation of the mitochondrial genome highlights that we still have a lot to learn about these metabolite transporters.
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Affiliation(s)
- Oluwaseun B. Ogunbona
- Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
- Department of Pathology & Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA, United States
| | - Steven M. Claypool
- Department of Physiology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
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24
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Hayasaka K, Numakura C. Adult-onset type II citrullinemia: Current insights and therapy. APPLICATION OF CLINICAL GENETICS 2018; 11:163-170. [PMID: 30588060 PMCID: PMC6296197 DOI: 10.2147/tacg.s162084] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Citrin deficiency is a recessively inherited metabolic disorder with age-dependent clinical manifestations. It causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Patients with NICCD present with intrahepatic cholestasis in the neonatal period and usually respond to the treatment with medium-chain triglyceride (MCT) supplement and lactose-restricted formula. In adulthood, CTLN2 develops in <10 % of the patients showing hyperammonemic encephalopathy. Patients with CTLN2 required liver transplantation for the most promising prognosis; however, they were successfully treated with MCT supplement with a low carbohydrate formula. Citrin deficiency is caused by mutations in SLC25A13 on chromosome 7q21.3, with a high frequency in East Asia, including Japan. Citrin is aspartate/glutamate transporter in mitochondria, a component of malate-aspartate nicotinamide adenine dinucleotide hydrogen shuttle, and is essential for the hepatic glycolysis. Although the precise pathophysiology of citrin deficiency remains unclear, recent reports for the effective MCT supplement therapy and downregulation of peroxisome proliferator-activated receptor α suggest that citrin deficiency impairs hepatic de novo lipogenesis coupled with glycolysis leading to the energy deficit of hepatocytes. Herein, we review the current therapeutic and pathological understanding of CTLN2.
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Affiliation(s)
- Kiyoshi Hayasaka
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan, .,Department of Pediatrics, Miyukikai Hospital, Kaminoyama, Japan,
| | - Chikahiko Numakura
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan,
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25
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Wada Y, Kikuchi A, Arai-Ichinoi N, Sakamoto O, Takezawa Y, Iwasawa S, Niihori T, Nyuzuki H, Nakajima Y, Ogawa E, Ishige M, Hirai H, Sasai H, Fujiki R, Shirota M, Funayama R, Yamamoto M, Ito T, Ohara O, Nakayama K, Aoki Y, Koshiba S, Fukao T, Kure S. Biallelic GALM pathogenic variants cause a novel type of galactosemia. Genet Med 2018; 21:1286-1294. [PMID: 30451973 DOI: 10.1038/s41436-018-0340-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 10/04/2018] [Indexed: 12/30/2022] Open
Abstract
PURPOSE Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. METHODS Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. RESULTS The highest blood galactose levels observed in each patient were 17.3-41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients' peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. CONCLUSION Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.
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Affiliation(s)
- Yoichi Wada
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Atsuo Kikuchi
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
| | | | - Osamu Sakamoto
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Yusuke Takezawa
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Shinya Iwasawa
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Tetsuya Niihori
- Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
| | - Hiromi Nyuzuki
- Department of Pediatrics, Niigata University School of Medicine, Niigata, Japan
| | - Yoko Nakajima
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan
| | - Erika Ogawa
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Mika Ishige
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Hiroki Hirai
- Department of Pediatrics, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Hideo Sasai
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Ryoji Fujiki
- Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan
| | - Matsuyuki Shirota
- Division of Interdisciplinary Medical Sciences, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryo Funayama
- Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masayuki Yamamoto
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Tetsuya Ito
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan
| | - Osamu Ohara
- Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan
| | - Keiko Nakayama
- Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoko Aoki
- Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
| | - Seizo Koshiba
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Toshiyuki Fukao
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Shigeo Kure
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.,Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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26
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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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27
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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28
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Lu CT, Yang J, Huang SM, Feng L, Li ZJ. Analysis of islet beta cell functions and their correlations with liver dysfunction in patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Medicine (Baltimore) 2017; 96:e8638. [PMID: 29137101 PMCID: PMC5690794 DOI: 10.1097/md.0000000000008638] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) primarily manifests in neonates or infants with hepatomegaly, liver dysfunction, and hypoglycemia. This study investigated the functions of islet beta cells and their correlations with liver dysfunction in NICCD patients.We retrospectively analyzed clinical data on liver function and islet beta cell functions for 36 patients diagnosed with NICCD and 50 subjects as the control group. The NICCD group had significantly higher total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate amino transferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) levels and albumin/globulin ratio (A/G) (P < .05), and lower ALB and GLB levels than the control group (P < .05). The differences in fasting blood glucose (FBG), fasting insulin, C-peptide (C-P), the homeostasis model of assessment for the insulin resistance index (HOMA-IR), fasting beta cell function (FBCI), and the HOMA beta cell function index (HBCI) between the NICCD and control groups were not significant (P > .05). A linear correlation was found between FBG and fasting insulin (P < .001) and between FBG and C-P in the NICCD patients (P = .001). Fasting insulin (P = .023), HOMA-IR (P = .023), FBCI (P = .049), and HBCI (P = .048) were positively correlated with increases in the ALT level. There was no difference in islet beta cell functions between the NICCD and control groups. The liver dysfunction may be correlated with islet beta cell functions in NICCD patients.
