Common Urea Cycle Disorder Research Articles

Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD.We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records.A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6–24) and 66 months (35–156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues.LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

Genetic Therapy Approaches for Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder with high unmet needs, as current dietary and medical treatments may not be sufficient to prevent hyperammonemic episodes, which can cause death or neurological sequelae. To date, liver transplantation is the only curative choice but is not widely available due to donor shortage, the need for life-long immunosuppression and technical challenges. A field of research that has shown a great deal of promise recently is gene therapy, and OTCD has been an essential candidate for different gene therapy modalities, including AAV gene addition, mRNA therapy and genome editing. This review will first summarise the main steps towards clinical translation, highlighting the benefits and challenges of each gene therapy approach, then focus on current clinical trials and finally outline future directions for the development of gene therapy for OTCD.

Anesthesia management protocol for liver transplantation as treatment for ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency is an X-linked genetic disorder that induces accumulation of ammonia in the liver and is the most common urea cycle disorder. The clinical manifestation of ornithine transcarbamylase deficiency is hyperammonemia that causes irreversible neurological damage. Liver transplantation is a curative therapy for ornithine transcarbamylase deficiency. The aim of this study is to suggest, from our previous experience, an anesthesia management protocol of liver transplantation for ornithine transcarbamylase deficiency, particularly focused on liver transplantation for cases with uncontrolled hyperammonemia. We retrospectively reviewed our anesthesia-related experience in all cases of liver transplantation for ornithine transcarbamylase deficiency in our center. Twenty-nine liver transplantation cases for ornithine transcarbamylase deficiency were found between November 2005 and March 2021 in our center. Of these, 25 cases were stable through the perioperative period. However, 2 cases with carrier donor graft had hyperammonemia after liver transplantation. Another two cases had uncontrolled hyperammonemia before liver transplantation, even with continuous hemodialysis. They underwent life-saving liver transplantation. Their metabolic status stabilized after the anhepatic phase. Liver transplantation for cases with uncontrolled hyperammonemia can be performed with proper management. Second, liver transplantation with carrier donors should be avoided because of the risk of postoperative recurrence.

The functional impact of 1,570 individual amino acid substitutions in human OTC

Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death, outcomes ameliorated by rapid diagnosis and treatment. Here, we develop a high-throughput functional assay for human OTC and individually measure the impact of 1,570 variants, 84% of all SNV-accessible missense mutations. Comparison to existing clinical significance calls, demonstrated that our assay distinguishes known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. This functional stratification allowed us to identify score ranges corresponding to clinically relevant levels of impairment of OTC activity. Examining the results of our assay in the context of protein structure further allowed us to identify a 13 amino acid domain, the SMG loop, whose function appears to be required in human cells but not in yeast. Finally, inclusion of our data as PS3 evidence under the current ACMG guidelines, in a pilot reclassification of 34 variants with complete loss of activity, would change the classification of 22 from variants of unknown significance to clinically actionable likely pathogenic variants. These results illustrate how large-scale functional assays are especially powerful when applied to rare genetic diseases.

Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on invitro residual enzymatic OTC activity. Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD registries. Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Residual enzymatic OTC activity reliably predicts the disease severity in mOTC-D and could thus serve as a tool for severity-adjusted evaluation of therapeutic strategies and counselling patients and parents.

S3154 Severe Noncirrhotic Hyperammonemia: What Urea-lly Should Consider

Introduction: Hyperammonemia is often the result of liver pathology. When hyperammonemia is not the result of liver disease, an occult disorder of metabolism must be on the differential for unexplained hyperammonemia, such as a urea cycle disorder (UCD). Case Description/Methods: A 57-year-old man with heart failure with recovered ejection fraction, atrial fibrillation, hypertension, and cervical neck fracture who had undergone a recent cervical spine corpectomy and fusion presented with worsening dysphagia and was found to have a cervical fluid collection for which he received a dexamethasone taper and a lumbar drain. He had no known underlying liver disease and denied significant alcohol history. He was later admitted to the intensive care unit (ICU) for unstable atrial fibrillation with rapid ventricular response (RVR). In the ICU, he became more somnolent and was unable to follow commands. Encephalopathy workup was significant for elevated BUN with normal creatinine, ammonia 772, and mildly elevated transaminases. His labs and imaging did not demonstrate cirrhosis or acute liver failure. Workup for inborn errors of metabolism showed mildly decreased citrulline. Urine and plasma amino acids were otherwise normal. His hyperammonemia resolved and his mentation improved with lactulose and rifaximin. UCD gene panel and further genetic workup is ongoing and to be continued outpatient. Discussion: Patients with elevations of ammonia present with encephalopathy, which may progress quickly to cerebral herniation. Survival requires immediate reduction of ammonia levels. Although the differential for hyperammonemia is broad, inborn errors of metabolism (IEM), like a UCD, should be considered when hyperammonemia is of unclear etiology. This patient’s liver workup revealed no findings consistent with cirrhosis or liver failure. Potential causes for his hyperammonemia include ischemic liver disease secondary to atrial fibrillation with RVR or degradation of blood products. IEMs may also be unmasked by steroid therapy, which is plausible in this patient who was on a steroid taper prior to his hyperammonemic state. Although IEMs often have early age of onset, UCDs have multiple modes of inheritance and can present at later stage. Ornithine transcarbamylase deficiency is the most common UCD and can present with reduced plasma citrulline in both kids and adults. Treatment for a potential IEM begins prior to confirmation of an etiology. Geneticists should be consulted early on for evaluation and management.

