Diagnosis Of Ornithine Transcarbamylase Deficiency Research Articles

Дефіцит орнітин-транскарбамілази - мало відоме орфанне захворювання в дитячій гепатології (клінічний випадок)

The article reviews literature and demonstrates personal observation of a preschool patient with ornithine transcarbamylase deficiency. This disease is characterized by an excessive accumulation of ammonia in the body, which leads to damage of the nervous system, gastrointestinal tract, and impaired liver function. It has a genetically determined mechanism of development associated with mutations in the OTC gene. Purpose - to study specific aspects of manifestation, clinical picture, course and diagnosis of ornithine transcarbamylase deficiency. Clinical case. Girl U. was admitted to the pediatric hepatology department with complaints of abdominal pain, periodic vomiting, accompanied by high ketones in urine test, irritability, tearfulness, emotional lability, and increased liver enzyme levels. Physical exam revealed hepatosplenomegaly. Bloodwork series showed transaminase levels 4-20 times ULN, hyperammonemia, and increased orotic acid in urine. A molecular genetic study was performed, and identified a variant of uncertain significance in the OTC gene associated with X-linked ornithine transcarbamylase deficiency. Metabolic therapy and protein-restricted nutrition were prescribed to prevent hyperammonemia. Conclusions. Transcarbamylase deficiency is a rare genetic disease characterized by excessive accumulation of ammonia in the body with typical clinical and laboratory symptoms. Detection of ammonia concentration and molecular genetic testing are crucial diagnostic components in children with liver diseases associated with other organs and systems damage. Untimely diagnosis and treatment correlates with the severity of the disease, the development of irreversible changes, disability and possible death in young age. The study was performed according to the principles of the Declaration of Helsinki. The informed consent of the child's parents was obtained for the conducted research. The authors declare no conflict of interest.

A complex case of delayed diagnosis of ornithine transcarbamylase deficiency in an adult patient with multiple comorbidities

We report the case of a medically complex African American adult female with ornithine transcarbamylase (OTC) deficiency diagnosed after lifelong protein aversion and new onset of chronic vomiting and abdominal pain with intermittent lethargy and confusion. Symptomatology was crucial to diagnosis as genetic testing did not identify any pathogenic variants in OTC; however, the patient's diagnosis was delayed despite her having longstanding symptoms of a urea cycle disorder (UCD). Her symptoms improved after treatment with a modified protein-restricted diet, long-term nitrogen-scavenger therapy, and supplemental L-citrulline. Adherence to her UCD management regimen remained a challenge due to her underlying frailty and other medical conditions, which included primary renal impairment (further exasperated by type 2 diabetes mellitus) and decreased left-ventricular function. She passed away 3 years after her OTC deficiency diagnosis due to complications of congestive heart failure. Her OTC deficiency did not have a major impact on her final illness, and appropriate OTC deficiency management was provided until the decision was made to withdraw medical care.

Ornithine transcarbamylase deficiency: A diagnostic odyssey

Ornithine transcarbamylase deficiency: A diagnostic odyssey

Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency

BackgroundThis study aimed to describe the clinical and biochemical features of Chinese patients with ornithine transcarbamylase deficiency (OTCD), and to investigate the mutation spectrum of OTC gene and their potential correlation with phenotype.MethodsSixty-nine patients with OTCD were enrolled between 2004 and 2019. Clinical and laboratory data were reviewed retrospectively from medical records.ResultsFifteen cases (13 males, 2 females) presented with early onset; 53 cases (21 males, 32 females) had late onset, and one female was asymptomatic. The median onset age was 1.5 years (range 1 day–56 years). Urine orotic acid levels were increased in all patients tested, while only 47.6% of patients showed decreased serum levels of citrulline. The peak plasma ammonia levels were higher in early-onset patients than in late-onset patients (P < 0.01). Fifty-four different mutations of OTC gene were identified and 18 of them were novel. R277W (10.6%) was the most common mutation, followed by G195R (4.6%) and A209V (3.0%). By June 2019, 41 patients had survived, 24 were deceased, and 4 were lost to follow-up. Among the survivors, 13 patients had received liver transplantation at a median age of 3 years, with a one-year survival rate of 100%. The mortality of OTCD is extremely high among patients with early onset (80.0% versus 24.5% in patients with late onset).ConclusionsThe evaluation of serum citrulline level is of limited value in diagnosis of OTCD, while urine orotic acid detection and genetic testing are more helpful.

Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency

Ornithine transcarbamylase deficiency(OTCD)is a most common ornithine cycle (urea cycle) disorder. It is a X-link inherited disorder caused by OTC gene mutation that in turn leads to reduction or loss of OTC enzyme activity. Its onset time is related to the lack of enzyme activity. Patients with neonatal onset usually have complete absence of OTC enzyme activity, which is mainly associated with male semi-zygotic mutations; and the disease progresses rapidly with high mortality rates. Patients with late onset vary in onset age and clinical manifestations, and the course of disease can be progressive or intermittent. The acute attack mainly manifests neuropsychiatric symptoms accompanied by digestive symptoms like liver function damage or even acute liver failure. Elevated blood ammonia is the main biochemical indicator of OTCD patients. Increased glutamine, decreased citrulline in blood, and increased orotic acid in urine are typical clinical manifestations for OTCD patients. Genetic testing of OTC gene is important for OTCD diagnosis. The goal of treatment is to minimize the neurological damage caused by hyperammonemia while ensuring the nutritional needs for patient development. For patients with poor response to medication and diet, liver transplantation is recommended under the condition of stable metabolic state and absence of severe neurological damage. During long-term treatment, physical growth indicators, nutrition status, liver function, blood ammonia and amino acids should be regularly monitored. This consensus aims to standardize the diagnosis and treatment of OTCD, improve the prognosis, reduce the mortality and disability of patients.

Genetic testing and prenatal diagnosis in seven pedigrees affected with ornithine transcarbamylase deficiency

To detect genetic variants among 7 pedigrees affected with ornithine transcarbamylase deficiency (OTCD) and provide prenatal diagnosis for them. The pedigrees were subjected to targeted next-generation sequencing (NGS) with a gene panel for inherited metabolic diseases. Suspected pathological variants were confirmed by Sanger sequencing of the probands and their family members. Prenatal diagnosis was provided for 4 of the pedigrees. Seven variants of the OTC gene, including c.583G>A (p.Gly195Arg), c.626C>T (p.Ala209Val), c.674C>T(p.Pro225Leu), c.482A>G (p.Asn161Ser), IVS1-2A>G, c.116G>T(p.Gly39Val), c.898delT(p.300Phefs*22), were detected, among which IVS1-2A>G, c.116G>A (p.Gly39Val) and c.898delT (p.300Phefs*22) were unreported previously. Three male fetuses were found to carry hemizygotic variants upon prenatal diagnosis. One female fetus were found to be heterozygous for a variant, and appeared to be normal at birth as well as by newborn screening. OTC gene variant is the etiology of OTCD in the 7 pedigrees. Genetic testing of OTC could assist physicians in OTCD diagnosis and provide genetic counseling and prenatal diagnosis for the pedigrees.

The phenotypic and mutational spectrum of Thai female patients with ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder affecting both males and females. Hemizygous males commonly present with severe hyperammonemic encephalopathy during the neonatal period. Heterozygous females have great phenotypic variability. The majority of female patients can manifest later in life or have unrecognized symptoms, making the diagnosis of OTCD in females very challenging. Here we report on three unrelated Thai female cases with OTCD presenting with different manifestations including aggressive behavior, acute liver failure and severe encephalopathy. Whole exome sequencing successfully identified disease-causing mutations in all three cases including two novel ones: the c.209_210delAA (p.Lys70Argfs*17) and the c.850T>A (p.Tyr284Asn). This study affirms variable symptoms in female patients with OTCD and emphasizes the importance of early recognition and prompt management for favorable outcomes. In addition, identification of two novel causative variants expands the genotypic spectrum of OTC.