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Affiliation(s)
- Chun-Ting Lu
- The First Affiliated Hospital of Jinan University
| | | | | | - Lie Feng
- Department of Endocrinology and Metabolism
| | - Ze-Jian Li
- Medical Centre of Stomatology, The First Affiliated Hospital of Jinan University, Guangdong, China
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29
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Bigot A, Tchan MC, Thoreau B, Blasco H, Maillot F. Liver involvement in urea cycle disorders: a review of the literature. J Inherit Metab Dis 2017; 40:757-769. [PMID: 28900784 DOI: 10.1007/s10545-017-0088-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 08/13/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022]
Abstract
Urea cycle disorders (UCDs) are inborn errors of metabolism of the nitrogen detoxification pathway and encompass six principal enzymatic deficiencies. The aging of UCD patients leads to a better knowledge of the long-term natural history of the condition and to the reporting of previously unnoticed manifestations. Despite historical evidence of liver involvement in UCDs, little attention has been paid to this organ until recently. Hence, we reviewed the available scientific evidence on acute and chronic liver dysfunction and liver carcinogenesis in UCDs and discuss their pathophysiology. Overall, liver involvement, such as acute liver failure or steatotic-like disease, which may evolve toward cirrhosis, has been reported in all six main UCDs. Excessive glycogen storage is also a prominent histologic feature, and hypoglycemia has been reported in citrin deficiency. Hepatocarcinomas seem frequent in some UCDs, such as in citrin deficiency, and can sometimes occur in non-cirrhotic patients. UCDs may differ in liver involvement according to the enzymatic deficiency. Ornithine transcarbamylase deficiency may be associated more with acute liver failure and argininosuccinic aciduria with chronic liver failure and cirrhosis. Direct toxicity of metabolites, downstream metabolic deficiencies, impaired tricarboxylic acid cycle, oxidative stress, mitochondrial dysfunction, energy deficit, and putative toxicity of therapies combine in various ways to cause the different liver diseases reported.
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Affiliation(s)
- Adrien Bigot
- CHRU de Tours, service médecine interne, Tours, France.
- CHRU de Tours, centre de référence des maladies héréditaires du métabolisme, Tours, France.
- Department of Genetic Medicine, Westmead Hospital, Sydney, Australia.
- Service de Médecine Interne, Hôpital Bretonneau, 2, boulevard Tonnelle, 37044, Tours, France.
| | - Michel C Tchan
- Department of Genetic Medicine, Westmead Hospital, Sydney, Australia
| | - Benjamin Thoreau
- CHRU de Tours, service médecine interne, Tours, France
- CHRU de Tours, centre de référence des maladies héréditaires du métabolisme, Tours, France
- Université François Rabelais, Tours, France
- UMR INSERM U 1069, Tours, France
| | - Hélène Blasco
- CHRU de Tours, centre de référence des maladies héréditaires du métabolisme, Tours, France
- Université François Rabelais, Tours, France
- CHRU de Tours, service de biochimie-biologie moléculaire, Tours, France
- UMR INSERM U930, 37000, Tours, France
| | - François Maillot
- CHRU de Tours, service médecine interne, Tours, France
- CHRU de Tours, centre de référence des maladies héréditaires du métabolisme, Tours, France
- Université François Rabelais, Tours, France
- UMR INSERM U 1069, Tours, France
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Lu CT, Shi QP, Li ZJ, Li J, Feng L. Blood glucose and insulin and correlation of SLC25A13 mutations with biochemical changes in NICCD patients. Exp Biol Med (Maywood) 2017; 242:1271-1278. [PMID: 28516797 DOI: 10.1177/1535370217710918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a hereditary metabolic disease arising from biallelic mutations of SLC25A13. This study aimed to explore the characteristics of fasting blood glucose (FBG), fasting insulin (FINS) and C-peptide (C-P) levels in NICCD infants, analyze their SLC25A13 genetic mutations and further discuss the correlation between SLC25A13 genetic mutations and biochemical changes. Seventy-two cases of infants with cholestasis disease were gathered. Among them, 36 cases with NICCD diagnosis were case group. Meanwhile, 36 cases with unknown etiology but excluded NICCD were control group. FBG, FINS, C-P, ALT, AST, GGT, ALP, TG, HDL-C, LDL-C and Non-HDL-C were collected from all subjects, and DNA was extracted from venous blood for SLC25A13 mutations detection. The incidence of hypoglycemia was 3% in NICCD group. There were no significant statistical difference of FBG, FINS and C-P between NICCD and INC groups ( P > 0.05). ALT, LDL-C and Non-HDL-C levels in NICCD group were lower than the INC group, while SLC25A13 mutations were associated with the level of GGT ( P < 0.05). Ten different SLC25A13 genetic mutations were detected, among which, 851del4, IVS16ins3kb, IVS6+5 G > A and 1638ins23 mutations made up 82% of all mutations. The incidence of hypoglycemia may be higher in small gestational age infants with NICCD. Low LDL-C may be one of the characteristics of dyslipidemia in NICCD infants. There was a correlation between SLC25A13 gene mutations distribution and the GGT level, but the meaning of this finding remains to be further in-depth study. Impact statement This study aims to compare FBG, FINS, C-P, other biochemical and clinical manifestations between NICCD and non-NICCD infants, and discuss differential diagnosis of NICCD and INC beyond the genetic analysis. And investigate the correlation between SLC25A13 genetic mutations and biochemical changes. This work presented that incidence of hypoglycemia may be higher in small gestational age infants with NICCD. Low LDL-C may be one of the characteristics of dyslipidemia in NICCD infants. There was a correlation between SLC25A13 gene mutations distribution and the GGT level.
