Diagnosis and treatment of urea cycle disorder in Japan

Abstract

Urea cycle disorder (UCD) is an inborn error of the metabolic pathway producing urea from ammonia, which occurs primarily in the liver. Decreased excretion of nitrogen in the urea cycle due to deficiency of carbamoyl phosphate synthase I (CPSI), ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), and N-acetyl glutamate synthase (NAGS) causes hyperammonemia. We examined the clinical manifestations, treatment, and prognosis of 177 patients with UCD from January 1999 to March 2009 in Japan. Compared with a previous study conducted in Japan, a larger number of patients survived without mental retardation, even when the peak blood ammonia was >360 μmol/L. In those with peak blood ammonia >360 μmol/L, an indicator of poor prognosis, the frequency of convulsions, mental retardation, brain abnormality on magnetic resonance imaging, hemodialysis, liver transplantation, and intake of non-protein formulas was significantly higher than in those with peak blood ammonia <360 μmol/L. In this article, we have reported the current state of UCD to evaluate prognosis and its relationship with peak blood ammonia and hemodialysis.Key words carbamoyl phosphate synthase I deficiency, hemodialysis, hyperammonemia, liver transplantation, ornithine transcarbamylase deficiency.The urea cycle is a pathway by which urea is produced from ammonia primarily in the liver (Fig. 1). 1 It is composed of four amino acids, namely ornithine, citrulline, argininosuccinic acid, and arginine. Citrulline is composed of ornithine and carbamoyl phosphate, and argininosuccinic acid is composed of citrulline and aspartic acid. Argininosuccinic acid is decomposed into fumaric acid and arginine, and arginine is disassembled into ornithine and urea. Ammonia is detoxified during the urea cycle to produce urea. Two nitrogen atoms in urea originate from aspartic acid and carbamoyl phosphate. Urea cycle disorder (UCD) is an inborn error of this metabolic pathway. Decreased excretion of nitrogen in the urea cycle due to deficiency of carbamoyl phosphate synthase (CPSI), ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), arginase (ARG) and N-acetyl glutamate synthase (NAGS) causes hyperammonemia.1-3 Additionally, N-acetyl glutamic acid is essential to the activity of CPSI. Decrease in N-acetyl glutamic acid secondary to abnormality of NAGS results in UCD, which causes hyperammonemia. CPSI and OTC are found in the mitochondria, and other enzymes are located outside of it. In citrin deficiency and lysinuric protein intolerance, the activity of the urea cycle decreases to cause hyperammonemia.There are many reports on the long-term prognosis of UCD patients in Japan and other countries, [3][4][5][6][7][8][9][10][11][12] including one by us on long-term prognosis and treatment of UCD patients. 13 As with the previous studies, we found that the prognosis and neurological symptoms of UCD patients improved with early treatment. Furthermore, hemodialysis was performed in UC...

Clinical and mutation analysis of 24 Chinese patients with ornithine transcarbamylase deficiency

“…Historical studies have demonstrated that the survival rate for symptomatic females was 80%‐90% and the prognosis was usually favorable . However, in the current study the survival rate for symptomatic females was extremely low.…”

“…favorable. [5][6][7] However, in the current study the survival rate for symptomatic females was extremely low. This finding reflects the poor prognosis for symptomatic females with OTCD in China, compared with other populations.…”

Citrulline for urea cycle disorders in Japan

“…Mean age at disease onset was 21 months and the mean age at l ‐citrulline initiation was 103 months. Initiation of l ‐citrulline occurred later than that of other treatments because l ‐citrulline has only recently been used for UCD patients in Japan . The mean initial dose of l ‐citrulline was 165 mg/kg/day with a gradual decrease in dosage to a mean of 128 mg/kg/day.…”

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“…Genetic defects involving these enzymes cause urea cycle disorders. 4,5 Argininosuccinate lyase catalyzes conversion of argininosuccinic acid into arginine and fumarate and is the only mammalian enzyme that generates endogenous arginine. The clinical manifestations of ASA change according to the degree of enzyme deficiency.…”

“…The prognosis has improved significantly in the last 20 years. 4,6 In addition to pharmacologic and dietary treatment, LT, liver cell transplant, stem cell transplant, and gene therapy are other treatment options (eg, liver cell transplant, stem cell transplant, and gene therapy are the other treatment options, which we can find some data in the literature; these treatment options need more clinical trials). Other than LT, these treatment options remain regarded as experimental or are currently in clinical trial status.…”