• Neonatal Medicine
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• v.18 no.2
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• pp.370-373
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• 2011

Citrin deficiency caused by the SLC25A13 gene mutations is associated with both neonatal-onset type II citrullinemia (CTLN2), also known as neonatal intrahepatic cholestasis caused by citrin deficiency and adult-onset CTLN2. Neonatal-onset CTLN2 is an autosomal recessive disorder characterized by poor growth, intrahepatic cholestasis, and increased serum citrulline. A 16-days old infant with hyperammonemia was referred for evaluation of increased plasma citrulline diagnosed using tandem mass spectrometry. Blood amino acid analysis showed significant elevation of citrulline. Mild elevation in serum galactose levels had been found. DNA analysis of the SLC25A13 gene in this patient showed two novel compound heterozygous mutations, c.221C>T in exon4 and c.1645C in exon16 (p.[Ser74Phe]+[Gln549X]). We suggest that infants with a high serum citrulline level on a tandem mass screening test are candidates for gene analysis and blood amino acid analysis for neonatal-onset CTLN2.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.16 no.1
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• pp.34-41
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• 2016

Adult-onset type II citrullinemia (CTLN2) is characterized by episodes of neurologic symptoms associated with hyperammonemia leading to disorientation, irritability, seizures, and coma. CTLN2 is distinct from classical citrullinemia, which is caused by a mutation of the argininosuccinic acid synthetase (ASS) gene. The serum citrulline level is elevated, while the activity of ASS in liver tissue is decreased. CTLN2 is known to have a poor prognosis if the proper treatment is not taken. We reported a female aged 37 years who developed recurrent attacks of altered consciousness, aberrant behavior, and vomiting. We initially suspected the patient had CTLN2 because of the signs of hyperammonemic encephalopathy, such as altered mentality, memory disturbance, and aberrant behaviors provoked by exercise-induced stress and excessive intravenous amino acid administration. Through her peculiar diet preferences and laboratory findings that included hyperammonemia and citrullinemia, we diagnosed the patient as CTLN2, and SLC25A13 sequencing revealed known compound heterozygous mutations (IVS11+1G>A, c.674C> A). Her parents were heterozygous carriers, and we identified that her older sister had the same mutations. The older sister had not experienced any episodes of hyperammonemia, but she had peculiar diet preferences. The patient and her sister have been well with conservative management. When considering the clinical course of CTLN2, it was meaningful that the older sister could be diagnosed early in an asymptomatic period and that preemptive treatment was employed. Through this case, CTLN2 should be considered in adults who present symptoms of hyperammonemic encephalopathy without a definite etiology. Because of its rare incidence and similar clinical features, CTLN2 is frequently misdiagnosed as hepatic encephalopathy, and it shows a poor prognosis due to the lack of early diagnosis and proper treatment. A high-carbohydrate diet, which is usually used to treat other urea cycle defects, can also exaggerate the clinical course of CTLN2, so proper metabolic screening tests and genetic studies should be performed.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.12 no.1
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• pp.35-41
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• 2012

Since the causative gene, SLC25A13 which encodes citrin, was discovered in 1999, over 500 cases with citrin deficiency have been identified. Two phenotypes can occur by citrin deficiency, neonatal intrahepatic cholestasis by citrin deficiency (NICCD) and adult-onset type II citrullinemia (CTLN2). Some patients with NICCD develop CTLN2 in their later lives. Although cholestatic jaundice is spontaneously resolved within the first year of life in most cases with NICCD, a few cases experience progressive hepatic failure. In this report, two neonates with severe type of NICCD were described. Both cases exhibited neonatal cholestatic jaundice, hyperammonemia and severe coagulopathy. Of note, plasma citrulline and blood galactose levels were extremely high. Serum ${\alpha}$-fetoprotein, plasma methionine, arginine, and threonine-to-serine ratio were elevated as well. SLC25A13 mutations were found in all the four alleles of both patients. With the commencement of lactose-free formula, coagulopathy and hyperammonemia were resolved, and galactose level was normalized. Currently, no factor has been identified to predict the prognosis of NICCD. More experiences are needed to build up the adequate therapeutic strategies for severe type of NICCD. Our experience, however, indicates that the degree of citrullinemia and galactosemia might reflect the severity.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.14 no.2
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• pp.186-190
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• 2014

Citrullinemia type 2 (citrin deficiency) is an autosomal recessive inborn error metabolism, caused by the SLC25A13 gene mutation. Citrin deficiency is associated with two clinical phenotype; neonatal-onset type II citrullinemia (CTLN2), also known as neonatal intraphepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset CTLN2. Clinical manifestations of NICCD include poor growth, intrahepatic cholestasis, liver dysfunction and increased plasma citrulline, methionine, threonine, arginine. The molecular diagnosis could be confirmed by SLC25A13 gene mutation analysis. A 3-month-old male infant with persistent jaundice was referred for evaluation. Newborn screening was normal at birth. Mild elevation of serum ammonia and AST/ALT were observed. Plasma amino acid analysis showed significantly elevated citrulline, methionine, threonine. DNA sequence analysis of the SLC25A13 gene revealed two compound heterozygous mutations, c.[852_855del]($p.Met285Profs^*2$) and [1180+1G>A]. We suggest that NICCD should be considered as one of the cause of in infants with cholestatic jaundice, although the newborn screening was normal.