Medical nutrition management and follow-up of patients with late-onset ornithine transcarbamylase deficiency / 中华实用儿科临床杂志

Objective:To explore the clinical characteristics and medical nutritional therapy of 6 patients with late-onset ornithine transcarbamylase (OTC) deficiency.Methods:The clinical features, biochemical data, gene variations and treatment outcomes of 6 children with late-onset OTC deficiency admitted to the Department of Clinical Nutrition, Children′s Hospital of Nanjing Medical University from January 2020 to April 2022 were retrospectively analyzed.The 6 patients were all intervened by a long-term medical nutrition management.Results:Liver dysfunction and hyperammonemia (172.1-348.0 μmol/L) were found in all the 6 children with late-onset OTC deficiency.Serum citrulline decreased in 3 patients (3.95-5.43 μmol/L). Three patients showed increased urine orotic acid (123.48-342.60 mmol/mol Cr). Urine uracil increased in 4 patients (106.77-1 207.26 mmol/mol Cr). Variations of the OTC gene [c.364G>C p. (E122Q), c.1028C>G p. (T343R), c.664-2(IVS6)A>C, c.635G>T p. (G212V), c.929_c.931delAAG p. (E310del), c.829C>T p. (R277W)] were identified in all patients.The 6 children were all managed by individualized medical nutrition program and followed up for a long time.During the follow-up period, 3 cases developed hypoproteinemia, acute metabolic crisis and growth retardation, 3 cases had normal growth and laboratory indicators, and 1 case received liver transplantation after 3 months of nutritional management. Conclusions:The clinical manifestations of OTC deficiency are non-specific.Blood amino acids, urine organic acids and genetic tests are important for the diagnosis.Long-term regular medical nutrition management is helpful to improve the prognosis and quality of life of children.

Newborn screening for ornithine transcarbamylase deficiency in Zhejiang Province and the follow-up analysis / 中华实用儿科临床杂志

Objective:To investigate the incidence, clinical characteristics and prognosis of ornithine transcarbamylase deficiency(OCTD) in newborns in Zhejiang Province.Methods:A retrospective research was conducted.A total of 4 261 036 newborns from Department of Genetics and Metabolism, Children′s Hospital, Zhejiang University School of Medicine, between January 2009 and December 2021 were screened for inherited metabolic disorders using tandem mass spectrometry.OCTD was confirmed by urine organic acid and OTC gene analysis.Patients with OTCD received guidance on diet and lifestyle management, and were treated with citrulline and arginine.Long-term follow-up was performed.Their growth and intellectual development were evaluated. Results:A total of 7 patients with OCTD were diagnosed, with an incidence of 1.6/1 million.All patients were males.Two patients had neonatal-onset OCTD, and the other 5 had late-onset OCTD.Symptoms occurred several times in 6 patients, inducing hyperammonemia and hepatic impairment.One patient had no clinical manifestation.One patient died in the neonatal period.Blood citrulline levels were decreased in 7 patients to varying degrees.Uracil levels were increased in 4 patients, and 1 of them was complicated with elevated orotic acid levels.All patients had hemizygote variations in the OTC gene, including 6 missense variations(c.604C>T, c.386G>A, c.779T>C, c.1019C>T, c.594C>G, c.931G>A) and 1 intron variation(c.514-35C>G). Two variants(c.594C>G, c.514-35C>G) were never reported previously. Conclusions:The OTCD incidence by newborn screening is low with 1.6/1 million in Zhejiang province.All patients are males and present hypocitrullinemia.The clinical manifestations of OTCD are highly heterogeneous.The neonatal-onset form is severe and survivors always suffer serious sequelae.The late-onset form is mostly manifested with hyperammonemia and hepatic impairment.There may be association between phenotype and genotype.Two novel OTC variants are identified, which further expands the mutational spectrum.

Neonate-onset ornithine transcarbamylase deficiency / 中国当代儿科杂志

The male neonate in this case study was admitted to the hospital at 15 hours of age due to respiratory distress for 15 hours and poor response for 3 hours after resuscitation from asphyxia. The neonate was highly unresponsive, with central respiratory failure and seizures. Serum ammonia was elevated (>1 000 μmol/L). Blood tandem mass spectrometry revealed a significant decrease in citrulline. Rapid familial whole genome sequencing revealed OTC gene mutations inherited from the mother. Continuous hemodialysis filtration and other treatments were given. Neurological assessment was performed by cranial magnetic resonance imaging and electroencephalogram. The neonate was diagnosed with ornithine transcarbamylase deficiency combined with brain injury. He died at 6 days of age after withdrawing care. This article focuses on the differential diagnosis of neonatal hyperammonemia and introduces the multidisciplinary management of inborn error of metabolism.

