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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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6
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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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Okano M, Yasuda M, Shimomura Y, Matsuoka Y, Shirouzu Y, Fujioka T, Kyo M, Tsuji S, Kaneko K, Hitomi H. Citrin-deficient patient-derived induced pluripotent stem cells as a pathological liver model for congenital urea cycle disorders. Mol Genet Metab Rep 2024; 40:101096. [PMID: 38872960 PMCID: PMC11170474 DOI: 10.1016/j.ymgmr.2024.101096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 05/19/2024] [Accepted: 05/21/2024] [Indexed: 06/15/2024] Open
Abstract
Citrin deficiency is a congenital secondary urea cycle disorder lacking useful disease models for effective treatment development. In this study, human induced pluripotent stem cells (iPSCs) were generated from two patients with citrin deficiency and differentiated into hepatocyte-like cells (HLCs). Citrin-deficient HLCs produced albumin and liver-specific markers but completely lacked citrin protein and expressed argininosuccinate synthase only weakly. In addition, ammonia concentrations in a medium cultured with citrin-deficient HLCs were higher than with control HLCs. Sodium pyruvate administration significantly reduced ammonia concentrations in the medium of citrin-deficient HLCs and slightly reduced ammonia in HLCs differentiated from control iPSCs, though this change was not significant. Our results suggest that sodium pyruvate may be an efficient treatment for patients with citrin deficiency. Citrin-deficient iPSCs are a pathological liver model for congenital urea cycle disorders to clarify pathogenesis and develop novel therapies.
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Affiliation(s)
- Mai Okano
- Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Masahiro Yasuda
- Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Yui Shimomura
- Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan
| | - Yoshikazu Matsuoka
- Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan
| | - Yasumasa Shirouzu
- Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan
| | - Tatsuya Fujioka
- Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan
| | - Masatoshi Kyo
- Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan
| | - Shoji Tsuji
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Hirofumi Hitomi
- Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University, Osaka, Japan
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8
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Suzuki T, Matsuura K, Imura N, Kawamura H, Kuno K, Fujiwara K, Nojiri S, Ito S, Togawa T, Kataoka H. Adult-onset Type II Citrullinemia Developed under Dietary Restrictions during Imprisonment. Intern Med 2024; 63:833-837. [PMID: 37495534 PMCID: PMC11008984 DOI: 10.2169/internalmedicine.1954-23] [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: 03/13/2023] [Accepted: 06/18/2023] [Indexed: 07/28/2023] Open
Abstract
A 29-year-old man presented with liver damage, and a liver biopsy was performed, but the cause was unclear. Thereafter, he was referred to our hospital. We found that he had been unable to consume carbohydrates in his diet and preferred fried chicken since childhood. In addition, he had shown disturbance of consciousness and abnormal behavior while he had been in prison, where dietary intake had been restricted. A plasma amino acid analysis revealed hypercitrullinemia. Therefore, we suspected adult-onset type II citrullinemia (CTLN2). Genetic testing showed pathologic variations in the SLC25A13 gene, which allowed us to make a definite diagnosis of CTLN2.
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Affiliation(s)
- Takanori Suzuki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Naoto Imura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Hayato Kawamura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Kayoko Kuno
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Kei Fujiwara
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Shunsuke Nojiri
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Shogo Ito
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Takao Togawa
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Japan
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9
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Murali CN, Barber JR, McCarter R, Zhang A, Gallant N, Simpson K, Dorrani N, Wilkening GN, Hays RD, Lichter-Konecki U, Burrage LC, Nagamani SCS. Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders. Mol Genet Metab 2023; 140:107696. [PMID: 37690181 PMCID: PMC10866211 DOI: 10.1016/j.ymgme.2023.107696] [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: 06/21/2023] [Revised: 09/01/2023] [Accepted: 09/02/2023] [Indexed: 09/12/2023]
Abstract
PURPOSE Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. METHODS We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. RESULTS Individuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. CONCLUSION Individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.
