• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.18 no.1
• /
• pp.23-29
• /
• 2018

Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonemia. CPS1D is caused by mutations in the CPS1 gene on chromosome 2q35. Based on the age of onset, there are two phenotypes: the neonatal type and the delayed-onset type. The severity of clinical manifestation depends on the degree of CPS1 residual enzymatic activity, and can result in hyperammonemia and neurological dysfunction. We report a case of CPS1D in a neonate who developed vomiting, decreased consciousness and hyperammonemia at 25th day after birth. She showed excellent response to treatment including hydration, ammonia-lowering drugs and a low-protein diet without hemodialysis. Her growth, development and neurological outcomes were fair at the last follow-up at 17 months of age.

• KSBB Journal
• /
• v.23 no.5
• /
• pp.381-386
• /
• 2008

Lipophilic ammonia is toxic gas and can easily diffuse across cell membranes. Excess ammonia is implicated in the pathogenesis of several metabolic disorders including hepatic encephalopathy and may result in the death. The purpose of this study was to clarify the inhibition effect of metronidazole on liver cell damage due to ammonia in human Hep G2 cell and rat hepatocytes. The effects of metronidazole were studied in ammonium chloride treated human Hep G2 cell (75 mM) and rat hepatocyte (100 mM) following $0.1{\mu}M$ metronidazole treatment. In MTZ+AC group, cell viabilities increased prominently and LDH activities decreased over 25% than AC group. Furthermore, ammonia level according to ammonium chloride treatment reduced over 30% and lipid peroxidation as an index of cell membrane damage decreased more than twice. By comparison with control, catalase activity showed more than 30% reduction in AC group while less than 10% reduction in MTZ+AC group, respectively. In addition, MTZ+AC group showed the similar cell structure as control in cell morphology study by using light microscope, and represented fluorescent intensity decrement compared with AC group in fluorescent microscopic study with avidin-TRITC fluorescent dye. And cleaved PARP expression due to ammonia reduced twofold or more in MTZ+AC group. As the results suggest, metronidazole may protect the liver cell by inhibiting cell damages due to ammonia and be used for an effective antagonist of ammonia in hyperammonemia.

• BMB Reports
• /
• v.39 no.4
• /
• pp.400-405
• /
• 2006

A 16-month old boy was referred to our hospital for evaluation of recurrent generalized tonic clonic seizures. Metabolic evaluation revealed significant hyperammonemia ($1,112\;{\mu}g/dl$). Amino acid/acylcarnitine screening using tandem mass spectrometry showed markedly increased plasma levels of citrulline ($1,350\;{\mu}M/l$) with undetectable levels of arginine and arginosuccinic acid. Urinary excretion of citrulline was markedly increased ($38,617\;{\mu}M/g$ creatinine). Brain MRI findings showed diffuse high-signal intensity lesions, that involved gray and white matter in both frontal lobes and insula with edematous changes; these findings were consistent with the acute stage of citrullinemia (CTLN). Mutation analysis of the argininosuccinate synthetase (ASS) gene, in this patient, showed a Gly324Ser mutation in exon 13, and a 67-bp duplication mutation in exon 15 (c.1128-6_1188dup67). The patient was confirmed as having late-onset CTLN1 and treated with anticonvulsants, lactulose enema, protein restricted diet and arginine. Here we describe a case of late-onset CTLN1 in a patient by biochemical analyses and ASS gene mutation confirmation. This is the first report of a Korean patient with late-onset CTLN1 confirmed by ASS gene mutation identification.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.12 no.1
• /
• pp.35-41
• /
• 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 Photoscience
• /
• v.9 no.2
• /
• pp.415-417
• /
• 2002

Juvenile visceral steatosis (JVS) mouse is an animal model of the systemic camitine deficiency. JVS mice first develop fatty liver following cardiac hypertrophy. hyperammonemia, etc. To clarify the relationship between fatty liver and other symptoms. lipid hydroperoxides levels of peripheral oragans in JVS mice at 1 month were determined by the use of phosphine derivatives. We also report here a new method to quantitate the lipid components level in fatty liver of JVS mice.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.2 no.1
• /
• pp.85-88
• /
• 2002

Methylmalonic acidemia is an inborn error of branched chain amino acid metabolism, clinically characterized by lethargy, vomiting, and hypertonia with abnormal movements, and biochemically characterized by ketoacidosis, hyperammonemia, and sometimes hyperglycinemia. Conventional treatment of methylmalonic acidemia incluides dietary protein restriction, bicarbonate, carnitine, and metronidazole. However, most patient have recurrent episodes of acidosis, and a significant number have neurologic deficits and renal impairment. We report the successful treatment of a patient with methylmalonic acidemia by liver transplantation.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.17 no.1
• /
• pp.31-37
• /
• 2017

Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is an autosomal recessive disorder of the urea cycle that causes hyperammonemia. Two forms of CPS1D are recognized: a lethal neonatal type and a less severe, delayed-onset type. Neonatal CPS1D cases often present their symptoms within the first days of life. Delayed-onset cases are predominantly adolescents or adults, and infantile delayed-onset cases are rare. Severe hyperammonemia in the neonatal period leads to serious brain damage, coma, and death if not treated promptly. Therefore, early diagnosis and acute treatment are crucial. Despite the improvement of treatments, including continuous hemodialysis, ammonia-lowering agents, and a low-protein diet, the overall outcome of severe forms of hyperammonemia often remains disappointing. As the liver is the only organ in which ammonia is converted into urea, liver transplantation has been considered as an elegant and radical alternative therapy to classical dietary and medical therapies. However, liver transplantation has many disadvantages, such as a considerable risk for technical complications and perioperative metabolic derangement, especially in neonates. Additionally, there is a lack of suitable donor organs in most countries. According to recent studies, liver cell transplantation is a therapeutic option and serves as a bridge to liver transplantation. Here, we report a Korean CPS1D patient with novel mutations in CPS1 who was treated by liver cell transplantation after being diagnosed in the neonatal period and showed a good neurodevelopmental outcome at the last follow-up at six months of age.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.16 no.1
• /
• pp.34-41
• /
• 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
• /
• v.15 no.1
• /
• pp.29-34
• /
• 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
• /
• v.16 no.2
• /
• pp.57-61
• /
• 2016

Isovaleric acidemia (IVA) is an autosomal recessively inherited organic acid disorder due to a defect of the enzyme isovaleryl-CoA dehydrogenase in the leucine metabolic pathway. Deficiency of this enzyme results in the accumulation of derivatives of isovaleryl-CoA. In acute illness in IVA, isovaleric acid and its derivatives accumulate and profound metabolic acidosis with ketosis, characteristic pungent body odor, hypoglycemia, and hyperammonemia can be developed. Additionally, recurrent vomiting, failure to thrive, developmental delay, epilepsy and mental retardation are chronic presenting symptoms and signs for IVA. On the result of newborn screening for inherited metabolic disorders, increased levels of isovalerylcarnitine (C5) are shown. However, C5 elevation can be accompanied with short/branched-chain acyl-CoA dehydrogenase (SBCAD) and therapy with certain antibiotics containing pivalic acid. Quantitative measurement of organic acids in urine and acylcarnitine profiles in plasma are necessary to differential diagnosis. Molecular genetic analysis of the IVD gene for IVA and ACADSB is also helpful to confirm IVA and SBCAD deficiency, respectively. Considering that IVA can be associated with significant morbidity and mortality at acute presentation of metabolic crisis, early diagnosis prior to the onset of symptoms by newborn screening enable to introduction of early treatment and prevention of acute and chronic complications.