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Objective: To determine the prevalence of citrin protein deficiency in neonates in Shijiazhuang, and further analyze the mutations of pathogenic genes. Methods: A total of 160 061 newborns in Shijiazhuang from January 2014 to December 2019 were detected for blood amino acid levels by tandem mass spectrometry (MS/ MS), and the genetic testing were performed for suspected infants. Results: Among the 160 061 newborns, 20 cases were screened as positive cases, including 1 case confirmed the diagnosis with SLC25A13 gene testing; and 1 case that was false negative in newborn screening. The latter child patient was admitted to the hospital due to yellowish skin aggravated in less than 1 month. The blood tandem mass spectrometry showed that citrulline and methionine were elevated. The results of urine organic acids showed that 4 -hydroxyphenyllactic acid and 4 - hydroxyphenylpyruvic acid were both significantly increased. The prevalence of citrin protein deficiency in Shijiazhuang is 2/160 061. The gene testing showed that one case was a compound heterozygous mutation of SLC25A13 gene. The mutation sites were c.1021+1G>A and c.851_854delTATG. There was no report of c.1021+ 1G>A in the human gene mutation database. Conclusions: The application of tandem mass spectrometry in neonatal disease screening can detect the citrin protein deficiency as early as possible. Some newborn patients may be false negative screening; the gene testing is helpful for the diagnosis of citrin protein deficiency. The prevalence of citrin deficiency in Shijiazhuang area is 2/160 061. In this paper, we reported a novel mutation site of SLC25A13 gene. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical phenotype and gene variation conditions in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), so as to provide a basis for genetic counseling and clinical diagnosis and treatment of the family. Methods: 11 cases of neonatal intrahepatic cholestasis who visited the Children's Hospital Affiliated to Zhengzhou University between February 2019 and March 2021 were selected as the study subjects. High-throughput sequencing technology was used to detect the gene variation condition in 11 neonatal patients and 100 normal control neonates. The suspicious loci and family members were verified by Sanger sequencing and QPCR technology. Results: All 11 children with NICCD had different degrees of jaundice and liver damage symptoms, combined with coagulation dysfunction and anemia ( n = 7), cardiac malformation ( n = 2), elevated myocardial enzymes ( n = 4), hyperlipidemia ( n = 1), hyperkalemia ( n = 1), persistent diarrhea ( n = 3), developmental delay ( n = 1). A total of 10 different types of SLC25A13 gene mutations were detected in 11 cases, including three frameshift mutations, two splicing changes, two missense mutations, one intron insertion, one nonsense mutation, and one heterozygous deletion. After reviewing literature and databases, c.1878delG(p.I627Sfs*73) and exon11 deletion were novel mutations that had not been reported at home or abroad. Conclusion: The clinical features of NICCD are non-specific, and genetic testing aids in the early and accurate diagnosis of the disease, providing an important basis for clinical treatment and genetic counseling for family members. In addition, the detection of novel mutation sites has enriched the SLC25A13 gene variation spectrum.

Objectives: To study the physical and neuropsychological development of children with Citrin deficiency (CD)., Methods: A total of 93 children, aged 1.9-59.8 months, who were diagnosed with CD by SLC25A13 gene analysis in the First Affiliated Hospital of Jinan University from August 2010 to August 2015, were enrolled as subjects. A retrospective analysis was performed for their birth condition and physical growth and neuropsychological development indices. Among these children, 7 underwent physical measurement and neuropsychological development assessment within 1 year old and after 1 year old, and therefore, a total of 100 cases were included for analysis., Results: For the 93 children with CD, the incidence rate of failure to thrive was 25% (23 children) and the proportion of small for gestational age was 47% (44 children). For the 100 cases of CD, the incidence rates of growth retardation, underweight, emaciation, overweight, and microcephalus were 23% (23 cases), 14% (14 cases), 4% (4 cases), 8% (8 cases), and 9% (9 cases), respectively. The incidence rate of neuropsychological developmental delay was 25% (25 cases), and the incidence rates of development delay in the five domains of adaptability, gross motor, fine motor, language, and social ability were 7% (7 cases), 15% (15 cases), 7% (7 cases), 9% (9 cases), and 7% (7 cases), respectively., Conclusions: Physical and neuropsychological developmental delay can be observed in children with CD, and physical and neuropsychological development should be regularly assessed.

