Neonatal-onset Ornithine Transcarbamylase Deficiency Research Articles

Role of liver transplantation in urea cycle disorders: Report from a nationwide study in Japan.

Urea cycle disorders (UCDs) are inherited metabolic diseases causing hyperammonemia by defects in urea cycle enzymes or transporters. Liver transplantation (LT) currently is the only curative treatment option until novel therapies become available. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to investigate the effect of LT in patients with UCDs in Japan. A total of 231 patients with UCDs were enrolled in this study. Of them, a total of 78 patients with UCDs (30 male and 16 female ornithine transcarbamylase deficiency (OTCD), 21 carbamoyl phosphate synthetase 1 deficiency (CPSD), 10 argininosuccinate synthetase deficiency (ASSD) and 1 arginase 1 deficiency (ARGD)) had undergone LT. Concerning the maximum blood ammonia levels at the onset time in the transplanted male OTCD (N=28), female OTCD (N=15), CPSD (N=21) and ASSD (N=10), those were median 634 (IQR: 277-1172), 268 (211-352), 806 (535-1382), and 628 (425-957) μmol/L, respectively. The maximum blood ammonia levels in female OTCD were thus significantly lower than in the other UCDs (all P < .01). LT was effective for long-term survival, prevented recurrent hyperammonemia attack, and lowered baseline blood ammonia levels in patients with UCDs. LT had limited effect for ameliorating neurodevelopmental outcome in patients with severe disease because hyperammonemia at the onset time already had a significant impact on the brain. Patients with ASSD may be more likely to survive without cognitive impairment by receiving early LT despite severe neonatal hyperammonemia ≥ 360 μmol/L. In patients with neonatal onset OTCD or CPSD, there may be additional factors with adverse effects on the brain that are not improved by LT.

Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene.

Ornithine transcarbamylase deficiency (OTCD), an X-linked disorder that results from mutations in the OTC gene, causes hyperammonemia and leads to various clinical manifestations. Mutations occurring close to the catalytic site of OTCase can cause severe OTCD phenotypes compared with those caused by mutations occurring on the surface of this protein. In this study, we report two novel OTC missense mutations, Q171H and N199H, found in Malaysian patients. Q171H and N199H caused neonatal onset OTCD in a male and late OTCD in a female, respectively. In silico predictions and molecular docking were performed to examine the effect of these novel mutations, and the results were compared with other 30 known OTC mutations. In silico servers predicted that Q171H and N199H, as well as 30 known missense mutations, led to the development of OTCD. Docking analysis indicated that N-(phosphonoacetyl)-L-ornithine (PALO) was bound to the catalytic site of OTCase mutant structure with minimal conformational changes. However, the mutations disrupted interatomic interactions in the catalytic site. Therefore, depending on the severity of disruption occurring at the catalytic site, the mutation may affect the efficiency of mechanism and functions of OTCase.

Brain Biomarkers of Long-Term Outcome of Neonatal Onset Urea Cycle Disorder

Urea cycle disorders (UCDs) are common inborn errors of metabolism, with an incidence of one in 30,000 births. They are caused by deficiencies in any of six enzymes and two carrier proteins, the most common being Ornithine Transcarbamylase Deficiency (OTCD). OTCD results in impairment to excrete nitrogen, causing toxic buildup of ammonia with resultant encephalopathy. Hyperammonemia (HA) induces the conversion of glutamate to glutamine in the brain. Excess glutamine in the brain causes osmotic changes, cerebral edema, changes in astrocyte morphology, and cell death. Acute symptoms of HA include vomiting, hyperventilation, seizures, and irritability. Long-term neurological effects include deficits in working memory and executive function. To date, there are no predictors of prognosis of infants with neonatal onset OTCD outside of the plasma ammonia level at presentation and duration of a hyperammonemic coma. We provide a comprehensive analysis of a 16-year-old male with neonatal onset of OTCD as an example of how brain biomarkers may be useful to monitor disease course and outcome. This male presented at 8 days of life with plasma ammonia and glutamine of 677 and 4024 micromol/L respectively, and was found to have a missense mutation in Exon 4 (p. R129H). Treatment included protein restriction, sodium benzoate, and citrulline, arginine, and iron. Despite compliance, he suffered recurrent acute hyperammonemic episodes triggered by infections or catabolic stressors. We discuss the long-term effects of the hyperammonemic episodes by following MRI-based disease biomarkers.

