Adult‐onset type II citrullinemia associated with idopathic hypertriglyceridemia as a preceding feature

Identification of 13 novel mutations including a retrotransposal insertion in SLC25A13 gene and frequency of 30 mutations found in patients with citrin deficiency

“…From our observation of Japanese patients, we consider that most homozygotes suffer from NICCD. Following amelioration, some homozygotes may suffer from CTLN2 (10-80 years of age) or be diagnosed as suffering from other diseases, such as pancreatitis (Ikeda et al 2004), hepatoma (Hagiwara et al 2003;Tsai et al 2006;Soeda et al 2008), hyperlipidemia (Imamura et al 2003;Terada et al 2006), fatty liver such as nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) Tanaka et al 2007) or psychosis (Ikeda et al 2001), but it is probable that many homozygotes remain healthy. To avoid misdiagnosis and mistreatment of patients with citrin deficiency, it is necessary to find them, to treat them properly, and to prevent severer outcomes.…”

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

“…Although our microarray analyses were performed primarily to uncover genes that might be involved in the major symptoms of citrin deficiency, they also have the potential to identify pathways involved in additional conditions associated with human citrin deficiency, such as an increased incidence of hepatocellular carcinoma, pancreatitis, steatohepatitis, and hyperlipidemia in CTLN2 patients (1,2,8,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). From our present results, we found profound changes in gene expression related to pathways involved in drug metabolism, fat metabolism, oxidative stress, and cell growth in the liver of double knock-out mice.…”

“…Although we have focused on the role of liver in the double knock-out mice in regards to human citrin deficiency, it is conceivable that extrahepatic tissues may also be contributing to the overall pheno-type observed in the double knock-out mice as both citrin and mGPD are constitutively knocked out in all tissues that express them. Our justification for focusing on the liver however, is based on the simple observation that liver transplantation appears to completely correct all defects present in CTLN2 patients (1,8,23,26,39), indicating that the liver is the most important for human citrin deficiency. Furthermore, previous studies of Ctrn-KO and mGPD-KO mice alone have both shown that they are grossly phenotypically normal under standard conditions (42,45); therefore, only metabolically active tissues requiring high NADH shuttle activities would likely present with a defect.…”

“…The elevated pancreatic secretory trypsin inhibitor in CTLN2 patients results from its up-regulated transcriptional expression in the liver (20). Finally, CTLN2 patients also have an increased incidence of hepatocellular carcinoma, pancreatitis, and hyperlipidemia (1,2,8,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

“…Following an apparently healthy period that can last from one to several decades, some patients with human citrin deficiency go on to develop severe CTLN2 (1,36,39). There have been a few patients with NICCD that have required liver transplantation because of severe, prolonged symptoms (40,41), and patients presenting with CTLN2 typically continue to worsen unless also treated by liver transplantation (1,8,23,26,39).…”