シトリン欠損症

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive metabolic disorder resulting from biallelic pathogenic variants of the SLC25A13 gene. Because NICCD requires immediate and specific dietary management, which differs fundamentally from the treatment of idiopathic neonatal hepatitis (INH), rapid and noninvasive diagnostic tools are crucial. The aim of this study was to systematically evaluate the diagnostic accuracy of amino acid-derived metabolic ratios. This retrospective study analyzed 29 patients with genetically-confirmed NICCD who were evaluated at a single tertiary center between 2011 and 2026. To comprehensively evaluate diagnostic utility, a two-tiered receiver operating characteristic analysis was conducted comparing the NICCD cohort with both a total INH clinical cohort (n = 39) and a genetically-negative INH subgroup (n = 18). The diagnostic performance of amino acid-derived metabolic ratios was comparable to that of individual citrulline levels. The citrulline/alanine and citrulline/tryptophan ratios achieved favorable diagnostic accuracy, maintaining an area under the curve > 0.95, sensitivity > 85%, 100% specificity, and 100% positive predictive value across both control cohorts. The threonine/alanine ratio exceeded the established threonine/serine ratio. Genotype-phenotype analysis indicated that the c.852_855del variant was associated with abnormal newborn screening (p = 0.016), whereas the IVS16ins3kb variant consistently yielded normal results (p = 0.011). The citrulline/alanine, citrulline/tryptophan, and threonine/alanine ratios serve as highly accurate biomarkers that reflect and enhance the detection of the unique metabolic profile of NICCD. Integration of these indices into clinical protocols can reduce the time to diagnosis and facilitate prompt dietary and medical interventions.

Citrin deficiency (CD) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the SLC25A13 gene, which encodes the mitochondrial aspartate-glutamate carrier 2, also known as citrin. We describe an 11-year-old Chinese boy presenting with recurrent acute pancreatitis secondary to severe hypertriglyceridemia during the FTTDCD/post-NICCD stage of citrin deficiency. The patient was relatively thin (his height and weight were at the 10th percentile on the growth curve for Chinese children), had a strong preference for soy products and an aversion to carbohydrates. Laboratory tests at presentation revealed severe hypertriglyceridemia (28.96 mmol/L), with a previously documented peak of 30.35 mmol/L. Abdominal computed tomography showed diffuse pancreatic enlargement and peripancreatic inflammatory changes, which, together with compatible abdominal pain, supported the diagnosis of acute pancreatitis. Genetic sequencing identified compound heterozygous pathogenic mutations in the SLC25A13 gene (exon 9: c.852_855delTATG; intron 6: c.615+5G > A). Plasma ammonia and citrulline levels were within normal limits. All of these findings supported a diagnosis of failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) in the post-NICCD phase. Management involved plasma exchange, a high-protein/high-fat/low-carbohydrate diet, and medium-chain triglyceride (MCT) supplementation, leading to clinical improvement. However, poor dietary adherence during follow-up resulted in two readmissions for recurrent pancreatitis. This case highlights that citrin deficiency should be considered in children with recurrent acute pancreatitis associated with severe hypertriglyceridemia, especially when accompanied by carbohydrate aversion and unusual dietary preferences, even in the absence of hyperammonemia or hypercitrullinemia.

The rapid expansion of therapies for rare diseases, including urea cycle disorders (UCDs), has intensified the need for endpoints that reflect meaningful benefit to patients. In rare inborn metabolic disorders, conventional clinical assessments and fragmented natural history data may not fully capture the daily disease burden. Citrin deficiency (CD) exemplifies this challenge: despite heterogeneous, age-dependent phenotypes, a "silent" or "adaptive" period is often described as largely asymptomatic based on clinical and biochemical measures. We present a patient-organization-led, patient-centered qualitative survey as a complementary approach to uncover "hidden" disease burden in a rare metabolic and urea cycle disorder. In an in-depth survey of seven adult CD patients, findings identified gaps between clinical descriptions and patient-reported disease burden. Fatigue and symptoms triggered by high carbohydrate intake emerged as key impacts on quality of life (QoL) among all surveyed patients. Other symptoms included under-recognized gastrointestinal (GI) issues, poor appetite, and psychological impacts. These findings contrasted with existing literature and questioned the concept of an asymptomatic adaptive phase. Although limited by the cohort size (n = 7), the current study illustrates how this approach can identify patient-important domains that standard clinical frameworks may under-capture. We propose that these domains should inform the development of fit-for-purpose patient-reported outcome measures (PROMs) and be integrated with relevant biochemical or molecular markers as endpoints for therapeutic studies and inform better research priorities and clinical management. More broadly, patient-organization-led qualitative surveying offers a scalable strategy to align translational efforts with outcomes that matter to patients across rare diseases.

