シトリン欠損症

Background: Adolescent and adult citrin deficiency (AACD), formerly known as adult-onset citrullinemia type II, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in SLC25A13. It is an underrecognized cause of recurrent hyperammonemic encephalopathy, particularly when hepatic function is relatively preserved. Methods: We report two unrelated Vietnamese young men, aged 21 and 18 years, who presented with recurrent neuropsychiatric episodes. Clinical, biochemical, imaging, electrophysiological, and genetic findings were evaluated; whole-exome sequencing findings were confirmed by Sanger sequencing. Results: Both patients had long-standing preferences for protein- and fat-rich foods and avoidance of carbohydrate-rich foods, together with episodic hyperammonemia (345.21 and 103.07 µmol/L during symptomatic episodes). The first patient had a history of neonatal jaundice, mild cirrhosis, and severe behavioral disturbances, whereas the second was markedly lean and had no structural liver disease. Acquired causes of hyperammonemia and portosystemic shunting were excluded. Both patients harbored the homozygous pathogenic SLC25A13 variant NM_014251.3.852_855del (p.Met285ProfsTer2). Ammonia-lowering therapy and a low-carbohydrate, protein- and fat-enriched diet supplemented with medium-chain triglycerides resulted in clinical improvement, with no recurrent encephalopathic episodes during 6 months of follow-up in either patient. Conclusions: AACD should be considered in adolescents and adults with otherwise unexplained recurrent hyperammonemic encephalopathy, especially when ammonia elevation is disproportionate to liver disease. Characteristic dietary preferences provide an important diagnostic clue, and molecular testing enables definitive diagnosis and timely management.

Amino acid metabolic disorders (AAMs) are a group of inherited metabolic diseases caused by defects in enzymes or transporters involved in amino acid metabolism. This systematic review and meta-analysis aimed to evaluate the incidence, disease spectrum, and regional distribution of AAMs in China. A comprehensive search of PubMed, Embase, Web of Science, and major Chinese databases identified studies published between January 2002 and December 2025. After rigorous screening and quality assessment, 65 studies were included, encompassing 16,757,850 newborns and 2928 confirmed AAM cases. The most prevalent subtypes included hyperphenylalaninemia (HPA), hypermethioninemia (MET), citrin deficiency (CD), citrullinemia type 1 (CTLN1), maple syrup urine disease (MSUD), ornithine transcarbamylase deficiency (OTCD), and tyrosinemia (HT). The pooled incidence of AAMs was estimated at 184.0 (95% confidence interval 155.0-218.0) per million newborns. Significant regional differences were observed in the overall incidence of AAMs, with a higher incidence in northern China than southern China (287.0 vs. 126.0 per million, p < 0.0001). This difference was largely attributable to the substantially higher prevalence of HPA in northern China, whereas other major AAM subtypes showed no significant north-south differences. In contrast, no significant north-south differences were identified for other major subtypes. Additionally, the proportion of tetrahydrobiopterin deficiency (BH4D) among HPA cases was significantly higher in southern China (p < 0.001). These findings provide comprehensive epidemiological evidence on AAMs in China and highlight the importance of region-specific newborn screening strategies.

Citrin deficiency (CD) is an autosomal recessive disorder and represents one of the urea cycle disorders. This study aims to analyze the detection rate, clinical features, and genetic mutation characteristics of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in the Hefei region of China. We conducted NICCD screening using tandem mass spectrometry (MS/MS) for infants born in Hefei City between January 2016 and December 2025. Screen-positive cases were subjected to genetic testing via next-generation sequencing (NGS), with subsequent validation by Sanger sequencing. Clinical manifestations, biochemical parameters, and genetic mutation profiles of confirmed cases were systematically analyzed. A total of 924,676 newborns underwent screening, identifying 17 cases of NICCD, yielding a detection rate of 1/54,393, with two false-negative cases identified. The most prevalent mutation site is c.852_855del (p.M285Pfs*2). Following diagnosis, health education, dietary guidance, and symptomatic treatment were administered, resulting in favorable outcomes in the majority of cases. However, one infant exhibited significant growth retardation despite early therapeutic intervention that normalized biochemical parameters. Furthermore, an infant was found to have gallstones at birth and subsequently diagnosed with a liver hemangioma at one year of age. Some patients may experience missed screenings due to delayed elevations in citrulline levels. Therefore, even for newborns with negative screening results, timely assessments of liver function, MS/MS, and genetic testing are recommended for infants experiencing prolonged jaundice. This approach enables early identification and intervention. The combination of MS/MS with genetic screening may serve as a reliable strategy to reduce false-negative results in NICCD screening.

Both citrin deficiency (CD) and citrullinemia type I (CTLN1) may be detected by elevated citrulline through newborn screening (NBS) or present as acute liver failure in later infancy, but they differ significantly in management. This may pose therapeutic challenges in the early period after presentation while awaiting diagnostic confirmation. We report a Chinese girl (birth weight 1.98 kg at 37 weeks) who was recalled on day 5 for elevated citrulline (47 μmol/L; cutoff < 25) and citrulline/arginine ratio of 7.34 at NBS on day 2. Citrulline rose to 264 μmol/L upon retesting on day 5. Initial investigations revealed INR of 3.4 and raised alkaline phosphatase, while ammonia, conjugated bilirubin, glucose, albumin, gamma-glutamyl transferase, and transaminases were normal. Suspected CTLN1 led to halting protein intake and starting high glucose infusion. Within 17 h, INR increased to 6.5 and albumin dropped. Worsening hepatic function following high-glucose intake and her small for gestation age status suggested CD. She improved rapidly after switching to lactose-free MCT-enriched formula. Genetic analysis revealed compound heterozygous known pathogenic mutations in the SLC25A13 gene, confirming the diagnosis of CD. This is the first report of CD presenting with neonatal acute liver failure without cholestasis. It highlights the importance of prompt differentiation between CD and CTLN1 in NBS recalls for safe and effective interim treatment.

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.