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Affiliation(s)
- Chaya N Murali
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA
| | - John R Barber
- Children's National Health System, Washington, DC, USA
| | | | - Anqing Zhang
- Children's National Health System, Washington, DC, USA
| | - Natalie Gallant
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
| | - Kara Simpson
- Children's National Health System, Washington, DC, USA
| | - Naghmeh Dorrani
- Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Ron D Hays
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Uta Lichter-Konecki
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Lindsay C Burrage
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA
| | - Sandesh C S Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
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10
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Cong PK, Khederzadeh S, Yuan CD, Ma RJ, Zhang YY, Liu JQ, Yu SH, Xu L, Gao JH, Pan HX, Li JC, Xie SY, Liu KQ, Tang BS, Zheng HF. Identification of clinically actionable secondary genetic variants from whole-genome sequencing in a large-scale Chinese population. Clin Transl Med 2022; 12:e866. [PMID: 35538921 PMCID: PMC9091982 DOI: 10.1002/ctm2.866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/17/2022] [Accepted: 04/22/2022] [Indexed: 11/12/2022] Open
Affiliation(s)
- Pei-Kuan Cong
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.,Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.,Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Saber Khederzadeh
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.,Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.,Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Cheng-Da Yuan
- Department of Dermatology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Rui-Jie Ma
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Yi-Yao Zhang
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Jun-Quan Liu
- Clinical Genome Center, KingMed Diagnostics, Co. Ltd., Guangzhou, Guangdong, China
| | - Shi-Hui Yu
- Clinical Genome Center, KingMed Diagnostics, Co. Ltd., Guangzhou, Guangdong, China
| | - Lin Xu
- WBBC Shandong Center, Binzhou Medical University, Yantai, Shandong, China
| | - Jian-Hua Gao
- WBBC Jiangxi Center, Jiangxi Medical College, Shangrao, Jiangxi, China
| | - Hong-Xu Pan
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jin-Chen Li
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shu-Yang Xie
- WBBC Shandong Center, Binzhou Medical University, Yantai, Shandong, China
| | - Ke-Qi Liu
- WBBC Jiangxi Center, Jiangxi Medical College, Shangrao, Jiangxi, China
| | - Bei-Sha Tang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hou-Feng Zheng
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.,Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.,Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
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11
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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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12
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Suzuki T, Wada Y, Mikami-Saito Y, Kikuchi A, Kure S. Usefulness of serum BUN or BUN/creatinine ratio as markers for citrin deficiency in positive cases of newborn screening. Mol Genet Metab Rep 2022; 30:100834. [PMID: 35242568 PMCID: PMC8856906 DOI: 10.1016/j.ymgmr.2021.100834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/10/2021] [Accepted: 12/11/2021] [Indexed: 10/25/2022] Open
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13
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张 妮, 张 占, 林 伟, 张 萌, 李 冰. Physical and neuropsychological development of children with Citrin deficiency. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2021; 23:1262-1266. [PMID: 34911610 PMCID: PMC8690716 DOI: 10.7499/j.issn.1008-8830.2108115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/01/2021] [Indexed: 01/24/2023]
Abstract
OBJECTIVES To study the physical and neuropsychological development of children with Citrin deficiency (CD). METHODS A total of 93 children, aged 1.9-59.8 months, who were diagnosed with CD by SLC25A13 gene analysis in the First Affiliated Hospital of Jinan University from August 2010 to August 2015, were enrolled as subjects. A retrospective analysis was performed for their birth condition and physical growth and neuropsychological development indices. Among these children, 7 underwent physical measurement and neuropsychological development assessment within 1 year old and after 1 year old, and therefore, a total of 100 cases were included for analysis. RESULTS For the 93 children with CD, the incidence rate of failure to thrive was 25% (23 children) and the proportion of small for gestational age was 47% (44 children). For the 100 cases of CD, the incidence rates of growth retardation, underweight, emaciation, overweight, and microcephalus were 23% (23 cases), 14% (14 cases), 4% (4 cases), 8% (8 cases), and 9% (9 cases), respectively. The incidence rate of neuropsychological developmental delay was 25% (25 cases), and the incidence rates of development delay in the five domains of adaptability, gross motor, fine motor, language, and social ability were 7% (7 cases), 15% (15 cases), 7% (7 cases), 9% (9 cases), and 7% (7 cases), respectively. CONCLUSIONS Physical and neuropsychological developmental delay can be observed in children with CD, and physical and neuropsychological development should be regularly assessed.