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Affiliation(s)
- Chun-Ting Lu
- 1 Science and Education Office, Jinan University, First Affiliated Hospital, Guangzhou 510630, China.,2 Department of Endocrinology and Metabolism, Jinan University, First Affiliated Hospital, Guangzhou 510630, China
| | - Qi-Ping Shi
- 2 Department of Endocrinology and Metabolism, Jinan University, First Affiliated Hospital, Guangzhou 510630, China
| | - Ze-Jian Li
- 3 Medical Centre of Stomatology, Jinan University, First Affiliated Hospital, Guangzhou 510630, China
| | - Jiong Li
- 4 Department of Anatomy, Medical School, Jinan University, Guangzhou 510630, China
| | - Lie Feng
- 2 Department of Endocrinology and Metabolism, Jinan University, First Affiliated Hospital, Guangzhou 510630, China
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Saheki T, Inoue K, Ono H, Fujimoto Y, Furuie S, Yamamura KI, Kuroda E, Ushikai M, Asakawa A, Inui A, Eto K, Kadowaki T, Moriyama M, Sinasac DS, Yamamoto T, Furukawa T, Kobayashi K. Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency. Mol Genet Metab 2017; 120:306-316. [PMID: 28259708 DOI: 10.1016/j.ymgme.2017.02.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/05/2017] [Accepted: 02/05/2017] [Indexed: 01/23/2023]
Abstract
Mice carrying simultaneous homozygous mutations in the genes encoding citrin, the mitochondrial aspartate-glutamate carrier 2 (AGC2) protein, and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), are a phenotypically representative model of human citrin (a.k.a., AGC2) deficiency. In this study, we investigated the voluntary oral intake and preference for sucrose, glycerol or ethanol solutions by wild-type, citrin (Ctrn)-knockout (KO), mGPD-KO, and Ctrn/mGPD double-KO mice; all substances that are known or suspected precipitating factors in the pathogenesis of human citrin deficiency. The double-KO mice showed clear suppressed intake of sucrose, consuming less with progressively higher concentrations compared to the other mice. Similar observations were made when glycerol or ethanol were given. The preference of Ctrn-KO and mGPD-KO mice varied with the different treatments; essentially no differences were observed for sucrose, while an intermediate intake or similar to that of the double-KO mice was observed for glycerol and ethanol. We next examined the hepatic glycerol 3-phosphate, citrate, citrulline, lysine, glutamate and adenine nucleotide levels following forced enteral administration of these solutions. A strong correlation between the simultaneous increased hepatic glycerol 3-phosphate and decreased ATP or total adenine nucleotide content and observed aversion of the mice during evaluation of their voluntary preferences was found. Overall, our results suggest that the aversion observed in the double-KO mice to these solutions is initiated and/or mediated by hepatic metabolic perturbations, resulting in a behavioral response to increased hepatic cytosolic NADH and a decreased cellular adenine nucleotide pool. These findings may underlie the dietary predilections observed in human citrin deficient patients.
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Affiliation(s)
- Takeyori Saheki
- Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan; Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan; Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
| | - Kanako Inoue
- Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
| | - Hiromi Ono
- Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
| | - Yuki Fujimoto
- Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
| | - Sumie Furuie
- Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
| | - Ken-Ichi Yamamura
- Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
| | - Eishi Kuroda
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan; Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Miharu Ushikai
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan; Department of Hygiene and Health Promotion Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan
| | - Akihiro Asakawa
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan
| | - Akio Inui
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan
| | - Kazuhiro Eto
- Department of Internal Medicine, Teikyo University, Tokyo 173-8605, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Mitsuaki Moriyama
- Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Izumisano 598-8531, Japan
| | - David S Sinasac
- Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Alberta T2N 2N1, Canada
| | - Takashi Yamamoto
- Faculty of Health Science, Kio University, Koryo 635-0832, Japan
| | - Tatsuhiko Furukawa
- Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Keiko Kobayashi
- Department of Molecular Metabolism and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
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Oh SH, Lee BH, Kim GH, Choi JH, Kim KM, Yoo HW. Biochemical and molecular characteristics of citrin deficiency in Korean children. J Hum Genet 2016; 62:305-307. [DOI: 10.1038/jhg.2016.131] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Revised: 09/23/2016] [Accepted: 09/26/2016] [Indexed: 11/09/2022]
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Lin WX, Zeng HS, Zhang ZH, Mao M, Zheng QQ, Zhao ST, Cheng Y, Chen FP, Wen WR, Song YZ. Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution. Sci Rep 2016; 6:29732. [PMID: 27405544 PMCID: PMC4942605 DOI: 10.1038/srep29732] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 06/21/2016] [Indexed: 12/21/2022] Open
Abstract
Citrin deficiency (CD) is a Mendelian disease due to biallelic mutations of SLC25A13 gene. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is the major pediatric CD phenotype, and its definite diagnosis relies on SLC25A13 genetic analysis. China is a vast country with a huge population, but the SLC25A13 genotypic features of CD patients in our country remains far from being well clarified. Via sophisticated molecular analysis, this study diagnosed 154 new CD patients in mainland China and identified 9 novel deleterious SLC25A13 mutations, i.e. c.103A > G, [c.329 - 154_c.468 + 2352del2646; c.468 + 2392_c.468 + 2393ins23], c.493C > T, c.755 - 1G > C, c.845_c.848 + 1delG, c.933_c.933 + 1insGCAG, c.1381G > T, c.1452 + 1G > A and c.1706_1707delTA. Among the 274 CD patients diagnosed by our group thus far, 41 SLC25A13 mutations/variations were detected. The 7 mutations c.775C > T, c.851_854del4, c.1078C > T, IVS11 + 1G > A, c.1364G > T, c.1399C > T and IVS16ins3kb demonstrated significantly different geographic distribution. Among the total 53 identified genotypes, only c.851_854del4/c.851_854del4 and c.851_854del4/c.1399C > T presented different geographic distribution. The northern population had a higher level of SLC25A13 allelic heterogeneity than those in the south. These findings enriched the SLC25A13 mutation spectrum and brought new insights into the geographic distribution of the variations and genotypes, providing reliable evidences for NICCD definite diagnosis and for the determination of relevant molecular targets in different Chinese areas.
