Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by SLC7A7 gene mutation and often involves severe lesions in multiple systems. Lung involvement is frequently seen in children with LPI and such children tend to have a poor prognosis. This article summarizes the clinical manifestations and gene mutation characteristics of three children diagnosed with LPI by SLC7A7 gene analysis. All three children had the manifestations of aversion to protein-rich food after weaning, delayed development, anemia, hepatosplenomegaly, and osteoporosis, as well as an increase in orotic acid in urine. In addition, interstitial pneumonia and diffuse pulmonary interstitial lesions were observed in two children. SLC7A7 gene detection showed three pathogenic mutations in these children, namely c.1387delG(p.V463CfsX56), c.1215G>A(p.W405X) and homozygous c.625+1G>A. After a definite diagnosis was made, all three children were given a low-protein diet and oral administration of citrulline [100 mg/(kg.d)], iron protein succinylate [4 mg/(kg.d)], calcium and zinc gluconates oral solution (10 mL/day) and vitamin D (400 IU/day). In addition, patient 3 was given prednisone acetate (5 mg/day). The children had varying degrees of improvement in symptoms and signs. It is hard to distinguish LPI from urea cycle disorder due to the features of amino acid and organic acid metabolism in LPI, and SLC7A7 gene analysis is the basis for a definite diagnosis of LPI.
Amino Acid Metabolism, Inborn Errors ; genetics ; Child ; Citrulline ; Fusion Regulatory Protein 1, Light Chains ; genetics ; Humans ; Lysine ; Mutation

OBJECTIVEThis study aimed at understanding clinical features, biochemistry and gene mutation in one Chinese pedigree which had a neonatal-onset ornithine transcarbamylase deficiency (OTCD) boy, and exploring the significance of ornithine transcarbamylase analysis in prenatal diagnosis.

METHODThe clinical and biochemical data of one case were analyzed. The amino acids in blood and organic acids in urine were analyzed by mass spectrum technology. The OTC gene mutation was detected using polymerase chain reaction (PCR) and DNA direct sequencing for the case, his parents and the fetus amniocyte and her blood after birth.

RESULTThe age of onset was 3 days after birth, he began to have poor reaction, difficulty to feed, high blood ammonia, infection, slight metabolic acidosis, which were consistent with the clinical diagnosis of urea cycle disorders. The boy died at the age of 9 days. Citrulline of blood was detected twice, and were 0.86 µm and 1.06 µm, respectively. The orotic acid was elevated (124 µm/M Creatinine), and urine lactic acid was significantly elevated. The citrulline and orotic acid in his parents and their second baby were normal in DBS and urine. One nonsense mutation in the OTC gene was found at the exon 9 (C. 958 C > T) and his mother was the heterozygote, which caused an arginine to terminate the code at position 320 of the protein (R320X). Two other mutations were also detected at intron 9 (C.1005 + 132 InsT) and intron 5 (C.542 + 134 G > G/A). But the analysis of his father's DNA, the fetus amniocyte and her blood was normal.

CONCLUSIONThe mutation of C. 958 C > T in OTC gene may occur during neonatal period. This mutation would result in a very severe symptom, even die suddenly several days after birth, if it was a boy. It needs more researches to discuss whether the C.1005 + 132 InsT in intron 9 and C.542 + 134 G > G/A in intron 5 were associated with the neonatal-onset OTCD. The DNA analysis of OTC gene could be utilized for the prenatal diagnosis.

Citrulline ; analysis ; DNA Mutational Analysis ; Exons ; Heterozygote ; Humans ; Infant, Newborn ; Male ; Ornithine Carbamoyltransferase ; genetics ; Ornithine Carbamoyltransferase Deficiency Disease ; genetics ; physiopathology ; Orotic Acid ; analysis ; Pedigree