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14
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Okamoto M, Okano Y, Okano M, Yazaki M, Inui A, Ohura T, Murayama K, Watanabe Y, Tokuhara D, Takeshima Y. Food Preferences of Patients with Citrin Deficiency. Nutrients 2021; 13:nu13093123. [PMID: 34579000 PMCID: PMC8468903 DOI: 10.3390/nu13093123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 01/25/2023] Open
Abstract
Citrin deficiency is characterized by a wide range of symptoms from infancy through adulthood and presents a distinct preference for a diet composed of high protein, high fat, and low carbohydrate. The present study elucidates the important criteria by patients with citrin deficiency for food selection through detailed analysis of their food preferences. The survey was conducted in 70 citrin-deficient patients aged 2–63 years and 55 control subjects aged 2–74 years and inquired about their preference for 435 food items using a scale of 1–4 (the higher, the more favored). The results showed that the foods marked as “dislike” accounted for 36.5% in the patient group, significantly higher than the 16.0% in the controls. The results also showed that patients clearly disliked foods with 20–24 (% of energy) or less protein, 45–54% (of energy) or less fat, and 30–39% (of energy) or more carbohydrate. Multiple regression analysis showed carbohydrates had the strongest influence on patients’ food preference (β = −0.503). It also showed female patients had a stronger aversion to foods with high carbohydrates than males. The protein, fat, and carbohydrate energy ratio (PFC) of highly favored foods among patients was almost the same as the average PFC ratio of their daily diet (protein 20–22: fat 47–51: carbohydrates 28–32). The data strongly suggest that from early infancy, patients start aspiring to a nutritional balance that can compensate for the metabolism dissonance caused by citrin deficiency in every food.
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Affiliation(s)
| | - Yoshiyuki Okano
- Okano Children’s Clinic, Izumi 594-0071, Japan;
- Department of Pediatrics, Hyogo College of Medicine, Nishinomiya 663-8501, Japan;
- Correspondence: ; Tel.: +81-725-40-1199; Fax: +81-725-40-1099
| | - Mai Okano
- Department of Pediatrics, Kansai Medical University, Hirakata 573-1010, 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, Kurume University School of Medicine, Kurume 830-0011, Japan;
- 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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15
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Fernández Tomé L, Stark Aroeira LG, Muñoz Bartolo G, de la Vega Bueno A, Camarena Grande C, Frauca Remacha E, Lledín Barbancho D, Alós Díez M, Quiles Blanco MJ, Guerra L, López Santamaría M, Hierro Llanillo L. Citrin deficiency: Early severe cases in a European country. Clin Res Hepatol Gastroenterol 2021; 45:101595. [PMID: 33386245 DOI: 10.1016/j.clinre.2020.101595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/03/2020] [Accepted: 12/12/2020] [Indexed: 02/04/2023]
Affiliation(s)
| | | | - Gema Muñoz Bartolo
- Paediatric Hepatology Service, University Hospital La Paz, Madrid, Spain
| | | | | | | | | | - María Alós Díez
- Paediatric Hepatology Service, University Hospital La Paz, Madrid, Spain
| | | | - Laura Guerra
- Department of Pathology, University Hospital La Paz, Madrid, Spain
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16
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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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17
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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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18
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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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20
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Wada Y, Arai-Ichinoi N, Kikuchi A, Sakamoto O, Kure S. Hypoketotic hypoglycemia in citrin deficiency: a case report. BMC Pediatr 2020; 20:444. [PMID: 32962675 PMCID: PMC7507238 DOI: 10.1186/s12887-020-02349-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/15/2020] [Indexed: 12/17/2022] Open
Abstract
Background Citrin deficiency (CD) is a recessive metabolic disease caused by biallelic pathogenic variants in SLC25A13. Although previous studies have reported ketosis in CD, it was observed at the time of euglycemia or mild hypoglycemia. Blood ketone levels concomitant with symptomatic or severe hypoglycemia in CD have not been a topic of focus despite its importance in identifying the etiology of hypoglycemia and assessing the ability of fatty acid utilization. Herein, we describe a patient with CD who had repeated episodes of hypoglycemia with insufficient ketosis. Case presentation A 1-year-old boy with repetitive hypoglycemia was referred to us to investigate its etiology. The fasting load for 13 h led to hypoketotic hypoglycemia, indicating the possibility of partial β-oxidation dysfunction. A genetic test led to the diagnosis of CD. The hypoglycemic episodes disappeared after switching to a medium-chain triglyceride-containing formula. Conclusions This case report suggests that symptomatic or severe hypoglycemia in patients with CD could be associated with relatively low levels of ketone bodies, implying that β-oxidation in these patients might possibly be partially disrupted. When encountering a patient with hypoglycemia, clinicians should check blood ketone levels and bear in mind the possibility of CD because excessive intravenous administration of glucose can cause decompensated symptoms in patients with CD as opposed to other disorders presenting with hypoketotic hypoglycemia, such as fatty acid oxidation disorders. Further studies in a large-scale cohort are warranted to confirm our speculation.