OBJECTIVE: Citrin deficiency (CD) is an autosomal recessive disease caused by mutations in the SLC25A13 gene. This study aimed to expand the current body of data on Chinese patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) by analyzing their clinical characteristics, genetic mutation spectrum, and long-term follow-up outcomes. METHODS: From May 2013 to April 2025, 60 children diagnosed with NICCD were enrolled in this retrospective study. Related data were obtained from medical records. RESULTS: Among 60 patients, common presentations included elevated aspartate aminotransferase (100%), infantile cholestasis (95.0%), elevated citrulline (96.7%), hyperlactatemia (93.3%), hypoproteinemia (81.7%), coagulation dysfunction (60.0%), hyperammonemia (48.3%) and chubby face (36.7%). Twenty-eight SLC25A13 variants were detected, with c.852_855delTATG (42.7%), IVS16ins3kb (15.4%) and c.615+5G>A (10.3%) being the most frequent. All patients were fed lactose-free milk powder enriched with medium-chain triglycerides (MCT) after diagnosis or suspected diagnosis. Ten patients were lost to follow-up. Among 50 followed patients, 30 were followed for > 5 years. Twenty-four patients showed typical dietary features. After discharge, 11 had hypoglycemic episodes, 5 had growth retardation, 11 had dyslipidemia and 3 progressed to failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). All patients remained in stable condition. CONCLUSION: Patients with neonatal intrahepatic cholestasis caused by citrin deficiency present with a variety of clinical manifestations. c.852_855delTATG, IVS16ins3kb and c.615+5G>A are the mutation hotspots of the SLC25A13 gene in Zhejiang, China. Early intervention leads to a good prognosis.

OBJECTIVE: To explore the genetic factors contributing to unexplained infant jaundice and evaluate the significance of gene screening related to jaundice. METHODS: Infants jaundice with unknown etiology attending the neonatology and pediatrics departments of Yuebei People's Hospital from January 2022 to July 2024 were selected as the subjects of this study. The exon regions of 161 jaundice-related genes were detected by targeted capture and high-throughput sequencing technology, and the results were statistically analyzed. RESULTS: A total of 56 infants were included in the study, with 29 cases (51.8%) showing positive results. These cases involved six diseases: Gilbert syndrome in 7 cases (12.5%), sodium taurocholate co-transporting polypeptide (NTCP) deficiency in 8 cases (14.2%), glucose-6-phosphate dehydrogenase (G6PD) deficiency in 4 cases (7.1%), a combination of Gilbert syndrome and G6PD deficiency in 5 cases (8.9%), citrin deficiency combined with G6PD deficiency in 1 case (1.8%), Dubin-Johnson syndrome combined with Rotor syndrome in 1 case (1.8%), NTCP deficiency combined with G6PD deficiency in 2 cases (3.6%), and NTCP deficiency combined with Gilbert syndrome in 1 case (1.8%). Among the 56 infants, 55 cases (98.2%) had one or more gene mutation sites, with only 1 case (1.8%) showing no mutation sites. The five high-frequency mutation sites were the UGT1A1 gene c.211G>A and c.-55_-54insAT sites, the G6PD gene c.1376G>T, c.871G>A, and c.1388G>A sites, and the SLC10A1 gene c.800C>T site. CONCLUSION: Genetic factors significantly contribute to the development of infant jaundice of unknown etiology. Common pathogenic genes include the UGT1A1, G6PD, and SLC10A1 genes, which have high-frequency mutation sites within the population. Conducting genetic screening for infants with jaundice of unknown etiology holds significant clinical importance.