Objective: To investigate the profiles of blood amino acid and acylcarnitine in early neonates with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and the sensitivity of newborn screening, and to explore potential biochemical metabolic markers for newborn screening program. Methods: Amino acid and acylcarnitine profiles in dried blood spots of newborn screening program were analyzed by tandem mass spectrometry (MS/MS). A total of 158 651 neonates born in Guangzhou from January 1, 2015 to June 30, 2019 were enrolled in this newborn screening program, and additionally 55 patients with NICCD confirmed by SLC25A13 gene analysis in Guangzhou Women and Children Medical Center were included in this study. NICCD screen-positive was defined as the cutoff value of citrulline (Cit) ≥ 30 μmol/L. The values of blood sampling time of the true positive group and those of the false negative group were compared by t -test. The levels of amino acid and acylcarnitine among different groups, including true positive group (Cit≥30 μmol/L), false negative group (Cit 21- < 30 μmol/L and Cit < 21 μmol/L) and the normal control group, were analyzed by F test, respectively. Results: Among 158 651 neonates, 39 neonates were positive for NICCD screening. Three of them were confirmed NICCD and 4 cases were found to be false negatives. The positive predictive value was 7.7% and the sensitivity was about 43.0%. Among 55 patients with NICCD, 18 cases (18/55, 32.7%) were true positives and 37 cases (37/55, 67.3%) were false negatives based on the cutoff value of citrulline in the dried blood spots for newborn screening. The blood sampling time was significantly different between true positive group and false negative group ((4.28±1.6) vs. (2.98±0.74) d, t= 4.06, P< 0.01). The increased levels of tyrosine((176.0±98.4) μmol/L), methionine ((37.0±26.9) μmol/L) and phenylalanine ((133.0±80.9)μmol/L) in Cit≥30 μmol/L group ( n= 18) were significantly different as compared with those in the other three groups, respectively ( F= 117.0, 58.5, 135.0, P< 0.01). The levels of arginine ( (10.0±9.2) , (11.0±9.3) , (9.0±17.8) μmol/L), valine ( (119.0±29.8) , (107.6±14.1) , (102±68) μmol/L) and leucine ( (167.0±37.1) , (161.0±37.7) , (163.5±180.6) μmol/L) were not statistically significant among groups of Cit≥30 μmol/L( n= 18), Cit21-<30 μmol/L( n= 7) and Cit < 21μmol/L( n= 30, P> 0.05), but they were significantly higher than those of the normal control group ((4±3), (78±21), (114.0±31.5) μmol/L, n= 1 000), respectively( F= 30.1, 23.0, 29.8, P< 0.01). Alanine (Ala) ( (150±50) , (156.0±30.2), (168±105), (152±52) μmol/L) levels showed no significant difference ( F= 0.86, P> 0.05) but the ratios of Ala/Cit (1.52±1.44, 6.82±1.56, 12.06±7.71, 19.42±6.27) decreased significantly among the four groups ( F= 69.0, P< 0.05). The acylcarnitine levels showed no statistically significant results among the different groups ( P> 0.05). With Cit≥30 μmol/L and Ala/Cit < 7.5 as cutoff values, the number of screen-positive cases reduced from 39 to 22 cases with no additional false negative case. With Cit≥21 μmol/L and Ala/Cit < 7.5 as cutoff values the number of screen-positive cases increased to 117 cases with 1 additional true positive. Conclusions: The profiles of blood amino acid in early neonates with NICCD present the increased levels of multiple amino acids including citrulline, tyrosine, methionine and phenylalanine, and decreased ratio of Ala/Cit. Taking citrulline and ratio of Ala/Cit as screening markers can improve the positive predictive value appropriately. The limited sensitivity of NICCD newborn screening may be related to early blood sampling time.