A novel splice site mutation in OTC gene of a female with ornithine transcarbamylase deficiency and her asymptomatic mosaic father

Ornithine transcarbamylase deficiency is an X-linked disease with a wide range of clinical severity and manifestation age both in males and females. Here, we describe a case which is caused by a novel c.78-1G[A splice site mutation, which on mRNA level leads to a 1-bp deletion and a frameshift (c.78delG (p.C27Vfs*11)) in OTC exon 2 in a young girl. The same mutation has been detected in a mosaic state in her asymptomatic father.

Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency / 浙江大学学报·医学版

Ornithine transcarbamylase deficiency(OTCD)is a most common ornithine cycle (urea cycle) disorder. It is a X-link inherited disorder caused by

Mutation Spectrum and Genotype-Phenotype Correlation in a Cohort of Argentine Patients with Ornithine Transcarbamylase Deficiency: A Single-Center Experience

Abstract X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Hemizygous males with complete deficiency manifest neonatal acute hyperammonemia, while those with partial deficiency have a late presentation. The symptomatology of heterozygotes depends on the inactivation pattern of X chromosome. Hyperammonemic episodes can cause neurological damage and are potentially fatal. Here, we match clinical, biochemical, and molecular findings with bioinformatics analyses to report genotype-phenotype correlations in 14 Argentine patients with OTCD from 11 unrelated families: 4 hemizygotes with neonatal onset (complete OTC gene deletion, 533C > T, c.540+1G > A, c.697delG); 4 hemizygotes with late onset (c.216+1G > A, c.386G > A, c.622G > A, c.829C > T); and 6 symptomatic heterozygotes (complete OTC gene deletion, c.533C > T, c.452T > G, c.540+1G > A, dupE1-9/delE10). Three of these mutations were previously unreported: c.540+1G > A, c.697delG, and dup1-9/del10. Our data highlight the relevance of combining molecular and bioinformatics analyses for accurate diagnosis and outcome prediction in suspected patients with OTCD and the importance of carrier testing for effective genetic counseling.

Lethal Hyperammonemia due to Ornithine Transcarbamylase Deficiency in a Patient with Severe Septic Shock / 대한구급학회지

Severe hyperammonemia can occur as a result of inherited or acquired liver enzyme defects in the urea cycle, among which ornithine transcarbamylase deficiency (OTCD) is the most common form. We report a very rare case of a 45-year-old Korean male who was admitted to the intensive care unit (ICU) due to severe septic shock with acute respiratory failure caused by Pneumocystis jiroveci pneumonia. During his ICU stay with ventilator care, the patient suffered from marked hyperammonemia (>1,700 µg/dL) with abrupt mental change leading to life-threatening cerebral edema. Despite every effort including continuous renal replacement therapy and use of a molecular adsorbent recirculating system (extracorporeal liver support-albumin dialysis) to lower his serum ammonia level, the patient was not recovered. The lethal hyperammonemia in the patient was later proven to be a manifestation of acquired liver enzyme defect known as OTCD, which is triggered by serious catabolic conditions, such as severe septic shock with acute respiratory failure.

Lethal Hyperammonemia due to Ornithine Transcarbamylase Deficiency in a Patient with Severe Septic Shock / 대한중환자의학회지

Severe hyperammonemia can occur as a result of inherited or acquired liver enzyme defects in the urea cycle, among which ornithine transcarbamylase deficiency (OTCD) is the most common form. We report a very rare case of a 45-year-old Korean male who was admitted to the intensive care unit (ICU) due to severe septic shock with acute respiratory failure caused by Pneumocystis jiroveci pneumonia. During his ICU stay with ventilator care, the patient suffered from marked hyperammonemia (>1,700 µg/dL) with abrupt mental change leading to life-threatening cerebral edema. Despite every effort including continuous renal replacement therapy and use of a molecular adsorbent recirculating system (extracorporeal liver support-albumin dialysis) to lower his serum ammonia level, the patient was not recovered. The lethal hyperammonemia in the patient was later proven to be a manifestation of acquired liver enzyme defect known as OTCD, which is triggered by serious catabolic conditions, such as severe septic shock with acute respiratory failure.