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Affiliation(s)
- Wei-Xia Lin
- Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Han-Shi Zeng
- Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Zhan-Hui Zhang
- Clinical Medicine Research Institute, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Man Mao
- Department of Laboratory Science, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Qi-Qi Zheng
- Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Shu-Tao Zhao
- Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Ying Cheng
- Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Feng-Ping Chen
- Department of Laboratory Science, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Wang-Rong Wen
- Department of Laboratory Science, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
| | - Yuan-Zong Song
- Department of Pediatrics, the First Affiliated Hospital, Jinan University, Guangzhou, 510630, China
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Identification of a Large SLC25A13 Deletion via Sophisticated Molecular Analyses Using Peripheral Blood Lymphocytes in an Infant with Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD): A Clinical and Molecular Study. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4124263. [PMID: 27127784 PMCID: PMC4835617 DOI: 10.1155/2016/4124263] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 02/23/2016] [Indexed: 12/16/2022]
Abstract
Background. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a Mendelian disorder arising from biallelic SLC25A13 mutations, and SLC25A13 genetic analysis was indispensable for its definite diagnosis. However, conventional SLC25A13 analysis could not detect all mutations, especially obscure large insertions/deletions. This paper aimed to explore the obscure SLC25A13 mutation in an NICCD infant. Methods. Genomic DNA was extracted to screen for 4 high-frequency SLC25A13 mutations, and then all 18 exons and their flanking sequences were analyzed by Sanger sequencing. Subsequently, cDNA cloning, SNP analyses, and semiquantitative PCR were performed to identify the obscure mutation. Results. A maternally inherited mutation IVS16ins3kb was screened out, and then cDNA cloning unveiled paternally inherited alternative splicing variants (ASVs) featuring exon 5 skipping. Ultimately, a large deletion c.329-1687_c.468+3865del5692bp, which has never been described in any other references, was identified via intensive study on the genomic DNA around exon 5 of SLC25A13 gene. Conclusions. An NICCD patient was definitely diagnosed as a compound heterozygote of IVS16ins3kb and c.329-1687_c.468+3865del5692bp. The large deletion enriched the SLC25A13 mutation spectrum, and its identification supported the concept that cDNA cloning analysis, along with other molecular tools such as semiquantitative PCR, could provide valuable clues, facilitating the identification of obscure SLC25A13 deletions.
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Inui A, Hashimoto T, Sogo T, Komatsu H, Saheki T, Fujisawa T. Chronic hepatitis without hepatic steatosis caused by citrin deficiency in a child. Hepatol Res 2016; 46:357-362. [PMID: 26190322 DOI: 10.1111/hepr.12559] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 07/01/2015] [Accepted: 07/14/2015] [Indexed: 02/08/2023]
Abstract
Citrin deficiency manifests as both neonatal intrahepatic cholestasis (NICCD) during early infancy and adult-onset type II citrullinemia during adulthood. Hepatic steatosis is most frequently observed in patients with citrin deficiency. Thus, non-alcoholic fatty liver disease that is unrelated to being overweight is considered one of the clinical features of citrin deficiency in children and adults. However, it remains unknown whether citrin deficiency is a cause of chronic hepatitis in the absence of fatty changes to the liver that occur during childhood. We encountered an 8-year-old girl who showed no clinical features of NICCD during infancy and had persistently elevated transaminase levels for several years. Liver biopsy showed widening of the portal tracts with intense mononuclear cell infiltration and mild fibrosis but no fatty changes. However, she had peculiar dietary habits similar to those that have been observed in many patients with citrin deficiency. In addition, a slightly elevated plasma citrulline level and a high pancreatic secretory trypsin inhibitor level were detected by blood examination, and she was diagnosed with citrin deficiency. Analysis of the SLC25A13 gene revealed the presence of the compound heterozygous mutations 851del4 and IVS13 + 1G > A. Thus, citrin deficiency should be included in the differential diagnosis of chronic hepatitis in children, even in the absence of hepatic steatosis.
