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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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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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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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Wang T, Ma J, Zhang Q, Gao A, Wang Q, Li H, Xiang J, Wang B. Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population. Front Genet 2019; 10:1052. [PMID: 31737040 PMCID: PMC6828960 DOI: 10.3389/fgene.2019.01052] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 10/01/2019] [Indexed: 12/30/2022] Open
Abstract
Expanded newborn screening for inborn errors of metabolism (IEMs) by tandem mass spectrometry (MS/MS) could simultaneously analyze more than 40 metabolites and identify about 50 kinds of IEMs. Next generation sequencing (NGS) targeting hundreds of IMEs-associated genes as a follow-up test in expanded newborn screening has been used for genetic analysis of patients. The spectrum, prevalence, and genetic characteristic of IEMs vary dramatically in different populations. To determine the spectrum, prevalence, and gene mutations of IEMs in newborns in Suzhou, China, 401,660 newborns were screened by MS/MS and 138 patients were referred to genetic analysis by NGS. The spectrum of 22 IEMs were observed in Suzhou population of newborns, and the overall incidence (excluding short chain acyl-CoA dehydrogenase deficiency (SCADD) and 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD)) was 1/3,163. The prevalence of each IEM ranged from 1/401,660 to 1/19,128, while phenylketonuria (PKU) (1/19,128) and Mild hyperphenylalaninemia (M-HPA) (1/19,128) were the most common IEMs, followed by primary carnitine uptake defect (PCUD) (1/26,777), SCADD (1/28,690), hypermethioninemia (H-MET) (1/30,893), 3-MCCD (1/33,412) and methylmalonic acidemia (MMA) (1/40,166). Moreover, 89 reported mutations and 51 novel mutations in 25 IMEs-associated genes were detected in 138 patients with one of 22 IEMs. Some hotspot mutations were observed for ten IEMs, including PAH gene c.728G > A, c.611A > G, and c.721C > T for Phenylketonuria, PAH gene c.158G > A, c.1238G > C, c.728G > A, and c.1315+6T > A for M-HPA, SLC22A5 gene c.1400C > G, c.51C > G, and c.760C > T for PCUD, ACADS gene c.1031A > G, c.164C > T, and c.1130C > T for SCAD deficiency, MAT1A gene c.791G > A for H-MET, MCCC1 gene c.639+2T > A and c.863A > G for 3-MCCD, MMUT gene c.1663G > A for MMA, SLC25A13 gene c.IVS16ins3Kb and c.852_855delTATG for cittrullinemia II, PTS gene c.259C > T and c.166G > A for Tetrahydrobiopterin deficiency, and ACAD8 gene c.1000C > T and c.286C > A for Isobutyryl coa dehydrogenase deficiency. All these hotspot mutations were reported to be pathogenic or likely pathogenic, except a novel mutation of ACAD8 gene c.286C > A. These mutational hotspots could be potential candidates for gene screening and these novel mutations expanded the mutational spectrum of IEMs. Therefore, our findings could be of value for genetic counseling and genetic diagnosis of IEMs.
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Affiliation(s)
- Ting Wang
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jun Ma
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Qin Zhang
- Genetic Clinic, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Ang Gao
- Genetic Clinic, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Qi Wang
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Hong Li
- Infertility Clinic, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jingjing Xiang
- Genetic Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Benjing Wang
- Newborn Screening Laboratory, Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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Zhang MH, Gong JY, Wang JS. Citrin deficiency presenting as acute liver failure in an eight-month-old infant. World J Gastroenterol 2015; 21:7331-7334. [PMID: 26109823 PMCID: PMC4476898 DOI: 10.3748/wjg.v21.i23.7331] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 02/10/2015] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
Citrin deficiency typically presents as neonatal intrahepatic cholestasis and resolves in late infancy. Here we report a case of citrin deficiency that presented as acute liver failure in late infancy in an apparently healthy child. The full-term male infant weighed 3400 g at birth, and exhibited normal development for eight months, at which time he contracted bronchial pneumonia. The infant developed jaundice and laboratory tests indicated elevated bilirubin and ammonia levels and an abnormal coagulation profile. Plasma amino acid analysis showed elevated levels of tyrosine, methionine, citrulline, and arginine. Citrin deficiency was suspected, and genomic DNA analysis revealed a mutation (IVS16ins3kb) in SLC25A13, which encodes a mitochondrial aspartate-glutamate carrier protein. The infant was immediately put on a lactose-free, medium-chain-triglyceride-enriched formula with ursodeoxycholic acid and lipid-soluble vitamins. However, cholestasis and abnormal laboratory indices persisted, and the infant died at the age of 11.5 mo, two days before a scheduled liver transplantation. This case demonstrates that citrin deficiency can present in late infancy as acute liver failure triggered by infection, and may require liver transplantation.
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