Presentación de un paciente con déficit de ornitín transcarbamilasa / Presentation of a Patient with Ornithine Transcarbamylase Deficiency

Se presentó un paciente de dos años de edad atendido por la Unidad de Cuidados Intensivos Pediátricos del Hospital Provincial Docente Octavio de la Concepción y de la Pedraja de Holguín, con un síndrome emético. Para realizar cromatografía de gases en orina fue necesario enviar la muestra de orina en un termo refrigerado y este a su vez en un refrigerador a - 20 oC, al laboratorio de la Clínica Universitaria de Freiburg, Alemania. Se determinó como diagnóstico definitivo un déficit de ornitín transcarbamilasa. El análisis bioquímico constituye la base del diagnóstico de esta enfermedad, pero el punto de partida en la investigación, es la hipótesis diagnóstica formulada sobre la base de los síntomas y signos clínicos del paciente. Se destacó que no existió una terapéutica específica. Presentó como complicación a largo plazo un retraso mental ligero. Es primordial realizar el diagnóstico precoz para evitar la muerte o las secuelas, que pueden ser evitables.

A two -year- old patient attended at Pediatric Intensive Care Unit of Octavio de la Concepción and Pedraja Provincial Teaching Hospital Holguín, with an emetic syndrome. To make urine gas chromatography was necessary to send the urine sample in a cooled flask and this in turn in a refrigerator at - 20 oC, the laboratory of the University Hospital of Freiburg, Germany. Definitive diagnosis was determined as a deficiency of ornithine transcarbamylase. Biochemical analysis forms the basis of the diagnosis of this disease, but the starting point in the investigation, the diagnostic hypothesis is formulated on the basis of clinical signs and symptoms of the patient. It was noted that there was no specific therapy. The patient presented a mild mental retardation as a long-term complication. It is important to perform early diagnosis to prevent death or sequelae, which may be preventable.

Clinical and OTC gene mutation analysis of one child with ornithine transcarbamylase deficiency / 中华实用儿科临床杂志

Objective To analyze the clinical and OTC gene mutation characteristics of 1 case with ornithine transcarbamylase deficiency (OTCD) and to deepen the understanding of OTCD.Methods One case of 14-month female OTCD patient was analyzed.Clinical data of the child patient was collected and venous blood 2 mL from the patient and her parents was extracted respectively.Polymerase chain reaction was used to amplify the fragment where various exon of OTC and its neighboring intron were distributed, followed by direct sequencing to detect mutation.Results It was showed that late-onset OTCD child patient had contracted the disease for 3 months,with intermittent drowsiness, vomiting and psychomotor development regression.Cerebellar ataxia was the main symptom of the child patient when she was taken to Tianjin Children's Hospital.According to brain MRI, the lesion was severe.Blood chemistry showed mild hepatic lesion and increased blood ammonia.According to urine gas chromatography mass spectrometry analysis,there was a rise in uracil and orotic acid.OTC genetic testing showed the child patient and her mother were in the 8th exon,c.852C ＞ G (p.Y284X).Missense mutation occurred in this locus.The mother had normal phenotype.Conclusions Clinically OTCD has the symptoms of hyperammonemia and the resulting in varying degrees of damage to the nervous system and the liver.Without clinical specificity, this disease is easy to be misdiagnosed.Methods like blood ammonia and urine metabolic disease screening, blood amino acid analysis and genetic testing help confirm the disease earlier.As for treatment, early intervention and chronic control of blood ammonia level to guard against hyperammonemia will lead to better curative effect.

Acute treatment of hyperammonemia by continuous renal replacement therapy in a newborn patient with ornithine transcarbamylase deficiency / 소아과

Ornithine transcarbamylase (OTC) deficiency is well known as the most common inherited disorder of the urea cycle, and 1 of the most common causes of hyperammonemia in newborns. We experienced a case of a 3-day-old boy with OTC deficiency who appeared healthy in the first 2 days of life but developed lethargy and seizure soon afterwards. His serum ammonia level was measured as >1700 microg/dL (range, 0 to 45 microg/dL). Continuous renal replacement therapy (CRRT) in the mode of continuous venovenous hemodiafiltration was immediately applied to correct the raised ammonia level. No seizure occurred after the elevated ammonia level was reduced. Therefore, CRRT should be included as 1 of the treatment modalities for newborns with inborn errors of metabolism, especially hyperammonemia. Here, we report 1 case of successful treatment of hyperammonemia by CRRT in a neonate with OTC deficiency.

A Case of Molecular Diagnosis of Ornithine Transcarbamylase Deficiency / 영남의대학술지

Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea cycle metabolism; it is inherited in an X-linked manner. The OTC catalyzes the third step of the urea cycle, the conversion of ornithine and carbamyl phosphate to citrulline. Deficiency of OTC leads to the accumulation of ammonia, causing neurological deficits. In most affected hemizygote males, OTC deficiency manifests as hyperammonemic coma that often leads to death in the newborn period, and those who recover from the coma may be neurologically impaired due to the sequelae of the hyperammonemic encephalopathy. In some, late-onset manifestations develop. We report a male neonate with early onset OT deficiency that had apnea and was comatous. On mutation analysis using DNA sequencing after polymerase chain reaction (PCR) amplification of the 10 exons, deletions of 10 bases in codon 285, causing a frame shift was detected in exon 8. The mother and a sister were diagnosed as female carriers. Therefore, genetic counseling and the risk assessment could be provided to the family.