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Affiliation(s)
- Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Takuji Hashimoto
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
- Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Sogo
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Chiba, Japan
| | - Takeyori Saheki
- Institute of Resource Development Analysis, Kumamoto University, Kumamoto, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
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Moriyama M, Fujimoto Y, Rikimaru S, Ushikai M, Kuroda E, Kawabe K, Takano K, Asakawa A, Inui A, Eto K, Kadowaki T, Sinasac DS, Okano Y, Yazaki M, Ikeda SI, Zhang C, Song YZ, Sakamoto O, Kure S, Mitsubuchi H, Endo F, Horiuchi M, Nakamura Y, Yamamura KI, Saheki T. Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency. Biochim Biophys Acta Mol Basis Dis 2015; 1852:1787-95. [DOI: 10.1016/j.bbadis.2015.04.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 04/21/2015] [Accepted: 04/27/2015] [Indexed: 10/23/2022]
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Chanprasert S, Scaglia F. Adult liver disorders caused by inborn errors of metabolism: review and update. Mol Genet Metab 2015; 114:1-10. [PMID: 25467056 DOI: 10.1016/j.ymgme.2014.10.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 10/23/2014] [Accepted: 10/23/2014] [Indexed: 12/22/2022]
Abstract
Inborn errors of metabolism (IEMs) are a group of genetic diseases that have protean clinical manifestations and can involve several organ systems. The age of onset is highly variable but IEMs afflict mostly the pediatric population. However, in the past decades, the advancement in management and new therapeutic approaches have led to the improvement in IEM patient care. As a result, many patients with IEMs are surviving into adulthood and developing their own set of complications. In addition, some IEMs will present in adulthood. It is important for internists to have the knowledge and be familiar with these conditions because it is predicted that more and more adult patients with IEMs will need continuity of care in the near future. The review will focus on Wilson disease, alpha-1 antitrypsin deficiency, citrin deficiency, and HFE-associated hemochromatosis which are typically found in the adult population. Clinical manifestations and pathophysiology, particularly those that relate to hepatic disease as well as diagnosis and management will be discussed in detail.
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Affiliation(s)
- Sirisak Chanprasert
- Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children Hospital, Houston, TX, USA
| | - Fernando Scaglia
- Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children Hospital, Houston, TX, USA.
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Molecular genetics of citrullinemia types I and II. Clin Chim Acta 2014; 431:1-8. [DOI: 10.1016/j.cca.2014.01.032] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 01/16/2014] [Accepted: 01/18/2014] [Indexed: 12/16/2022]
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Ikeda SI, Takei YI, Hashikura Y. Liver transplantation as treatment for neurological disorders. Expert Rev Neurother 2014; 3:547-55. [DOI: 10.1586/14737175.3.4.547] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China. PLoS One 2013; 8:e74544. [PMID: 24069319 PMCID: PMC3777997 DOI: 10.1371/journal.pone.0074544] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 08/02/2013] [Indexed: 12/19/2022] Open
Abstract
Background The human SLC25A13 gene encodes citrin, the liver-type mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), and SLC25A13 mutations cause citrin deficiency (CD), a disease entity that encompasses different age-dependant clinical phenotypes such as Adult-onset Citrullinemia Type II (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). The analyses of SLC25A13 gene and its protein/mRNA products remain reliable tools for the definitive diagnoses of CD patients, and so far, the SLC25A13 mutation spectrum in Chinese CD patients has not been well-characterized yet. Methods and Results By means of direct DNA sequencing, cDNA cloning and SNP analyses, 16 novel pathogenic mutations, including 9 missense, 4 nonsense, 1 splice-site, 1 deletion and 1 large transposal insertion IVS4ins6kb (GenBank accession number KF425758), were identified in CTLN2 or NICCD patients from China, Japan and Malaysia, respectively, making the SLC25A13 variations worldwide reach the total number of 81. A large NICCD cohort of 116 Chinese cases was also established, and the 4 high-frequency mutations contributed a much larger proportion of the mutated alleles in the patients from south China than in those from the north (χ2 = 14.93, P<0.01), with the latitude of 30°N as the geographic dividing line in mainland China. Conclusions This paper further enriched the SLC25A13 variation spectrum worldwide, and formed a substantial contribution to the in-depth understanding of the genotypic feature of Chinese CD patients.
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Chen R, Wang XH, Fu HY, Zhang SR, Abudouxikuer K, Saheki T, Wang JS. Different regional distribution of SLC25A13 mutations in Chinese patients with neonatal intrahepatic cholestasis. World J Gastroenterol 2013; 19:4545-4551. [PMID: 23901231 PMCID: PMC3725380 DOI: 10.3748/wjg.v19.i28.4545] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Revised: 04/24/2013] [Accepted: 06/04/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the differences in the mutation spectra of the SLC25A13 gene mutations from specific regions of China.
METHODS: Genetic analyses of SLC25A13 mutations were performed in 535 patients with neonatal intrahepatic cholestasis from our center over eight years. Unrelated infants with at least one mutant allele were enrolled to calculate the proportion of SLC25A13 mutations in different regions of China. The boundary between northern and southern China was drawn at the historical border of the Yangtze River.
RESULTS: A total of 63 unrelated patients (about 11% of cases with intrahepatic cholestasis) from 16 provinces or municipalities in China had mutations in the SLC25A13 gene, of these 16 (25%) were homozygotes, 28 (44%) were compound heterozygotes and 19 (30%) were heterozygotes. In addition to four well described common mutations (c.851_854del, c.1638_1660dup23, c.615+5G>A and c.1750+72_1751-4dup17insNM_138459.3:2667 also known as IVS16ins3kb), 13 other mutation types were identified, including three novel mutations: c.985_986insT, c.287T>C and c.1349A>G. According to the geographical division criteria, 60 mutant alleles were identified in patients from the southern areas of China, 43 alleles were identified in patients from the border, and 4 alleles were identified in patients from the northern areas of China. The proportion of four common mutations was higher in south region (56/60, 93%) than that in the border region (34/43, 79%, χ2 = 4.621, P = 0.032) and the northern region (2/4, 50%, χ2 = 8.288, P = 0.041).
CONCLUSION: The SLC25A13 mutation spectra among the three regions of China were different, providing a basis for the improvement of diagnostic strategies and interpretation of genetic diagnosis.