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Affiliation(s)
- Yoichi Wada
- Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
| | - Natsuko Arai-Ichinoi
- Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Atsuo Kikuchi
- Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Osamu Sakamoto
- Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan
| | - Shigeo Kure
- Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi, 980-8574, Japan.,Tohoku Medical Megabank Organization, 2-1, Seiryomachi, Aobaku, Sendai, Miyagi, 980-8573, Japan
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21
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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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22
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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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23
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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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24
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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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25
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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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26
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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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27
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Numakura C, Tamiya G, Ueki M, Okada T, Maisawa SI, Kojima-Ishii K, Murakami J, Horikawa R, Tokuhara D, Ito K, Adachi M, Abiko T, Mitsui T, Hayasaka K. Growth impairment in individuals with citrin deficiency. J Inherit Metab Dis 2019; 42:501-508. [PMID: 30715743 DOI: 10.1002/jimd.12051] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 01/04/2019] [Indexed: 11/06/2022]
Abstract
Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Owing to a defect in the NADH-shuttle, citrin deficiency impairs hepatic glycolysis and de novo lipogenesis leading to hepatic energy deficit. To investigate the physiological role of citrin, we studied the growth of 111 NICCD-affected subjects (51 males and 60 females) and 12 NICCD-unaffected subjects (five males and seven females), including the body weight, height, and genotype. We constructed growth charts using the lambda-mu-sigma (LMS) method. The NICCD-affected subjects showed statistically significant growth impairment, including low birth weight and length, low body weight until 6 to 9 months of age, low height until 11 to 13 years of age, and low body weight in 7 to 12-year-old males and 8-year-old females. NICCD-unaffected subjects showed similar growth impairment, including low birth weight and height, and growth impairment during adolescence. In the third trimester, de novo lipogenesis is required for deposition of body fat and myelination of the developing central nervous system, and its impairment likely causes low birth weight and length. The growth rate is the highest during the first 6 months of life and slows down after 6 months of age, which is probably associated with the onset and recovery of NICCD. Adolescence is the second catch-up growth period, and the proportion and distribution of body fat change depending on age and sex. Characteristic growth impairment in citrin deficiency suggests a significant role of citrin in the catch-up growth via lipogenesis.
