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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.

Background Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder with heterogeneous clinical manifestations. This study aimed to characterize the clinical, biochemical, and genetic spectrum of NICCD and evaluate treatment outcomes. Methods This retrospective cohort study analyzed molecularly confirmed cases of NICCD admitted to Shenzhen Children’s Hospital between March 2019 and April 2023. Comprehensive clinical data were extracted from electronic records and analyzed using descriptive statistical methods. Results The cohort ( n  = 15) demonstrated universal jaundice (100%) and hyperammonemia (93.3%), with the predominant c.851_854del variant (52%) associated with earliest onset (median 3 days) and most severe cholestatic features (100% jaundice, 60% hepatomegaly). Key metabolic abnormalities included universal citrulline elevation (100%) and frequent methionine increase (93.3%), while threonine/tyrosine disturbances showed genotype-dependent patterns. All patients achieved complete symptom resolution (median 32 days) and significant growth improvement with lactose-free MCT formula and ursodeoxycholic acid therapy, though rare variants (compound heterozygous c.1399 C > T/c.1638_1660dup) exhibited markedly prolonged recovery (88 days vs. cohort median 32 days). Conclusions This study delineates the clinical-genetic spectrum of NICCD and confirms the efficacy of MCT-based therapy. Genotype-phenotype correlations suggest variant-specific disease severity, warranting multicenter validation for rare mutations.

Background: Little is known about the optimal dietary treatment for citrin deficiency. Our aim is to describe the management of UK citrin deficiency patients. Methods: A longitudinal retrospective review was performed. Data were collected from medical records on presenting signs and symptoms, dietary management and clinical outcome. Results: data were collected on 32 patients from 21 families. 50% were females (16/32). Median age at diagnosis was 4 y (5 days–35 y) with 12 patients diagnosed in the neonatal period with neonatal intrahepatic cholestasis (NICCD), eight later in childhood (FTTDCD) and 12 by family screening based on index cases from five families. No patient had adult-onset type II citrullinemia. The patient age at the time of data collection was a median of 11 y (1–44 y). 91% (29/32) of patients had normal physical and neurological development, 47% (15/32) experienced recurrent unexplained abdominal pain and 9% (3/32) episodes of hypoglycaemia. Siblings had different phenotypes (5 families had > 1 affected patient). Most patients preferred high protein foods, limiting sugar-containing foods. Only 41% (13/32) were prescribed a low CHO, high protein, high fat diet (restriction varied) and two used medium chain triglyceride (MCT) supplements. No patient was prescribed drug therapy. Twenty-five per cent (8/32) of patients were underweight and 41% (13/32) had height <−1 z-scores. Conclusions: patients presented with various phenotypes, symptoms and suboptimal growth. Symptoms and biochemical markers improved with age, but height remained low in some. More research is necessary to assess the effectiveness of dietary approaches in improving clinical outcomes and symptoms in citrin deficiency.

Background Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) has high prevalence in East Asia, and has been reported in other parts of the world. NICCD is also the most common form of genetic cholestasis among East Asians. There has been reports of mortalities or liver transplants associated with NICCD, but risk factors associated with poor outcome were unknown. Our objective is to report NICCD mortalities in a tertiary pediatric hepatology center, and to explore associated risk factors along with implications to clinical practice. Method This is a retrospective analysis of NICCD cases collected from June 2003 until January 2017 in the Children’s Hospital of Fudan University. Clinical, biochemical, and genetic data were compared between deceased cases and survivors without liver transplant. Results Sixty-one confirmed NICCD cases, including 52 cases in the survival group, and 9 cases in the mortality group, were included in the analysis. Mean age at referral in the mortality group was significantly higher when compared to the survival group (9.58 ± 5.03 VS 3.96 ± 3.13 months, p  < 0.000). The proportion with infection in the mortality group was significantly higher than the survival group ( p  = 0.023). 44.4% of patients in the mortality group did not receive lactose-free and/or medium chain triglycerides enriched (LF/MCT) formula, and this percentage was significantly higher than the survival group (9.6%, p  = 0.021). Mean platelet (PLT) count in the mortality group was significantly lower than the survival group ( p  = 0.010). Mean serum gamma-glutamyl transpeptidase (GGT), and total cholesterol (TCH) levels were significantly lower in the mortality group when compared to the survival group with p values of 0.001, and 0.019, respectively. Those who died had higher serum ammonium levels than survivors ( p  = 0.016). Mean level of citrulline was significantly lower in the mortality group compared to the survival group ( p  = 0.010). On the other hand, mean level of tyrosine was significantly higher in the mortality group than that of the survival group ( p  = 0.015). Conclusion Late referral, presence of infection, delayed treatment with LF/MCT formula, lower platelet count, lower levels of GGT, total cholesterol, blood citrulline, and higher level of blood ammonia and tyrosine, were associated with poor prognosis in NICCD.

Background: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a rare autosomal recessive disease. The incidence of citrin deficiency is estimated between 1/10,000 and 1/20,000 in Taiwan. Case report: This report describes a case of a 42 day old female infant who suffered from prolonged jaundice, poor weight gain, and anemia. The initial total/direct bilirubin levels were 8.1/3.11 mg/dL. Liver biopsy was performed at 47 days old. The pathology revealed lobules marked with macrovesicular and microvesicular fatty metamorphosis. The serum amino acid profile showed elevated levels of threonine, methionine, citrulline, and arginine. Newborn screening disclosed normal results, but the genetic study revealed SLC25A13 mutation 851–854 del and 615 + 5G > A. The genetic study of her parents showed that the father carried the SLC25A13 mutation 851–854 del and the mother carried the SLC25A13 mutation 615 + 5G > A. Treatment with ursodeoxycholic acid decreased the bilirubin levels to a normal range at the age of 5 months. Conclusion: This report illustrates that hepatic steatosis is a feature of NICCD. For every young infant patient who develops cholestasis, the pediatrician must consider NICCD as a differential diagnosis even if newborn screening shows normal findings.