Severe Hyperammonaemia with Metabolic Acidosis in a Neonate: a Case Report of Ornithine Transcarbamylase Deficiency (OTCD)

Ornithine transcarbamylase (OTC) deficiency (OTCD), the most common urea cycle disorder, is an X-linked genetic disorder due to complete or partial lack of the OTC enzyme. Its clinical presentation depends on the degree of enzyme deficiency and ranges from an acute neonatal metabolic crisis with a high mortality rate through to an asymptomatic adult. We present a case of a newborn baby boy who presented with poor feeding, vomiting, lethargy, and respiratory distress. Laboratory investigations revealed severe hyperammonaemia, hyperglutaminaemia, hyperalaninaemia, absence of citrulline, and marked orotic aciduria. Family screening confirmed the presence of an OTC disease-causing mutation in his mother. It was a heterozygous mutation, c.316G>A. p. Gly106Arg in exon 4.

Severe Hyperammonaemia with Metabolic Acidosis in a Neonate: a Case Report of Ornithine Transcarbamylase Deficiency (OTCD)

Ornithine transcarbamylase (OTC) deficiency (OTCD), the most common urea cycle disorder, is an X-linked genetic disorder due to complete or partial lack of the OTC enzyme. Its clinical presentation depends on the degree of enzyme deficiency and ranges from an acute neonatal metabolic crisis with a high mortality rate through to an asymptomatic adult. We present a case of a newborn baby boy who presented with poor feeding, vomiting, lethargy, and respiratory distress. Laboratory investigations revealed severe hyperammonaemia, hyperglutaminaemia, hyperalaninaemia, absence of citrulline, and marked orotic aciduria. Family screening confirmed the presence of an OTC disease-causing mutation in his mother. It was a heterozygous mutation, c.316G>A. p. Gly106Arg in exon 4.

Unfavorable clinical outcomes in patients with carbamoyl phosphate synthetase 1 deficiency

PurposeCarbamoyl phosphate synthetase 1 (CPS1) deficiency affects the first step of urea cycle and is a severe form of urea cycle disorder (UCD). The severity of hyperammonemic encephalopathy determines the clinical course of UCDs. Here, we describe the genetic and clinical characteristics of CPS1 deficiency in Korea. Patient and methodsThis study included seven patients with CPS1 deficiency genetically confirmed from January 1992 to September 2020. The peak ammonia level during the first crisis, the half time of peak ammonia level, the initial plasma amino acid levels, and neurological outcomes were compared between CPS1 deficiency and two common UCDs (i.e., 17 patients with argininosuccinate synthetase 1 deficiency and 24 patients with ornithine transcarbamylase deficiency). ResultEleven CPS1 mutations were identified, including 10 novel mutations. Eight mutations were missense. Six patients with CPS1 deficiency had neonatal type. The peak ammonia level, initial glutamate level, and accompanying rate of irreversible neurological damages were highest in patients with CPS1 deficiency. The patient with late-onset CPS1 deficiency responded dramatically to N-carbamylglutamate treatment. ConclusionThe clinical manifestations of CPS1 deficiency were the most severe among UCDs. Considering the high proportion of missense mutations, responsiveness to N-carbamylglutamate would be evaluated in a future study.