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Affiliation(s)
- Chikahiko Numakura
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Gen Tamiya
- Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan
- Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Masao Ueki
- Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Tomoo Okada
- Department of Nutrition and Health Science, Kanagawa Institute of Technology, Kanagawa, Japan
| | - Shun-Ichi Maisawa
- Department of Pediatrics, Morioka Children's Hospital, Morioka, Japan
| | - Kanako Kojima-Ishii
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Murakami
- Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Reiko Horikawa
- Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan
| | - Daisuke Tokuhara
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Ito
- Department of Pediatrics and Neonatology, Graduate School of Medical, Sciences, Nagoya City University, Nagoya, Japan
| | - Masanori Adachi
- Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Takahiro Abiko
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Tetsuo Mitsui
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Kiyoshi Hayasaka
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
- Department of Pediatrics, Miyukikai Hospital, Kaminoyama, Japan
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28
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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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29
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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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30
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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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31
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Sangkhathat S, Laochareonsuk W, Maneechay W, Kayasut K, Chiengkriwate P. Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand. J Pediatr Genet 2018; 7:67-73. [PMID: 29707407 DOI: 10.1055/s-0038-1632395] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 01/14/2018] [Indexed: 02/08/2023]
Abstract
Biliary atresia (BA) is the most severe form of obstructive cholangiopathy occurring in infants. Definitive diagnosis of BA usually relies on operative findings together with supporting pathological patterns found in the extrahepatic bile duct. In infancy, overlapping clinical patterns of cholestasis can be found in other diseases including biliary hypoplasia and progressive familial intrahepatic cholestasis. In addition, BA has been reported as a phenotype in some rare genetic syndromes. Unlike BA, other cholangiopathic phenotypes have their own established genetic markers. In this study, we used these markers to look for other cholestasis entities in cases diagnosed with BA. DNA from 20 cases of BA, diagnosed by operative findings and histopathology, were subjected to a study of 19 genes associated with infantile cholestasis syndromes, using whole exome sequencing. Variant selection focused on those with allele frequencies in dbSNP150 of less than 0.01. All selected variants were verified by polymerase chain reaction-direct sequencing. Of the 20 cases studied, 13 rare variants were detected in 9 genes: 4 in JAG1 (Alagille syndrome), 2 in MYO5B (progressive familial intrahepatic cholestasis [PFIC] type 6), and one each in ABCC2 (Dubin-Johnson syndrome), ABCB11 (PFIC type 2), UG1A1 (Crigler-Najjar syndrome), MLL2 (Kabuki syndrome), RFX6 (Mitchell-Riley syndrome), ERCC4 (Fanconi anemia), and KCNH1 (Zimmermann-Laband syndrome). Genetic lesions associated with various cholestatic syndromes detected in cases diagnosed with BA raised the hypothesis that severe inflammatory cholangiopathy in BA may not be a distinct disease entity, but a shared pathology among several infantile cholestatic syndromes.
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Affiliation(s)
- Surasak Sangkhathat
- Pediatric Surgery Unit, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Wison Laochareonsuk
- Pediatric Surgery Unit, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Wanwisa Maneechay
- Central Research Laboratory, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Kanita Kayasut
- Anatomical Pathology Unit, Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Piyawan Chiengkriwate
- Pediatric Surgery Unit, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
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32
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Buffet A, Morin A, Castro-Vega LJ, Habarou F, Lussey-Lepoutre C, Letouzé E, Lefebvre H, Guilhem I, Haissaguerre M, Raingeard I, Padilla-Girola M, Tran T, Tchara L, Bertherat J, Amar L, Ottolenghi C, Burnichon N, Gimenez-Roqueplo AP, Favier J. Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer Res 2018; 78:1914-1922. [PMID: 29431636 DOI: 10.1158/0008-5472.can-17-2463] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 12/14/2017] [Accepted: 01/31/2018] [Indexed: 11/16/2022]
Abstract
Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation.Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914-22. ©2018 AACR.
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Affiliation(s)
- Alexandre Buffet
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Aurélie Morin
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Luis-Jaime Castro-Vega
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Florence Habarou
- Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Biochimie Métabolique, Paris, France
| | - Charlotte Lussey-Lepoutre
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Eric Letouzé
- Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France.,INSERM, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, Paris, France.,Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France.,Université Paris Diderot, Paris, France
