• Neonatal Medicine
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• v.17 no.2
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• pp.250-253
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• 2010

Citrullinemia type I is an urea cycle defect caused by mutations in the argininosuccinate synthetase (ASS1) gene. We report a novel argininosuccinate synthetase gene mutation in a Korean family with type I citrullinemia. Metabolic evaluation revealed significant hyperammonemia. Amino acid/acylcarnitine screening using tandem mass spectrometry showed high level of citrulline. Plasma amino acid analysis showed high level of citrulline and the urine organic acid analysis showed makedly increased level of orotic acid. To confirm diagnosis of citrullinemia we did mutation analysis of the ASS1 gene. The patient was found to have mutations of c.689G>C (p.G230A) and c.892G>A (p.E298K), which were new types of argininosuccinate synthetase gene mutation have never been reported in Korea. We report a novel case of argininosuccinate synthetase 1 gene mutation and suggest that the gene study to the family members is necessary to carry out when a patient is diagnosed as citrullinemia.

• 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.15 no.1
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• pp.29-34
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• 2015

Citrullinemia type1 is an autosomal recessive disorder of the urea cycle characterized by neonatal or late onset of hyperammonemia caused by a deficiency of the enzyme argininosuccinate synthetase (ASS). An ASS1 deficiency demonstrates fatal clinical manifestations that are characterized by the neonatal metabolic coma and early death when untreated. It causes a broad spectrum of effects, ranging from a mild disorder to a severe mental retardation, epilepsy, neurologic deficits. An acute neonatal form is the most common. Infants are normal at birth followed by an acute illness characterized by vomiting, lethargy, seizures and coma. These medical problems are life-threatening in many cases. A later onset form is less frequent and may be milder than the neonatal form. This later-onset form is associated with severe headaches, visual dysfunction, motor dysfunction, and lack of energy. Citrullinemia type1 is caused by mutations in the ASS1 gene located on chromosome 9q34.1 that encodes argininosuccinate synthetase, the third enzyme of the urea cycle catalyzing the formation of argininosuccinic acid from citrulline and aspartic acid. The enzyme is distributed in tissues including liver and fibroblasts. This mutation leads to hyperammonemia, arginine deficiency and elevated citrulline level. In the urea cycle, argininosuccinate synthetase catalyses the conversion of citrulline and aspartate to argininosuccinate.. Here, we describe a female newborn patient with lethargy, rigidity and hyperammonemia who was diagnosed as citrullinemia type1 with a c.[421-2A>G], c.[1128-6_1188dup] mutation.

• 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.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.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.6 no.1
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• pp.96-107
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• 2006

Citrin deficiency resulting from mutations of SLC25A13is associated with two major clinical phenotypes; neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type 2 citrullinemia (CTLN2). In Korea, 7 cases of citrin deficiency have been diagnosed based on biochemical and molecular findings. Four NICCD cases were identified by newborn screening using MS/MS or presenting symptoms like cholestatic jaundice. They are all males, presenting with conjugated hyperbilirubinemia, elevated liver enzymes, hypoalbuminemia, mild hyperammonemia, elevated citrullin, methionine and threonine. All of them have been spontaneously recovered from hepatic manifestation by the age of 6-8 months. Mutation analysis has been performed using their genomic & cDNAs obtained from skin fibroblasts. They turned out to be compound heterozygotes carrying each of 851del4, IVS11+1G>A, and IVS13+1G>A. Three CTLN2 patients were identified. Two adult male patients presented with a sudden loss of consciousness, seizure, vomiting, hyperammonemia and citrullinemia in their twenties. They carried an IVS13+1G>A, 851del4, and IVS11+1G>A mutant alleles. The other CTLN2 patient was 52 year old female patient, manifesting lethargy, altered consciousness, irritability and hyperammonemia. Similar clinical symptoms had recurred at the delivery of first and second babies in her past medical history. She was managed by hemodialysis and survived with neurological sequellae. Also, we screened the presence of 9 common mutations in 500 Korean newborns using dried blood spot of filter papers. Only a allele carried 854del4 mutation. In conclusion, the entire picture of citrin deficiency in Korea including incidence, genotype, clinical features and natural courses, is still vague at the present time.