Placental Pathology in Maternal Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, inherited in an X-linked manner. Males are severely affected. Female phenotypes vary from asymptomatic to severe, and symptoms may be triggered by high metabolic states like childbirth. Literature on OTC deficiency in pregnancy and placental pathology is limited. Pathology records were searched at a single referral center from 2000-2020 and identified three placental cases from two mothers heterozygous for OTC deficiency. Placental pathology and maternal and neonatal history were reviewed in detail. The placenta from one symptomatic mother carrying an affected male fetus showed widespread high-grade fetal vascular malperfusion (FVM) lesions of varying age. These lesions were not seen in the two placentas from the asymptomatic mother. In cases of symptomatic maternal OTC deficiency, our findings highlight the need for placental examination. Since thrombotic events in the placenta have the potential to associate with fetal and neonatal endothelial damage, a high index of suspicion for neonatal thrombosis may be warranted.

Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders

Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unravelled Beclin‐1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell‐penetrating autophagy‐inducing Tat‐Beclin‐1 (TB‐1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB‐1 reduced urinary orotic acid and improved survival under protein‐rich diet in spf‐ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB‐1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin‐1‐dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.

An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency.

OTC splicing mutations are generally associated with the severest and early disease onset of ornithine transcarbamylase deficiency (OTCD), the most common urea cycle disorder. Noticeably, splicing defects can be rescued by spliceosomal U1snRNA variants, which showed their efficacy in cellular and animal models. Here, we challenged an U1snRNA variant in the OTCD mouse model (spf/ash) carrying the mutation c.386G > A (p.R129H), also reported in OTCD patients. It is known that the R129H change does not impair protein function but affects pre-mRNA splicing since it is located within the 5′ splice site. Through in vitro studies, we identified an Exon Specific U1snRNA (ExSpeU1O3) that targets an intronic region downstream of the defective exon 4 and rescues exon inclusion. The adeno-associated virus (AAV8)-mediated delivery of the ExSpeU1O3 to mouse hepatocytes, although in the presence of a modest transduction efficiency, led to increased levels of correct OTC transcripts (from 6.1 ± 1.4% to 17.2 ± 4.5%, p = 0.0033). Consistently, this resulted in increased liver expression of OTC protein, as demonstrated by Western blotting (~3 fold increase) and immunostaining. Altogether data provide the early proof-of-principle of the efficacy of ExSpeU1 in the spf/ash mouse model and encourage further studies to assess the potential of RNA therapeutics for OTCD caused by aberrant splicing.

Retrospective evaluations revealed pre-symptomatic citrulline concentrations measured by newborn screening were significantly low in late-onset ornithine transcarbamylase deficiency patients

IntroductionOrnithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Late-onset OTCD manifests after the neonatal period; therefore, if pre-symptomatic diagnosis and treatment are performed, it can improve the prognosis by preventing hyperammonemia. However, pre-symptomatic diagnosis is unreliable as the specific screening marker of OTCD has not been established yet. This retrospective study aimed to evaluate the pre-symptomatic blood citrulline levels in patients with late-onset OTCD. MethodsPatients with late-onset OTCD who were born after the newborn screening based on tandem mass spectrometry (MS/MS-NBS) was started and were referred to Hyogo College of Medicine Hospital between 2014 and 2018 were included. Pre-symptomatic blood citrulline levels measured by MS/MS-NBS were retrospectively evaluated. ResultsFour patients were included in this study. The pre-symptomatic blood citrulline levels were 2.02, 4.50, 4.97, and 3.75 µmol/l, respectively. Compared with the citrulline levels in all newborns in Hyogo prefecture, these values were significantly low. ConclusionsThese results suggest the possibility that hypocitrullinemia detected by the MS/MS-NBS can be used as a screening marker for some patients with late-onset OTCD. Further retrospective evaluation of pre-symptomatic citrulline levels in patients with late-onset OTCD, as well as prospective monitoring of hypocitrullinemia on the MS/MS-NBS should be conducted.

Urea cycle disorders in Argentine patients: clinical presentation, biochemical and genetic findings