Multidisciplinary perinatal management of a woman and her baby with ornithine transcarbamylase deficiency

Objective To investigate the clinical features and gene mutation of a newborn with neonatal–onset ornithine transcarbamylase deficiency (OTCD) and report the multidisciplinary perinatal management of the mother with late–onset OTCD. Methods The clinical features, biochemical data and the treatment of a newborn boy with OTCD and his mother admitted by Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine in April, 2013, were collected. The ornithine transcarbamylase (OTC) gene in the family was analyzed. Results Serum ammonium in the male newborn gradually increased to 1 020 μmol/L at 48 h after birth. His blood amino acids level and urine organic acid level showed a pattern indicative of OTCD [blood arginine (97.43 μmol/L, reference 1.00–25.00 μmol/L), citrulline (27.43 μmol/L, reference 4.00–30.00 μmol/L), ornithine (161.66 μmol/L, reference 10.00–120.00 μmol/L) and methionine (70.45 μmol/L, reference 10.00–50.00 μmol/L); urine uracil (67.11 μmol/mol Crea, reference 0.00–7.00 μmol/mol Crea) and orotic acid (1 372.66 μmol/mol Crea, reference 0.00–1.50 μmol/mol Crea)]. DNA studies revealed a c.583G>A (G195R) homozygous mutation of the OTC gene. His mother was heterozygous for OTCD and developed acute hyperammonemia during pregnancy. Her blood showed a normal–leveled arginine (8.44 μmol/L, reference 1.50–25.00 μmol/L), a normal–leveled citrulline(8.41 μmol/L, reference 7.00–35.00 μmol/L), an elevated glutamate(279.15 μmol/L, reference 45.00–200.00 μmol/L). Her urine uracil (51.55 μmol/mol Crea, reference 0.00–7.00 μmol/mol Crea) and orotic acid (38.75 μmol/mol Crea, reference 0.00–1.50 μmol/mol) were elevated. Successful management of her prenatal and postpartum blood ammonia level was achieved after administration of pharmacologic nitrogen scavengers and protein limitation. DNA studies revealed a c.583G>A (G195R) heterozygous mutation in the newborn's mother and grandmother. Conclusions General management on pregnant OTCD women is effective. Male newborn patients often have a poor prognosis. Key words: Ornithine carbamoyltransferase deficiency disease; Urea cycle disorders, inborn; Infant, newborn; Peripartum period

Analysis of clinical features, biochemical analysis and gene mutations in one Chinese pedigree with neonatal-onset ornithine transcarbamylase deficiency

This 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. The 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. The 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. The 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.

Ornithine transcarbamylase deficiency: A possible risk factor for thrombosis

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect. Thromboembolic complications have not heretofore been linked with this diagnosis. We describe four patients with neonatal-onset OTC deficiency who developed vascular thromboses. One patient had arterial thrombosis; the rest developed venous thromboses. Multiple pro-thrombotic risk factors were identified. Low plasma arginine levels were observed in all patients at the time of thrombosis. Arginine deficiency and the resultant nitric oxide insufficiency may contribute to thrombotic risk. Careful normalization of plasma arginine and citrulline levels and increased surveillance for thrombotic complications should be considered in patients with OTC deficiency.

Complex management of a patient with a contiguous Xp11.4 gene deletion involving ornithine transcarbamylase: A role for detailed molecular analysis in complex presentations of classical diseases

A male infant was diagnosed prenatally with a partial ornithine transcarbamylase ( OTC) gene deletion and managed from birth. However, he displayed neurological abnormalities and developed pleural effusions, ascites and anasarca not solely explained by OTC deficiency (OTCD). Further evaluation of the gene locus using exon-specific PCR and high-density SNP array copy number analysis revealed a 3.9-Mb deletion from Xp11.4 to Xp21.1 including five additional gene deletions, three causing the known genetic diseases: Retinitis pigmentosa (RP3), X-linked chronic granulomatous disease (CGD) and McLeod syndrome. The case illustrates (1) the complexities of managing a patient with neonatal onset OTCD, CGD, RP3 and McLeod syndrome, (2) the need for detailed evaluation in seemingly “isolated” gene deletions and (3) the clinical utility of high-density copy number analysis for rapidly characterizing chromosomal lesions.