OBJECTIVES: To investigate genotype-phenotype characteristics and long-term prognosis of neonatal carbamoyl phosphate synthetase 1 (CPS1) deficiency among children through newborn screening in Zhejiang province. METHODS: The clinical and follow-up data of children with CPS1 deficiency detected through neonatal screening and confirmed by tandem mass spectrometry and genetic testing in Zhejiang Province Newborn Disease Screening Center from September 2013 to August 2023 were retrospectively analyzed. RESULTS: A total of 4 056 755 newborns were screened and 6 cases of CPS1 deficiency were diagnosed through phenotypic and genetic testing. Ten different variations of CPS1 genewere identified in genetic testing, including 2 known pathogenic variations (c.2359C>T and c.1549+1G>T) and 8 unreported variations (c.3405-1G>T, c.2372C>T, c.1436C>T, c.2228T>C, c.2441G>A, c.3031G>A, c.3075T>C and c.390-403del). All patients had decreased citrulline levels (2.72-6.21 μmol/L), and varying degrees of elevated blood ammonia. The patients received restricted natural protein intake (special formula), arginine and supportive therapy after diagnosis, and were followed-up for a period ranging from 9 months to 10 years. Three patients experienced hyperammonemia, and one patient each had attention deficit hyperactivity disorder, transient facial twitching and increased muscle tone. One patient died, while the other five surviving patients had normal scores of the Ages & Stages Questionnaires (ASQ) and Griffiths Development Scales up to the present time; 4 cases had combined height or weight lag and one case was normal in height and weight. CONCLUSIONS Low citrulline levels and hyperammonemia are common in CPS1 deficiency patients in Zhejiang. Most gene variants identified were specific to individual families, and no hotspot mutations were found. Early diagnosis through newborn screening and following standardized treatment can significantly improve the prognosis of the patients.
Child ; Humans ; Infant, Newborn ; Carbamoyl-Phosphate Synthase I Deficiency Disease/therapy* ; Neonatal Screening ; Follow-Up Studies ; Hyperammonemia ; Citrulline/genetics* ; Retrospective Studies ; Mutation

Two clinical phenotypes for citrin deficiency (CD) have been reported. One is adult-onset citrullinemia type II (CTLN2) and another is neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). A child with CD and who had failure to thrive (FTT) and dyslipidemia as main clinical manifestations is reported here. Both the weight-and length-for-age at 18 months dropped below the 3rd percentile in the corresponding WHO anthropometry percentile charts, while blood biochemical analysis revealed dramatically increased triglyceride and total cholesterol, together with reduced HDL-cholesterol. Inquiries revealed his aversion to rice and fondness for fish since the age of one year, a peculiar habit which could not be corrected. Since the age of two years, the peculiar diet became more obvious, and slightly increased citrulline and threonine levels were detected on blood amino acid analysis. At the age of two years and five months he was suspected to have CD. Since then, he has been fed in accordance with his own food preferences, and FTT improved gradually, with weight-for-age, in particular, recovering beyond the 3rd percentile at three years of age, and dyslipidemia was also ameliorated gradually. SLC25A13 gene analysis revealed a homozygote of 851del4, and CD was thus confirmed. Diet survey at four years and seven months revealed a fondness for high-protein and low-carbohydrate foods, such as seafood, meat, eggs and milk. This child presented with FTT and dyslipidemia as main clinical manifestations and this was a novel CD phenotype different from NICCD and CTLN2.
Body Weight ; Calcium-Binding Proteins ; deficiency ; Cholestasis, Intrahepatic ; etiology ; Citrulline ; blood ; Dyslipidemias ; etiology ; Failure to Thrive ; etiology ; Humans ; Infant ; Lipids ; blood ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutation ; Organic Anion Transporters ; deficiency ; Phenotype

Lysinuric protein intolerance (LPI) is a rare inherited metabolic disease, caused by defective transport of dibasic amino acids. Failure to thrive, hepatosplenomegaly, hematological abnormalities, and hyperammonemic crisis are major clinical features. However, there has been no reported Korean patient with LPI as of yet. We recently encountered a 3.7-yr-old Korean girl with LPI and the diagnosis was confirmed by amino acid analyses and the SLC7A7 gene analysis. Her initial chief complaint was short stature below the 3rd percentile and increased somnolence for several months. Hepatosplenomegaly was noted, as were anemia, leukopenia, elevated levels of ferritin and lactate dehydrogenase, and hyperammonemia. Lysine, arginine, and ornithine levels were low in plasma and high in urine. The patient was a homozygote with a splicing site mutation of IVS4+1G > A in the SLC7A7. With the implementation of a low protein diet, sodium benzoate, citrulline and L-carnitine supplementation, anemia, hyperferritinemia, and hyperammonemia were improved, and normal growth velocity was observed.
Amino Acid Metabolism, Inborn Errors/complications/diet therapy/*genetics ; Antifungal Agents/therapeutic use ; Antigens, CD98 Light Chains/genetics ; Asian Continental Ancestry Group/*genetics ; Carnitine/therapeutic use ; Child, Preschool ; Citrulline/therapeutic use ; Diet, Protein-Restricted ; Disorders of Excessive Somnolence/complications/*diagnosis/drug therapy ; Female ; Growth Disorders/complications/*diagnosis ; Homozygote ; Humans ; Hypercalcemia/complications/*diagnosis ; Metabolic Diseases/complications/*diagnosis ; Mutation ; Nephrocalcinosis/complications/*diagnosis ; Republic of Korea ; Sequence Analysis, DNA ; Sodium Benzoate/therapeutic use ; Vitamin B Complex/therapeutic use