| | - Hervé Lefebvre
- Service d'Endocrinologie, Diabète et Maladies Métaboliques, INSERM U982, Centre Hospitalier Universitaire de Rouen, Rouen Cedex, France
| | - Isabelle Guilhem
- Service d'Endocrinologie-Diabétologie-Nutrition, CHU de Rennes, Hôpital Sud, Rennes, France
| | | | - Isabelle Raingeard
- Service d'Endocrinologie, CHU Montpellier, Hôpital Lapeyronie, Montpellier Cedex 5, France
| | - Mathilde Padilla-Girola
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer
| | - Thi Tran
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Lucien Tchara
- Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Biochimie Métabolique, Paris, France
| | - Jérôme Bertherat
- Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Service d'Endocrinologie "Centre de référence maladies rares de la surrénale", Hôpital Cochin, Assistance Publique, Hôpitaux de Paris, Paris, France.,Centre Expert National COMETE-Cancer de la surrénale, Paris, France
| | - Laurence Amar
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Centre Expert National COMETE-Cancer de la surrénale, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'hypertension artérielle et médecine vasculaire, Paris, France
| | - Chris Ottolenghi
- Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Biochimie Métabolique, Paris, France
| | - Nelly Burnichon
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France
| | - Anne-Paule Gimenez-Roqueplo
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer. .,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Centre Expert National COMETE-Cancer de la surrénale, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France
| | - Judith Favier
- INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer. .,Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, 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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35
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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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36
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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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Inherited metabolic diseases in the Southern Chinese population: spectrum of diseases and estimated incidence from recurrent mutations. Pathology 2015; 46:375-82. [PMID: 24992243 DOI: 10.1097/pat.0000000000000140] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Inherited metabolic diseases (IMDs) are a large group of rare genetic diseases. The spectrum and incidences of IMDs differ among populations, which has been well characterised in Caucasians but much less so in Chinese. In a setting of a University Hospital Metabolic Clinic in Hong Kong, over 100 patients with IMDs have been seen during a period of 13 years (from 1997 to 2010). The data were used to define the spectrum of diseases in the Southern Chinese population. Comparison with other populations revealed a unique spectrum of common IMDs. Furthermore, the incidence of the common IMDs was estimated by using population carrier frequencies of known recurrent mutations. Locally common diseases (their estimated incidence) include (1) glutaric aciduria type 1 (∼1/60,000), (2) multiple carboxylase deficiency (∼1/60,000), (3) primary carnitine deficiency (∼1/60,000), (4) carnitine-acylcarnitine translocase deficiency (∼1/60,000), (5) glutaric aciduria type 2 (∼1/22,500), (6) citrin deficiency (∼1/17,000), (7) tetrahydrobiopterin-deficient hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency (∼1/60,000), (8) glycogen storage disease type 1 (∼1/150,000). In addition, ornithine carbamoyltransferase deficiency and X-linked adrenoleukodystrophy are common X-linked diseases. Findings of the disease spectrum and treatment outcome are summarised here which may be useful for clinical practice. In addition, data will also be useful for policy makers in planning of newborn screening programs and resource allocation.
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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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Liu G, Wei X, Chen R, Zhou H, Li X, Sun Y, Xie S, Zhu Q, Qu N, Yang G, Chu Y, Wu H, Lan Z, Wang J, Yang Y, Yi X. A novel mutation of the SLC25A13 gene in a Chinese patient with citrin deficiency detected by target next-generation sequencing. Gene 2014; 533:547-53. [DOI: 10.1016/j.gene.2013.10.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2012] [Revised: 10/06/2013] [Accepted: 10/11/2013] [Indexed: 01/29/2023]
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Wongkittichote P, Sukasem C, Kikuchi A, Aekplakorn W, Jensen LT, Kure S, Wattanasirichaigoon D. Screening of SLC25A13 mutation in the Thai population. World J Gastroenterol 2013; 19:7735-7742. [PMID: 24282362 PMCID: PMC3837273 DOI: 10.3748/wjg.v19.i43.7735] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 08/29/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the prevalence of SLC25A13 mutations in the Thai population.
METHODS: A total of 1537 subjects representing the Thai population were screened for a novel pathologic allele p.Met1? (c.2T > C) and six previously known common SLC25A13 mutations: [I] (c.851_854delGTAT), [II] (g.IVS11 + 1G > A), [III] (c.1638_1660dup), [IV] (p.S225X), [V] (IVS13 + 1G > A), and [XIX] (g.IVS16ins3kb) using a newly developed TaqMan and established HybProbe assay, respectively. Sanger sequencing was employed for specimens showing an aberrant peak to confirm the targeted mutation as well as the unknown aberrant peaks detected. Frequencies of the mutations identified were compared in each region. Carrier frequency and disease prevalence of citrin deficiency caused by SCL25A13 mutations were estimated.