Prenatal treatment of ornithine transcarbamylase deficiency

Purpose of studyPatients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. Methods usedTwo heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. Summary of resultsTherapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24–48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. ConclusionPrenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

G389(P) A case for early ammonia testing in all encephalopathic patients: female patients with x-linked ornithine transcarbamylase deficiency

<h3></h3> We report the case of a 14-year-old girl admitted to PICU following a four-day history of vomiting, unusual behaviour and progressive drowsiness. She had depressed consciousness and encephalopathic features, thus requiring intubation and ventilation. The initial CT and MR scans were unremarkable and an encephalopathy screen, including plasma ammonia was performed on admission. Shortly after admission the patient developed seizures and signs of raised intracranial pressure with a right fixed, dilated pupil. The pre-ictal ammonia concentration was markedly elevated at 638umol/L. A repeat urgent CT brain showed diffuse cerebral oedema with signs of brain herniation; neuroprotective measures were therefore initiated. Attempts to rapidly reduce ammonia levels by haemofiltration and infusions of sodium benzoate and phenylbutyrate were biochemically successful. Despite a quick decline in ammonia levels the patient developed central diabetes insipidus and showed no signs of neurological recovery, with persistent fixed, dilated pupils. Biochemical investigations strongly suggested a diagnosis of ornithine transcarbamylase deficiency (OTCD) with low citrulline and increased urinary orotic acid. DNA for mutation analysis and a liver biopsy or enzyme studies were sent to confirm the diagnosis. Brain stem testing 5 days post- admission confirmed brain stem death. OTCD is the commonest inborn error of the urea cycle and shows X-linked inheritance. The classic presentation in male hemizygotes is with life threatening hyperammonaemic coma shortly after birth but milder variants present later. The phenotype in female heterozygotes is variable and depends on the pattern of X-chromosome inactivation in hepatocytes. This can range from severe neonatal encephalopathy to being completely asymptomatic throughout life. Survival and neurocognitive outcomes can be better than in severely affected males but are variable. Aggressive treatment of hyperammonaemic crises, dietary management with low protein diets, and alternative pathway therapy prevent further cognitive decline. This case highlights the importance of early ammonia testing in encephalopathic patients regardless of age. A diagnosis of OTCD should be considered in patients with hyperammonaemia regardless of sex. Early recognition and appropriate treatment are critical to avoid severe brain damage and death.

Analysis of clinical features, metabolic profiling and gene mutations of patients with ornithine transcarbamylase deficiency

To analyze the clinical features, metabolic profiling and gene mutations of patients with ornithine transcarbamylase deficiency (OTCD) and explore the molecular pathogenesis of OTCD in order to provide a solution for molecular diagnostics and genetic counseling. Clinical data of 3 neonates were analyzed. The amino acids level in blood was analyzed with mass spectrum technology. PCR was used to amplify all the 10 exons of OTC gene. The PCR products were directly sequenced to detect the mutations. All of the 3 cases had neonatal onset and showed poor reaction, feeding difficulty, convulsion and neonatal infection. Citrulline levels were significantly decreased. Case 1 had a missense mutation of Y183C. Case 2 showed a missense mutation of V339G in exon 10. And a missense mutations of W332S in exon 9 was detected in case 3. Analysis of OTC gene sequences can be used for the diagnosis of OTCD and screening of asymptomatic carriers. Mutation analysis is important for prenatal diagnosis of individuals with a positive family history and genetic counseling. The V339G and W332S mutations have been discovered for the first time. Patients with such mutations may have onset of the disease during neonatal period.