• Journal of Genetic Medicine
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• v.4 no.1
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• pp.53-63
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• 2007

Purpose : Tandem mass spectrometry (MS/MS) is effective screening test for inherited metabolic diseases. In this study, we estimate potential costs and benefits of using tandem mass spectrometry (MS/MS) to screen new borns for inherited metabolic diseases (phenylketonuria, BH4 deficiency, citrullinemia, maple syrup urine disease, propionic aciduria, isovaleric aciduria, glutaric aciduria type 1, LCHAD deficiency) in Korea. Methods : From April 2001 to March 2004, 79,179 new borns were screened for amino acid disorders, organic acid disorders, and fatty acid oxidative disorders. Twenty-eight new borns were diagnosed with one of the metabolic disorder and the collective estimated prevalence amounted to 1 in 2,800 with a sensitivity of 97.67%, a specificity of 99.28%, a recall rate of 0.05%, and a positive preditive value of 6.38%. We calculated and compared the total costs in case when neonatal screening on pheny lketonuria, BH4 deficiency, citrullinemia, maple syrup urine disease, propionic aciduria, isovaleric aciduria, glutaric aciduria type 1, LCHAD deficiency is implemented, and when not. Results : If the neonatal screening on pheny lketonuria, BH4 deficiency, citrullinemia, maple syrup urine disease, propionic aciduria, isovaleric aciduria, glutaric aciduria type 1, LCHAD deficiency is implemented, total benefits far exceed costs at a ratio of 1.40:1. Conclusion : Although, this study only concerns the monetary aspects of the neonatal screening, tandem mass spcetrometry for neonatal screening is cost-effective compared with not screening. The study appears to support the introduction of tandem mass spectrometry into a Korea neonatal screening programme for inherited metabolic diseases.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.12 no.1
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• pp.23-34
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• 2012

Purpose: Acute symptomatic seizures are caused by structural changes, inflammation or metabolic changes of brain, such as tumor, stroke, meningitis, encephalitis and metabolic disorders. Inherited metabolic disorders that can cause seizures are organic acidopathies, lysosomal storage disorders, peroxisomal disorders and mineral disorders. We have done this study to find out the importance of organic acidopathies causing seizure disorders in Korean childhood and adolescent patients. Method: Retrograde analysis for 1,306 patients with seizure disorders whose clinical informations are available and have done urine organic acid analysis for 5 years period, between Jan. 1st 2007 to Dec. 31th 2011. Statistical analysis was done with Student's t test using SPSS. Result: Out of 1,306 patients, 665 patients (51%) showed abnormalities on urine organic acid analysis. The most frequent disease was mitochondrial respiratory chain disorders (394, 30.1%), followed by mandelic aciduria (127, 9.7%), ketolytic defects (81, 6.2%), 3-hydroxyisobutyric aciduria (19, 1.4%), glutaric aciduria type II (10, 0.8%), ethylmalonic aciduria (4), propionic aciduria (4), methylmalonic aciduria (3), glutaric aciduria type I (3), pyruvate dehydrogenase deficiency (3), pyruvate carboxylase deficiency (3), isovaleric aciduria (2), HMG-CoA lyase deficiency (2), 3-methylcrotonylglycinuria (2), fatty acid oxidation disorders (2), fumaric aciduria (1), citrullinemia (1), CPS deficiency (1), MCAD deficiency (1). Conclusion: On neonatal period, mandelic aciduria due to infection was found relatively frequently. Mitochondrial disorders are most frequent etiologic disease on all age group, followed by ketolytic defects and various organic acidopathies. The number and diversities of organic acidopathies emphasize meticulous evaluation of basic routine laboratory examinations and organic acid analysis with initial sample on every seizure patient.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.17 no.2
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• pp.69-76
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• 2017

Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene on chromosome 7q21.3, and a type of urea cycle disorder that causes hyperammonemia. Although neonatal intrahepatic cholestasis and adult-onset type II citrullinemia, a type of citrin deficiency, have been described well in many articles for several decades, failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), the other type of citrin deficiency, has been only identified recently. There was previously no case report about FTTDCD in Korea. Patients with FTTDCD could present with loss of appetite, fatigue, failure to thrive, hypoglycemia, hypercitrullinemia, dyslipidemia, and an increased lactate/pyruvate ratio. Routine evaluation may not reveal the cause of hypoglycemia caused by citrin deficiency. We recently had a case that presented with recurrent hypoglycemia in a 30-month-old boy. Chemistry profiling, urine organic acid analysis, plasma acylcarnitine analysis, and hormone studies indicated values within the normal range or non-specific findings. Mutation analysis to identify the cause of hypoglycemia identified the subject as a compound heterozygote carrying each of the c.852_855del ($p.Met285Profs^*2$), and c.1177+1G>A mutant alleles. We report here on this unusual case of citrin deficiency presenting with FTTDCD for the first time in Korea.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.15 no.3
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• pp.155-159
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• 2015

Citrin deficiency (OMIN #605814) is an autosomal recessive disorder caused by the SLC25A13 gene mutation with abnormal biochemical findings, including increased serum ammonia, citrulline, arginine, galactose, serum threonine-to-serine ratio, serum pancreatic secretory trypsin inhibitor, and alpha-fetoprotein. Citrin deficiency can manifest in three ways: in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as citrullinemia type 2 (CTLN2) with recurrent hyperammonemia and neuropsychiatric symptoms. We report a 35-day-old asymptomatic patient with citrin deficiency who had abnormal biochemical findings.