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Okano Y, Kobayashi K, Ihara K, Ito T, Yoshino M, Watanabe Y, Kaji S, Ohura T, Nagao M, Noguchi A, Mushiake S, Hohashi N, Hashimoto-Tamaoki T. Fatigue and quality of life in citrin deficiency during adaptation and compensation stage. Mol Genet Metab 2013; 109:9-13. [PMID: 23453692 DOI: 10.1016/j.ymgme.2013.01.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 01/30/2013] [Accepted: 01/30/2013] [Indexed: 10/27/2022]
Abstract
Citrin-deficient children and adolescents between adult-onset type II citrullinemia and neonatal intrahepatic cholestasis by citrin deficiency do not have clear clinical features except for unusual diet of high-fat, high-protein, and low-carbohydrate food. The aims of the present study are to characterize fatigue and quality of life (QOL) in citrin-deficient patients during adaptation and compensation stage, and to define the relationship between fatigue and QOL. The study subjects were 55 citrin-deficient patients aged 1-22years (29 males) and 54 guardians. Fatigue was evaluated by self-reports and proxy-reports of the PedsQL Multidimensional Fatigue Scale. QOL was evaluated by the PedsQL Generic Core Scales. Both scale scores were significantly lower in child self-reports (p<0.01 and p<0.05, respectively) and parent proxy-reports (p<0.01 and p<0.01, respectively) than those of healthy children. Citrin-deficient patients with scores of 50 percentile or less of healthy children constituted 67.5% of the sample for the Fatigue Scale and 68.4% for the Generic Core Scales. The PedsQL Fatigue Scale correlated with the Generic Core Scales for both the patients (r=0.56) and parents reports (r=0.71). Assessments by the patients and their parents showed moderate agreement. Parents assessed the condition of children more favorably than their children. The study identified severe fatigue and impaired QOL in citrin-deficient patients during the silent period, and that such children perceive worse fatigue and poorer QOL than those estimated by their parents. The results stress the need for active involvement of parents and medical staff in the management of citrin-deficient patients during the silent period.
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Affiliation(s)
- Yoshiyuki Okano
- Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, 663-8501, Japan.
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Saheki T, Inoue K, Ono H, Katsura N, Yokogawa M, Yoshidumi Y, Furuie S, Kuroda E, Ushikai M, Asakawa A, Inui A, Eto K, Kadowaki T, Sinasac DS, Yamamura KI, Kobayashi K. Effects of supplementation on food intake, body weight and hepatic metabolites in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse model of human citrin deficiency. Mol Genet Metab 2012; 107:322-9. [PMID: 22921887 DOI: 10.1016/j.ymgme.2012.07.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 07/24/2012] [Accepted: 07/24/2012] [Indexed: 01/19/2023]
Abstract
The C57BL/6:Slc23a13(-/-);Gpd2(-/-) double-knockout (a.k.a., citrin/mitochondrial glycerol 3-phosphate dehydrogenase double knockout or Ctrn/mGPD-KO) mouse displays phenotypic attributes of both neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2), making it a suitable model of human citrin deficiency. In the present study, we show that when mature Ctrn/mGPD-KO mice are switched from a standard chow diet (CE-2) to a purified maintenance diet (AIN-93M), this resulted in a significant loss of body weight as a result of reduced food intake compared to littermate mGPD-KO mice. However, supplementation of the purified maintenance diet with additional protein (from 14% to 22%; and concomitant reduction or corn starch), or with specific supplementation with alanine, sodium glutamate, sodium pyruvate or medium-chain triglycerides (MCT), led to increased food intake and body weight gain near or back to that on chow diet. No such effect was observed when supplementing the diet with other sources of fat that contain long-chain fatty acids. Furthermore, when these supplements were added to a sucrose solution administered enterally to the mice, which has been shown previously to lead to elevated blood ammonia as well as altered hepatic metabolite levels in Ctrn/mGPP-KO mice, this led to metabolic correction. The elevated hepatic glycerol 3-phosphate and citrulline levels after sucrose administration were suppressed by the administration of sodium pyruvate, alanine, sodium glutamate and MCT, although the effect of MCT was relatively small. Low hepatic citrate and increased lysine levels were only found to be corrected by sodium pyruvate, while alanine and sodium glutamate both corrected hepatic glutamate and aspartate levels. Overall, these results suggest that dietary factors including increased protein content, supplementation of specific amino acids like alanine and sodium glutamate, as well as sodium pyruvate and MCT all show beneficial effects on citrin deficiency by increasing the carbohydrate tolerance of Ctrn/mGPD-KO mice, as observed through increased food intake and maintenance of body weight.