BackgroundThe incidence, prevalence, and molecular epidemiology of urea cycle disorders (UCDs) in Argentina remain underexplored. The present study is the first to thoroughly assess the clinical and molecular profiles of UCD patients examined at a single reference center in Argentina.ResultsForty-nine UCD cases were collected. About half (26/49, 53%) manifested neonatally with classical presentation and had a high mortality (25/26, 96%). Ornithine transcarbamylase deficiency (OTCD) was the most common UCD (26 patients). Argininosuccinate synthetase deficiency (ASSD) was detected in 19 cases, while argininosuccinate lyase deficiency (ASLD) was diagnosed in 4 cases. Molecular genetic analysis revealed 8 private OTC mutations and two large deletion/duplication events in the OTC gene. Most mutations in the ASS1 and ASL genes were recurrent missense changes, and four alterations were novel. The clinical outcome of our UCD cohort was poor, with an overall mortality of 57% (28/49 cases), and a 28% (6/21) disability rate among the survivors.ConclusionsMost patients in our case series showed severe neonatal onset, with high morbidity/mortality. We detected in total 19 mutations, most of them recurrent and of high frequency worldwide. Noteworthy, we highlight the presence of a geographic cluster with high prevalence of a point mutation in the ASS1 gene. This study suggests that these disorders may be more frequent than commonly assumed, and stresses the need for increased awareness amongst health professionals and greater availability of diagnostic tools for accurate identification, early diagnosis, and timely treatment.

Low prevalence of argininosuccinate lyase deficiency among inherited urea cycle disorders in Korea.

Argininosuccinic aciduria (ASA), which is considered to be the second most common urea cycle disorder (UCD), is caused by an argininosuccinate lyase deficiency and is biochemically characterized by elevation of argininosuccinic acid and arginine deficiency. In addition to hyperammonemia, other characteristic features of ASA include hepatic fibrosis, hypertension, neurocognitive deficiencies, and trichorrhexis nodosa. Herein, we retrospectively reviewed the clinical findings, biochemical profiles, and genotypic characteristics of five Korean patients with ASA, who showed typical phenotypes and biochemical findings of the disease. Molecular analysis of these patients revealed six novel ASL mutations. Next, we investigated the prevalence of all types of UCDs in Korea. Of note, over a two decade periods, ASA was only detected in 6.3% of patients with a UCD, which made it the fourth most common UCD in Korea. In comparison with Caucasians, in whom ASA is the second most common UCD, ASA is comparatively rare in East Asian populations, including Japanese and Koreans. These findings suggest the possibility of geographic variation in UCDs among ethnic groups.

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

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 part...

Variability of OTC deficiency in heterozygous carriers: Case report of a family

We present three case reports of a family affected by ornithine transcarbamylase deficiency (OTC-D), the most common urea cycle disorder. The case reports demonstrate the variable clinical phenotype of OTC-D in heterozygous carriers, even in one family. Based on these reports, OTC-D and its biochemical hallmarks are discussed.

Posterior fossa syndrome in a patient with an ornithine transcarbamylase deficiency

The posterior fossa syndrome (PFS) is a well-known clinical entity and mainly occurs in children. Ornithine transcarbamylase deficiency (OTC) is the most common urea cycle disorder, which occurs in an estimated 1 per 50.000 live births in Japan. Symptoms are mostly due to hyperammonemia and include nausea, vomiting, lethargia and even convulsions and coma. Common neurological symptoms at presentation of a hyperammonemia are a decreased level of consciousness, abnormal motor function or seizures. In this case we describe a girl with late onset OCT deficiency presenting with transient mutism and subsequent dysarthria, ataxia and behavioural changes. This is an exceptional report of a not yet described neurologic syndrome in OTC.Synopsis: Neurologic symptoms in ornithine transcarbamylase deficiency do not only occur during an episode of hyperammonemia and may present as a transient neurologic symptoms compatible with the posterior fossa syndrome.

Novel liver findings in Ornithine Transcarbamylase Deficiency due to Xp11.4-p21.1 microdeletion

Ornithine transcarbamylase deficiency (OTCD, OMIM 311250), the most common urea cycle disorder, results in impaired synthesis of citrulline from carbamoyl phosphate and ornithine. Individuals have been identified with OTCD due to a contiguous gene deletion at Xp11.4-p21.1 and unique clinical features, described as the “extended OTCD phenotype”. We present a male with neonatal-lethal OTCD due to a 1.87Mb microdeletion at Xp11.4-p21.1 (37126841-38998991 hg18). Autopsy revealed a novel histological finding of hepatocyte globular and granular inclusions. Such inclusions have not been described in OTCD or other metabolic disorders and are not an associated finding in neonatal liver failure due to other causes. The deleted region includes the gene SYTL5, potentially involved in RAB27A-dependent membrane trafficking in the liver and placenta. We propose that the contiguous gene deletion could contribute to the severity of the clinical presentation here and hypothesize that deletion of SYTL5 could contribute to the liver findings.

Late‐Onset Ornithine Transcarbamylase Deficiency Presenting With Asymptomatic Liver Dysfunction

Late‐Onset Ornithine Transcarbamylase Deficiency Presenting With Asymptomatic Liver Dysfunction