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.

Background Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder and one of the most common inherent causes of cholestatic jaundice in Asian infants. Mutations in the SLC25A13 gene, which encodes citrin protein expressed in the liver, have been identified as the genetic cause for NICCD. Case presentation Here, we report a 4-month-old female with clinical features including jaundice, hyperbilirubinemia, hyperlactacidemia, and abnormal liver function. The patient was diagnosed with NICCD by differential diagnosis using genetic analysis. Mutations in 60 jaundice-related genes were tested by using amplicon sequencing, which was performed on an Ion S5XL genetic analyzer. A compound heterozygous mutation in the SLC25A13 gene was identified, consisting of a known deletion SLC25A13: c.852_855delTATG and a novel splicing mutation SLC25A13: c.1841 + 3_1841 + 4delAA. Sanger sequencing for the proband and her parents was performed to validate the result and reveal the source of mutations. Conclusion A compound heterozygous mutation in the SLC25A13 gene was identified in a 4-month-old female patient with NICCD. Our data suggest that amplicon sequencing is a helpful tool for the differential diagnosis of inherited diseases with similar symptoms. Further studies of the mutation spectrum of neonatal jaundice in China are warranted.

Citrin deficiency is a recessively inherited metabolic disorder with age-dependent clinical manifestations. It causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Patients with NICCD present with intrahepatic cholestasis in the neonatal period and usually respond to the treatment with medium-chain triglyceride (MCT) supplement and lactose-restricted formula. In adulthood, CTLN2 develops in <10 % of the patients showing hyperammonemic encephalopathy. Patients with CTLN2 required liver transplantation for the most promising prognosis; however, they were successfully treated with MCT supplement with a low carbohydrate formula. Citrin deficiency is caused by mutations in on chromosome 7q21.3, with a high frequency in East Asia, including Japan. Citrin is aspartate/glutamate transporter in mitochondria, a component of malate-aspartate nicotinamide adenine dinucleotide hydrogen shuttle, and is essential for the hepatic glycolysis. Although the precise pathophysiology of citrin deficiency remains unclear, recent reports for the effective MCT supplement therapy and downregulation of peroxisome proliferator-activated receptor α suggest that citrin deficiency impairs hepatic de novo lipogenesis coupled with glycolysis leading to the energy deficit of hepatocytes. Herein, we review the current therapeutic and pathological understanding of CTLN2.

Deficiency of citrin, liver-type mitochondrial aspartate-glutamate carrier, is an autosomal recessive disorder caused by mutations of the SLC25A13 gene on chromosome 7q21.3 and has two phenotypes: neonatal intrahepatic cholestatic hepatitis (NICCD) and adult-onset type II citrullinemia (CTLN2). So far, we have described 19 SLC25A13 mutations. Here, we report 13 novel SLC25A13 mutations (one insertion, two deletion, three splice site, two nonsense, and five missense) in patients with citrin deficiency from Japan, Israel, UK, and Czech Republic. Only R360X was detected in both Japanese and Caucasian. IVS16ins3kb identified in a Japanese CTLN2 family seems to be a retrotransposal insertion, as the inserted sequence (2,667-nt) showed an antisense strand of processed complementary DNA (cDNA) from a gene on chromosome 6 ( C6orf68 ), and the repetitive sequence (17-nt) derived from SLC25A13 was found at both ends of the insert. All together, 30 different mutations found in 334 Japanese, 47 Chinese, 11 Korean, four Vietnamese and seven non-East Asian families have been summarized. In Japan, IVS16ins3kb was relatively frequent in 22 families, in addition to known mutations IVS11 + 1G > A, 851del4, IVS13 + 1G > A, and S225X in 189, 173, 48 and 30 families, respectively; 851del4 and IVS16ins3kb were found in all East Asian patients tested, suggesting that these mutations may have occurred very early in some area of East Asia.

Background SLC25A13 gene mutations cause citrin deficiency, which leads to neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Information on the mutation spectrum of SLC25A13 in the Chinese population is limited. The aim of this study was to explore the mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and various forms of aminoacidemia. Methods Sequence analyses were performed on 39 infants with intrahepatic cholestasis and various forms of aminoacidemia. Novel mutations were subjected to homology and structural analyses. Western blots were performed when liver specimens available. Results Genetic testing revealed the presence of SLC25A13 gene mutations (9 heterozygotes, 6 homozygotes and 13 compound heterozygotes) in 28 infants. Subsequent Western blot analysis revealed 22 cases of citrin deficiency, accounting for 56.4% of the 39 patients. Twelve types of mutations, including nine known mutations and three novel mutations, were found. Of the 49 mutated alleles, known ones include 851del4 (26 alleles, 53.1%), 1638ins23 (6 alleles, 12.2%), IVSl6ins3kb (3 alleles, 6.1%), IVS6+5G>A (2 alleles, 4.1%), E601K (2 alleles, 4.1%) and IVS11+1G>A, R184X, R360X and R585H (1 allele each, 2.0%). The three novel mutations were a splice site change (IVS6+1G>A), a deletion mutation (1092_1095delT) and a missense mutation (L85P), each in one allele. Conclusions The mutation spectrum of the SLC25A13 gene in a Chinese population of infants with intrahepatic cholestasis with various forms of aminoacidemia was found to be different from that of other population groups in East Asia. The SLC25A13 gene mutation is the most important cause of infantile intrahepatic cholestasis with various forms of aminoacidemia.