Ornithine Transcarbamylase Deficiency Presenting as Recurrent Abdominal Pain in Childhood

Recurrent abdominal pain remains one of the most common symptoms in pediatrics. We present the case of a 3-year-old girl who had recurrent episodes of abdominal pain requiring more than 13 visits to the emergency department. A diagnosis of ornithine transcarbamylase deficiency was eventually made. Urea cycle disorders often present beyond the neonatal period with frequent vomiting episodes; however, recurrent abdominal pain as a presenting symptom is unusual. Unnecessary invasive investigations of recurrent abdominal pain in childhood can be avoided by considering inborn errors of metabolism earlier in the differential diagnosis.

An exon 1 deletion in OTC identified using chromosomal microarray analysis in a mother and her two affected deceased newborns: Implications for the prenatal diagnosis of ornithine transcarbamylase deficiency

We describe the outcome of two consecutive pregnancies with a clinical presentation of ornithine transcarbamylase (OTC) deficiency (OTCD) without a molecular diagnosis. A 119 kb deletion on Xp11.4 including the OTC gene was detected in the mother. The same deletion was identified in the blood spots from deceased male newborns. In patients with a clinical and biochemical presentation of OTCD and negative OTC sequencing, whole genome or targeted chromosomal microarray analysis (CMA) with coverage of the OTC and neighboring genes should be performed as a reflex test.

Anesthetic implications of ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder associated with potentially fatal episodes of hyperammonemia. Children with OTCD often require anesthesia. There is insufficient information regarding perioperative complications and optimal management of anesthesia in these patients. To retrospectively review the medical records of children with OTCD to ascertain the nature and frequency of peri-procedural complications. The electronic medical records of Mayo Clinic patients with OTCD who underwent anesthesia between the dates of January 2003 and September 2009 were reviewed. Nine patients with OTCD underwent 25 anesthetics using a variety of anesthetic techniques, including four major surgeries. Eleven procedures were performed prior to OTCD diagnosis and those patients were not receiving therapy for a urea cycle disorder. In the other cases, patients were on a variety of therapies for OTCD. Fourteen patients were outpatient procedures. Clinical signs of postoperative metabolic decompensation did not occur. In this series, patients with OTCD tolerated anesthesia well. Choice of perioperative management of OTCD and the choice of anesthetic technique should be individualized and based on clinical circumstances, but should have the underlying aim of minimizing protein catabolism. It appears patients with stable OTCD may undergo minor procedures as outpatients safely.

Osmotic Demyelination Syndrome as a Consequence of Treating Hyperammonemia in a Patient with Ornithine Transcarbamylase Deficiency

A 7-year-old female patient with a new diagnosis of ornithine transcarbamylase deficiency was treated for hyperammonemia with a standard protocol. Several days later, she developed ataxia, dysmetria, and dysarthria. Magnetic resonance imaging of the brain demonstrated pontine and extrapontine white matter changes consistent with osmotic demyelination. Classically described as a consequence of hyponatremia treatment, osmotic demyelination syndrome has rarely been associated with other entities. This case suggests a potentially serious complication of the standard therapy for hyperammonemia in patients with ornithine transcarbamylase deficiency.

Estimation of the total number of disease‐causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential

Ornithine transcarbamylase deficiency (OTCD), the X-linked, most frequent urea cycle error, results from mutations in the OTC gene, encoding a 354-residue polypeptide. To date 341 OTCD clinical mutations, including 222 missense single nucleotide changes (mSNCs), have been compiled (Hum Mutat 2006;27:626). OTCD mutation detection might be simplified if the entire repertoire of OTCD-causing mutations were known. We estimate the size of this repertoire from 23 new OTCD patients exhibiting 22 different mutations, of which 9, including 4 mSNCs, are novel. The complete repertoire of OTCD-causing mutations is estimated as 560 mutations (95% confidence interval, 422-833 mutations), including 290 mSNCs (95% confidence interval, 230-394 mSNCs). Thus, OTCD diagnosis based on the screening for known mutations might attain 90% sensitivity in <5 years. Since disease-causing mSNCs represent <20% of the 2064 possible OTC mSNCs, simple approaches are essential for discrimination between causative and trivial mSNCs. Observation of the OTC structure appears a simple approach for such discrimination, comparing favourably in our sample with three formalized structure-based and/or sequence-based in silico assessment methods, and supporting the causation of complete deficiency by the mutations p.Pro305Arg and p.Ser96Phe, and of partial deficiency by p.Asp41Gly, p.Glu122Gly, p.Leu179Phe, p.Pro220Thr and p.Glu273del. Five non-mSNC novel mutations (p.Gly71X, a 7-nucleotide and a 10-nucleotide duplication and deletion in exon 5, G>A transitions at bases +1 and +5 of introns 4 and 9, respectively) are obviously pathogenic. The previously reported mSNCs p.Arg26Gln, p.Arg40His, p.Glu52Lys, pLys88Asn, p.Arg129His, p.Asn161Ser, p.Thr178Met, p.His202Tyr, p.Ala208Thr and p.His302Arg, found in our cohort, are also discussed.

Human Hepatocyte Isolation for Liver Cell Therapy: Whole Marginal Livers or Healthy Segments from Splitting?

We read with interest the article recently published in Transplantation by Mitry et al. (1). The authors reported their experience with human hepatocytes isolated from segment IV obtained from split-liver procedures and used the isolated liver cells for transplantation in a 1-day-old boy with antenatal diagnosis of ornithine transcarbamylase deficiency. The hepatocyte isolation procedure was carried out in three cases (in two cases the caudate lobe was also used) without affecting the outcome of the split-liver grafts transplanted into six patients. However, the authors do not state whether the right lobes (segment V to VIII) were transplanted into small-sized adult or large-sized pediatric recipients, nor the graft to recipient body weight ratio. The time (3 hr) required for ex-situ removal of segment IV might have jeopardized the quality of the graft, as several authors have reported better results for in situ than ex-situ split liver (2–3). Moreover, retaining segment IV with the right lobe graft could allow a greater hepatic volume for normal-sized adults without any problems related to the relative ischemia of the lateral part of segment IV (4). Regarding the isolation of human hepatocytes, according to our experience of routine use (almost 100 organs up to now) of marginal livers, deemed unusable for transplantation at harvesting (usually whole organs with macrosteatosis greater than 50%–60% but also several nonviral cirrhotic livers), for hepatocytes isolation we reported (5) an average cell yield of more than 7×106 hepatocytes per gram of liver tissue digested with a median viability of 73%±14%. Recently we improved our results in terms of viability achieving an average value of 80%±13% (unpublished data). The data from our experience using marginal livers are not different in terms of cell yield per gram of tissue digested (7×106 vs. 6.68×106) from those reported in the article by Mitry et al. (1), although we obtained a higher total number of hepatocytes (8×109 vs. 5.14×108). Median viability obtained by Mitry and collaborators was slightly higher (89%±8%) presumably due to the better quality of the liver tissue used. Although the use of segment IV, obtained from split-liver, for human hepatocytes isolation might increase the hepatic tissue available for research and for clinical liver cell therapy, the routine use of livers not usable for organ transplantation produced similar results in terms of cell yield and viability. Moreover, it might permit the development of large-scale tissue banking without risk of harming the outcome of recipients of whole organ or split-liver transplants. Umberto Baccarani Mauricio Sainz-Barriga Gian Luigi Adani Andrea Risaliti Fabrizio Bresadola Department of Surgery and Transplantation University Hospital Udine Udine, Italy Annibale Donini Division of Emergency and General Surgery Policlinico Monteluce Perugia Perugia, Italy Umberto Baccarani Andrea Sanna Fabrizio Bresadola Annibale Donini Bank of Human Hepatocytes University of Ferrara and Udine Ferrara and Udine, Italy

Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma

Ornithine transcarbamylase deficiency (OTCD) is an X-linked inherited disease and the most common inborn error in urea synthesis in human patients. In adult heterozygous patients, OTCD can be responsible for life-threatening hyperammonemic coma. We report the case of a 32-year-old woman admitted to our hospital with seizures after a recent high protein load. Her parents related a history of recurrent episodes of vomiting, meat refusal, lethargy, and convulsions since childhood, and measurement of plasma ammonemia levels was the key to early diagnosis of OTCD. We report the pathophysiologic characteristics, clinical features, clinical course, and differential diagnosis of OTCD and discuss the therapeutic options, including continuous venovenous hemodiafiltration and pharmacologic therapy for reduction of plasma ammonemia levels. A diagnosis of OTCD should be considered in adult nonhepatic patients with hyperammonemic coma, particularly if they have a history of protein avoidance and neurologic symptoms. Early recognition and appropriate treatment are critical to avoid severe brain damage and death. [Ann Emerg Med. 2003;41:104-109.]

An autopsy case of ornithine transcarbamylase deficiency

We present an autopsy case of ornithine transcarbamylase (OTC) deficiency with grumose degeneration in the dentate nucleus of the cerebellum. The patient had intractable neonatal convulsions and hyperammonemia from the 3rd day after birth. Diagnosis of OTC deficiency was made based on null activity of the enzyme and four-base deletions in exon 9 of the OTC gene. Death was due to sepsis as well as disseminated intravascular coagulation at 1 year and 2 months of age. Neuropathology showed multiple cystic changes and ulegyria in the bilateral frontal and parietal lobes. Multiple cysts were associated with the region, which was infiltrated with macrophages surrounded by astroglia showing palisading pattern. Ferrugination was marked in the thalamus and severe neuronal loss with astrogliotic change in the CA1-2 area of the hippocampus. Grumose degeneration was noted in the dentate nucleus of the cerebellum. This is the first report of grumose degeneration in OTC deficiency.

Multiorgan donation from a donor with unrecognized ornithine transcarbamylase deficiency

Abstract Ornithine transcarbamylase (OTC) deficiency, the most common inherited urea cycle disorder, shows a spectrum of severity ranging from severe neonatal hyperammonemic coma to no symptoms among adults. We report on the multiorgan procurement from a donor who died of cerebral edema due to unrecognized late-onset OTC deficiency. The donor's OTC deficiency was diagnosed retrospectively since the liver graft recipient developed cerebral edema postoperatively due to hyperammonemia. Plasma ammonia was extremely elevated (3793 umol/1), but was not accompanied by general liver dysfunction. Post mortem, the diagnosis of OTC deficiency was established by enzyme and molecular analysis in a biopsy of the transplanted liver. In contrast to the fatal course of the liver graft recipient, the kidney, lung, and heart transplantations were successful. Ten months after transplantation these recipients were alive and showed good graft function. This case demonstrates the importance of careful donor evaluation, particularly if the donor's cause of death is obscure.

Ornithine transcarbamylase deficiency: neonatal diagnostic

OBJECTIVE: To drive pediatrician's attention to a urea cycle enzyme deficiency. The prognosis is directly related to the early diagnosis and treatment. METHODS: We describe a newborn patient who present lethargy, vomitus and seizures 48 hours afther birth. We investigated this patient and the diagnosis of ornithine transcarbamylase deficiency was made. Treatment was started immediately. RESULTS: We followed the patient until he was 1 year old, when he had liver transplant with a good outcome of the disease. CONCLUSION: The ornithine transcarbamylase deficiency is a rare and very serious disease. Any newborn whose evolution is similar to that of a septic patient without any infection must be investigated for this disease. The prognosis is directly related to the early diagnosis and treatment.