Analysis of urinary markers for ornithine transcarbamylase deficiency by gas chromatography-mass spectrometry / 基础医学与临床

Objective To develope both qualitative and quantitative analytic method of the four urinary markers,i.e.lactate,uracil,orotate and hippurate,from ornithine transcarbamylase deficiency(OTCD) by Gas Chromatography-Mass Spectrometry(GC-MS).Methods Urea in urine samples was decomposed with urease,and heptadecanoiate was added as internal standard,then protein was denatured with ethanol and removed by centrifugation.After evaporation,the residue was derivatized trimethylsilylly by BSTFA/TMCS,and analyzed by GC-MS.ResultsThe markers can be separated in total ion current profiles,with indentifications confirmed by mass spectra.The significantly elevated levels of lactate,uracil and orotate in urine from OTCD patient were droped to normal or subnormal levels,together with large amount of hippurate excretion in the urine,after clinical therapeutic measures,including introduction of benzoic acid,were performed.Conclusion GC-MS analysis of the urinary markers is a valuable tool for the diagnosis and evaluation of the therapeutic outcome of OTCD.

Successful Preimplantation Genetic Diagnosis for Ornithine Transcarbamylase Deficiency, Junctional Epidermolysis Bullosa and Lactic Acidosis Using Duplex Nested PCR: Delivery of Healthy Baby by Specific Preimplantation Genetic Diagnosis for Ornithine Tran / 대한산부인과학회잡지

OBJECTIVE: Preimplantation genetic diagnosis (PGD) is reserved for couples with a risk of transmitting a serious and incurable disease, and hence avoids the undesirable therapeutic abortion. Herein, we report the result of PGD to carriers at risk of transmitting ornithine transcarbamylase (OTC) deficiency, junctional epidermolysis bullosa (EB) and lactic acidosis (LA) due to defect of pyruvate dehydrogenase alpha1 gene, respectively. METHODS: The ovarian stimulation, oocyte retrieval and ICSI procedure were undergone by conventional protocols. PGD for single gene disorders was carried out after biopsy of one or two blastomeres from the embryos on the third day. We performed the duplex nested PCR of the simultaneous amplification for the causative mutation loci as well as the SRY gene on Y chromosome in case of OTC deficiency and LA. Two different mutation loci of ITGB4 gene in EB case were amplified by the same protocol. The PCR products were analyzed by agarose gel electrophoresis, restriction fragment length polymorphism analysis or direct DNA sequencing. RESULTS: A total of 26 embryos were analyzed by duplex nested PCR. One or two blastomeres were biopsied, and successful diagnosis rate of PGD with PCR was 92.3% (24/26). There was no contamination in all PCR samples of negative controls (n=67). Five embryos (19.2%) were diagnosed as normal embryos, which were transferred to the mothers' uterus in each cases. In OTC deficiency case, singleton pregnancy was established. At 17 weeks of gestation, genetic normality of OTC gene in fetus was confirmed by amniocentesis. A healthy baby was successfully delivered at 36 weeks of gestation in OTC deficiency case. Unfortunately, pregnancies were not achievement in cases of EB and LA. CONCLUSION: This is the first report in Korea that healthy baby was born after specific PGD for OTC deficiency. Our results demonstrate that duplex nested PCR for single cell is an efficient method in identifying the gender and single gene mutation or two different mutation loci, simultaneously. This PGD procedure could provide normal healthy baby to the couple with a high risk of transmitting genetic diseases.

A Case of Ornithine Transcarbamylase Deficiency Successfully Treated with Protein Restriction and Living Related Liver Transplantation

Ornithine transcarbamylase deficiency(OTCD), the most common inborn error of the urea cycle, is inherited in X-linked manner. In affected hemizygote males, OTCD manifests hyperammonemic coma that often leads to death during the newborn period. Our patient was at high risk for inborn error of urea cycle metabolism, since his two elder brothers died a few days after birth due to hyperammonemia. He was diagnosed as OTCD based on biochemical profiles and direct sequencing of the OTC gene. He has been managed with Ross metabolic protocol including protein restriction, administration of sodium benzoate, phenylacetate, arginine, citrulline, and diet therapy (Cyclinex-I ) since birth. At the 8 months of age, we performed living-related liver transplantation(LRLT) using his father's left lateral segment. The patient's serum ammonia level was restored to normal after LRLT without protein restriction. During postoperative follow up for 10 months, he was still in normal neurological and developmental status.