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Affiliation(s)
- Takeyori Saheki
- Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan
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Lin WX, Zhang ZH, Deng M, Cai XR, Song YZ. Multiple ovarian antral follicles in a preterm infant with neonatal intrahepatic cholestasis caused by citrin deficiency: A clinical, genetic and transcriptional analysis. Gene 2012; 505:269-75. [DOI: 10.1016/j.gene.2012.06.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2012] [Revised: 06/03/2012] [Accepted: 06/07/2012] [Indexed: 01/14/2023]
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Kikuchi A, Arai-Ichinoi N, Sakamoto O, Matsubara Y, Saheki T, Kobayashi K, Ohura T, Kure S. Simple and rapid genetic testing for citrin deficiency by screening 11 prevalent mutations in SLC25A13. Mol Genet Metab 2012; 105:553-8. [PMID: 22277121 DOI: 10.1016/j.ymgme.2011.12.024] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2011] [Revised: 12/29/2011] [Accepted: 12/30/2011] [Indexed: 12/29/2022]
Abstract
Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and has two disease outcomes: adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency. The clinical appearance of these diseases is variable, ranging from almost no symptoms to coma, brain edema, and severe liver failure. Genetic testing for SLC25A13 mutations is essential for the diagnosis of citrin deficiency because chemical diagnoses are prohibitively difficult. Eleven SLC25A13 mutations account for 95% of the mutant alleles in Japanese patients with citrin deficiency. Therefore, a simple test for these mutations is desirable. We established a 1-hour, closed-tube assay for the 11 SLC25A13 mutations using real-time PCR. Each mutation site was amplified by PCR followed by a melting-curve analysis with adjacent hybridization probes (HybProbe, Roche). The 11 prevalent mutations were detected in seven PCR reactions. Six reactions were used to detect a single mutation each, and one reaction was used to detect five mutations that are clustered in a 21-bp region in exon 17. To test the reliability, we used this method to genotype blind DNA samples from 50 patients with citrin deficiency. Our results were in complete agreement those obtained using previously established methods. Furthermore, the mutations could be detected without difficulty using dried blood samples collected on filter paper. Therefore, this assay could be used for newborn screening and for facilitating the genetic diagnosis of citrin deficiency, especially in East Asian populations.
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Affiliation(s)
- Atsuo Kikuchi
- Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
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Saheki T, Inoue K, Ono H, Tushima A, Katsura N, Yokogawa M, Yoshidumi Y, Kuhara T, Ohse M, Eto K, Kadowaki T, Sinasac DS, Kobayashi K. Metabolomic analysis reveals hepatic metabolite perturbations in citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mice, a model of human citrin deficiency. Mol Genet Metab 2011; 104:492-500. [PMID: 21908222 DOI: 10.1016/j.ymgme.2011.08.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 08/14/2011] [Accepted: 08/14/2011] [Indexed: 02/08/2023]
Abstract
The citrin/mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse displays phenotypic attributes of both neonatal intrahepatic cholestasis and adult-onset type II citrullinemia, making it a suitable model of human citrin deficiency. In the present study, we investigated metabolic disturbances in the livers of wild-type, citrin (Ctrn) knockout, mGPD knockout, and Ctrn/mGPD double-knockout mice following oral sucrose versus saline administration using metabolomic approaches. By using gas chromatography/mass spectrometry and capillary electrophoresis/mass spectrometry, we found three general groupings of metabolite changes in the livers of the double-knockout mice following sucrose administration that were subsequently confirmed using liquid chromatography/mass spectrometry or enzymatic methods: a marked increase of hepatic glycerol 3-phosphate, a generalized decrease of hepatic tricarboxylic acid cycle intermediates, and alterations of hepatic amino acid levels related to the urea cycle or lysine catabolism including marked increases in citrulline and lysine. Furthermore, concurrent oral administration of sodium pyruvate with sucrose ameliorated the hyperammonemia induced by sucrose, as had been shown previously, as well as almost completely normalizing the hepatic metabolite perturbations found. Overall, we have identified additional metabolic disturbances in double-KO mice following oral sucrose administration, and provided further evidence for the therapeutic use of sodium pyruvate in our mouse model of citrin deficiency.
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Affiliation(s)
- Takeyori Saheki
- Institute for Health Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima, Japan.
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Hayasaka K, Numakura C, Toyota K, Kimura T. Treatment with lactose (galactose)-restricted and medium-chain triglyceride-supplemented formula for neonatal intrahepatic cholestasis caused by citrin deficiency. JIMD Rep 2011; 2:37-44. [PMID: 23430852 DOI: 10.1007/8904_2011_42] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2010] [Revised: 03/21/2011] [Accepted: 03/22/2011] [Indexed: 01/30/2023] Open
Abstract
Citrin plays a role in the transfer of NADH-reducing equivalent from cytosol to mitochondria as part of the malate-aspartate shuttle in liver. Citrin deficiency may cause an impairment of glycolysis due to an increase in the cytosolic NADH/NAD ratio leading to an energy shortage in the liver. Mutations of the SLC25A13 gene are responsible for neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Most patients with NICCD show a resolution of symptoms within the first year of life, but some patients present with severe symptoms and require liver transplantation. We treated four patients including three siblings with NICCD by lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula. This formula rapidly improved the clinical condition and laboratory findings. Early treatment was more effective and did not require long-term administration. Lactose (galactose)-restriction can avoid further increase in the cytosolic NADH/NAD ratio in the liver and MCT supplementation can provide energy to hepatic cells by producing an excess of acetyl-CoA in mitochondria. Early treatment with lactose (galactose)-restricted and MCT-supplemented formula is recommended for patients with NICCD and possibly for patients with CTLN2.