RESULTS: p.Met1? was identified in the heterozygous state in 85 individuals, giving a carrier frequency of 1/18, which suggests possible selective advantage of this variant. The question of p.Met1? homozygote lethality remains unanswered which may serve as an explanation as to why this homozygote has yet to be identified in patients/controls even with high allele frequency. The p.Met1? mutation has rarely been studied in populations other than Thai and Chinese; therefore, may have been overlooked. Development of the TaqMan assay in the present study would allow a simple, rapid, and cost-effective method for mass screening. Heterozygous mutations: [XIX] and [I] were identified in 17 individuals, giving a carrier rate of 1/90 and a calculated homozygote rate of 1/33000. Two novel variants, g.IVS11 + 17C > G and c.1311C > T, of unknown clinical significance were identified at low frequency.
CONCLUSION: This study highlighted the current underestimation of citrin deficiency and suggests the possible selective advantage of the p.Met1? allele.
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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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Wu QP, Wang LL, Chen XQ, Tang Q, Shan QW, Huang L, Lian SJ, Yun X, Gao GP, Chen Y. Screening of SLC25A13 gene mutations in infants with idiopathic intrahepatic cholestasis in Guangxi. Shijie Huaren Xiaohua Zazhi 2013; 21:1120-1125. [DOI: 10.11569/wcjd.v21.i12.1120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To screen SLC25A13 gene mutations in idiopathic infantile hepatitis cholestasis in Guangxi, China.
METHODS: Sixty-three patients with idiopathic infantile cholestasis, who were hospitalized in the Department of Pediatrics of the First Affiliated Hospital of Guangxi Medical University from September 2010 to June 2012, and 50 infants without intrahepatic cholestasis were included in this study. Genomic DNA was prepared from peripheral blood of all subjects for further analysis. For the case group, Citrin deficiency was screened using the tandem mass spectrometry (MS-MS, using blood samples) and gas chromatography mass spectrometry (GC-MS, using urine samples). Direct gene sequencing was performed in patients who were suspected to have Citrin deficiency. Twelve common SLC25A13 gene hot-spot mutations were screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) in the remaining patients and controls.
RESULTS: MS-MS and GC-MS analyses suggested that five patients were suspected to have Citrin deficiency, but the 12 common SLC25A13 gene hot-spot mutations were not detected in these patients in a further DNA sequencing analysis. The 12 common SLC25A13 gene hot-spot mutations were also not detected by PCR-SSCP in the remaining patients and controls.
CONCLUSION: The 12 common SLC25A13 gene hot-spot mutations were not found in patients who were suspected to have Citrin deficiency and the other patients and controls. Other rare SLC25A13 gene mutations should be screened in more patients.
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Häberle J. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. Arch Biochem Biophys 2013; 536:101-8. [PMID: 23628343 DOI: 10.1016/j.abb.2013.04.009] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 04/16/2013] [Accepted: 04/17/2013] [Indexed: 02/08/2023]
Abstract
An increased concentration of ammonia is a non-specific laboratory sign indicating the presence of potentially toxic free ammonia that is not normally removed. This does occur in many different conditions for which hyperammonemia is a surrogate marker. Hyperammonemia can occur due to increased production or impaired detoxification of ammonia and should, if associated with clinical symptoms, be regarded as an emergency. The conditions can be classified into primary or secondary hyperammonemias depending on the underlying pathophysiology. If the urea cycle is directly affected by a defect of any of the involved enzymes or transporters, this results in primary hyperammonemia. If however the function of the urea cycle is inhibited by toxic metabolites or by substrate deficiencies, the situation is described as secondary hyperammonemia. For removal of ammonia, mammals require the action of glutamine synthetase in addition to the urea cycle, in order to ensure lowering of plasma ammonia concentrations to the normal range. Independent of its etiology, hyperammonemia may result in irreversible brain damage if not treated early and thoroughly. Thus, early recognition of a hyperammonemic state and immediate initiation of the specific management are of utmost importance. The main prognostic factors are, irrespective of the underlying cause, the duration of the hyperammonemic coma and the extent of ammonia accumulation. This paper will discuss the biochemical background of primary and secondary hyperammonemia and will give an overview of the various underlying conditions including a brief clinical outline and information on the genetic backgrounds.
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Affiliation(s)
- Johannes Häberle
- Division of Metabolism, University Children's Hospital Zurich, Steinwiesstr. 75, 8032 Zurich, Switzerland.
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50
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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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