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Affiliation(s)
- K Hayasaka
- Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan,
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Fu HY, Zhang SR, Wang XH, Saheki T, Kobayashi K, Wang JS. The mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and aminoacidemia. J Gastroenterol 2011; 46:510-8. [PMID: 20927635 DOI: 10.1007/s00535-010-0329-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Accepted: 09/10/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND SLC25A13 gene mutations cause citrin deficiency, which leads to neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Information on the mutation spectrum of SLC25A13 in the Chinese population is limited. The aim of this study was to explore the mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and various forms of aminoacidemia. METHODS Sequence analyses were performed on 39 infants with intrahepatic cholestasis and various forms of aminoacidemia. Novel mutations were subjected to homology and structural analyses. Western blots were performed when liver specimens available. RESULTS Genetic testing revealed the presence of SLC25A13 gene mutations (9 heterozygotes, 6 homozygotes and 13 compound heterozygotes) in 28 infants. Subsequent Western blot analysis revealed 22 cases of citrin deficiency, accounting for 56.4% of the 39 patients. Twelve types of mutations, including nine known mutations and three novel mutations, were found. Of the 49 mutated alleles, known ones include 851del4 (26 alleles, 53.1%), 1638ins23 (6 alleles, 12.2%), IVSl6ins3kb (3 alleles, 6.1%), IVS6+5G>A (2 alleles, 4.1%), E601K (2 alleles, 4.1%) and IVS11+1G>A, R184X, R360X and R585H (1 allele each, 2.0%). The three novel mutations were a splice site change (IVS6+1G>A), a deletion mutation (1092_1095delT) and a missense mutation (L85P), each in one allele. CONCLUSIONS The mutation spectrum of the SLC25A13 gene in a Chinese population of infants with intrahepatic cholestasis with various forms of aminoacidemia was found to be different from that of other population groups in East Asia. The SLC25A13 gene mutation is the most important cause of infantile intrahepatic cholestasis with various forms of aminoacidemia.
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Affiliation(s)
- Hai-Yan Fu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai 201102, People's Republic of China
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Mudd SH. Hypermethioninemias of genetic and non-genetic origin: A review. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2011; 157C:3-32. [PMID: 21308989 DOI: 10.1002/ajmg.c.30293] [Citation(s) in RCA: 147] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia. The genetic conditions are: (1) Homocystinuria due to cystathionine β-synthase (CBS) deficiency. At least 150 different mutations in the CBS gene have been identified since this deficiency was established in 1964. Hypermethioninemia is due chiefly to remethylation of the accumulated homocysteine. (2) Deficient activity of methionine adenosyltransferases I and III (MAT I/III), the isoenzymes the catalytic subunit of which are encoded by MAT1A. Methionine accumulates because its conversion to S-adenosylmethionine (AdoMet) is impaired. (3) Glycine N-methyltrasferase (GNMT) deficiency. Disruption of a quantitatively major pathway for AdoMet disposal leads to AdoMet accumulation with secondary down-regulation of methionine flux into AdoMet. (4) S-adenosylhomocysteine (AdoHcy) hydrolase (AHCY) deficiency. Not being catabolized normally, AdoHcy accumulates and inhibits many AdoMet-dependent methyltransferases, producing accumulation of AdoMet and, thereby, hypermethioninemia. (5) Citrin deficiency, found chiefly in Asian countries. Lack of this mitochondrial aspartate-glutamate transporter may produce (usually transient) hypermethioninemia, the immediate cause of which remains uncertain. (6) Fumarylacetoacetate hydrolase (FAH) deficiency (tyrosinemia type I) may lead to hypermethioninemia secondary either to liver damage and/or to accumulation of fumarylacetoacetate, an inhibitor of the high K(m) MAT. Additional possible genetic causes of hypermethioninemia accompanied by elevations of plasma AdoMet include mitochondrial disorders (the specificity and frequency of which remain to be elucidated). Non-genetic conditions include: (a) Liver disease, which may cause hypermethioninemia, mild, or severe. (b) Low-birth-weight and/or prematurity which may cause transient hypermethioninemia. (c) Ingestion of relatively large amounts of methionine which, even in full-term, normal-birth-weight babies may cause hypermethioninemia.
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Affiliation(s)
- S Harvey Mudd
- Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD, USA.
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High resolution melting analysis for the detection of SLC25A13 gene mutations in Taiwan. Clin Chim Acta 2010; 412:460-5. [PMID: 21134364 DOI: 10.1016/j.cca.2010.11.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 11/06/2010] [Accepted: 11/20/2010] [Indexed: 11/24/2022]
Abstract
BACKGROUND Citrin, encoded by SLC25A13 gene, is a mitochondrial solute transporter with a crucial role in urea, nucleotide and protein synthesis. SLC25A13 mutations cause two phenotypes, adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This study aimed to develop a high resolution melting (HRM) analysis for SLC25A13 mutation scanning and determine the carrier rate in Taiwan. METHODS DNAs from healthy subjects (n=479), and patients with hepatocellular carcinoma (HCC, n=100) and NICCD (n=5) were scanned in exons 6, 9, 11, 16, and 17 and parts of introns of SLC25A13 using HRM analysis. All mutations detected by HRM analysis were further confirmed by TaqMan method and/or direct sequencing. RESULTS In healthy subjects, seventeen carriers with mutants c.851_854del (n=10), c.1638_1660dup, c.615+5G>A (n=4), and two novel mutants, c.475C>T and c.1658G>A, were detected. The frequency of carriers was about 1/28. In patients with HCC, there were only 2 carriers with c.851_854del mutant. Patients with NICCD (n=5) diagnosed during 2007 and 2008, harbored compound heterozygous mutations c.851_854del/c.1177+1G>A, c.851_854del/c.1638_1660dup (n=2), c.851_854del/c.615+5G>A, and c.1638_1660dup/c.615+5G>A. CONCLUSIONS HRM analysis is a simple, rapid and robust method for detecting SLC25A13 mutations in clinical laboratories. SLC25A13 mutations may not be a major contributor to the pathogenesis of HCC in Taiwan.
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