Ornithine Transcarbamylase Deficiency Research Articles

Adeno-associated virus vector-based gene therapies for pediatric diseases.

Gene therapy using adeno-associated virus (AAV) is a rapidly developing technology with widespread treatment potential. AAV2 vectors injected directly into the brain by stereotaxic brain surgery have shown good results in treating aromatic l-amino acid decarboxylase deficiency. Moreover, gene therapy using the AAV9 vector, which crosses the blood-brain barrier, has been performed in more than 2000 patients worldwide as a disease-modifying therapy for spinal muscular atrophy. AAV vectors have been applied to the development of gene therapies for various pediatric diseases. Gene therapy trials for hemophilia and ornithine transcarbamylase deficiency are underway. Clinical trials are planned for glucose transporter I deficiency, Niemann-Pick disease type C, and spinocerebellar ataxia type 1. The genome of AAV vectors is located in the episome and is rarely integrated into chromosomes, making the vectors safe. However, serious adverse events such as hepatic failure and thrombotic microangiopathy have been reported, and ongoing studies are focusing on developing more efficient vectors to reduce required dosages.

Evaluation of oxidative damage to biomolecules and inflammation in patients with urea cycle disorders

Urea cycle disorders (UCD) are inborn errors of metabolism that occur due to a loss of function in enzymes and transporters involved in the urea cycle, causing an intoxication by hyperammonemia and accumulation of metabolites. Patients can develop hepatic encephalopathy (HE), severe neurological and motor disabilities, and often death. The mechanisms involved in the pathophysiology of UCD are many and complex, but there are strong indications that oxidative stress and inflammation are present, being responsible for at least part of the cellular damage that occurs in these diseases. The aim of this study was to evaluate oxidative and nitrosative damage and inflammation in UCD, to better understand the pathophysiology mechanisms of these diseases. We evaluated the nitrite and nitrate content, thiobarbituric acid-reactive substances (TBARS), carbonyl protein content and a panel of cytokines in plasma sample of 14 patients. The UCD patients group consisted of individuals affected with ornithine transcarbamylase deficiency (n = 8), carbamoyl phosphate synthetase deficiency (n = 2), argininosuccinate synthetase deficiency (n = 2); arginase 1 deficiency (n = 1) and argininosuccinate lyase deficiency (n = 1). Patients mean age at diagnosis was 5.25 ± 9.86 years-old and mean concentrations were compared with healthy individuals of matched age and gender. We found a significant reduction in nitrogen reactive species in patients when compared to controls. TBARS was increased in patients, indicating lipid peroxidation. To evaluate protein oxidative damage in UCD, the carbonyl content was measured, and the results also demonstrated an increase in this biomarker. Finally, we found that UCD patients have enhanced concentrations of cytokines, with pro-inflammatory interleukins IL-6, IL-8, interferon-γ and TNF-α, and anti-inflammatory IL-10 being increased when compared to the control group. In conclusion, our results demonstrate that oxidative stress and inflammation occurs in UCD and probably contribute to the severe brain damage present in patients.

A curious case of confusion

A curious case of confusion

PCR102 Development of Conceptual Frameworks and PRO Measures in Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase deficiency (OTC) is a rare inborn error of metabolism that directly results in high ammonia blood levels, leading to symptoms of confusion, vomiting, coma, and cognitive functioning impairments. The objective of this research was to develop disease-specific, content-valid patient-reported outcome measures (PROs) for use in OTC deficiency using a patient-centric outcomes assessment approach.

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.

Resultados materno-fetales de las gestaciones de mujeres atendidas en una unidad de errores innatos del metabolismo

IntroductionIntermediate Inborn Errors of Metabolism (IEM) are a group of inherited diseases that include phenylketonuria (PKU), tyrosinemia II (TSII), organic acidaemias and ornithine transcarbamylase deficiency (OTCD), among others. They are increasingly more common in adults due to improved management. This has allowed more affected women to consider having children with good prospects. However, pregnancy may worsen metabolic control and/or increase maternal-foetal complications. The objective is to analyse the characteristics and outcomes of pregnancies of our patients with IEM. MethodsRetrospective descriptive study. Pregnancies of women with IEM attended to at the adult IEM referral unit of the Hospital Universitario Virgen del Rocío were included. The qualitative variables were described as n(%) and the quantitative as P50(P25-P75). Results24 pregnancies were recorded: 12 newborns were healthy, 1 inherited their mother's disease, 2 had maternal phenylketonuria syndrome, 1 was stillborn (gestational week 31 + 5), 5 were spontaneous abortions and 3 were voluntarily terminated. The gestations were divided into metabolically controlled and uncontrolled. ConclusionsPregnancy planning and multidisciplinary management through to postpartum is essential to ensure maternal and foetal health. The basis of treatment in PKU and TSII is a strict protein-limited diet. Events that increase protein catabolism in organic acidaemias and DOTC should be avoided. Further investigation of pregnancy outcomes in women with IEM is needed.

A simple screening method for heterozygous female patients with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD), caused by X-linked OTC mutations, is characterized by life-threatening hyperammonemia. Heterozygous female patients are often asymptomatic and usually have milder disease than affected male patients, but can have higher morbidity and mortality rates if the disease progresses prior to diagnosis. Our purpose was to establish a screening method for female heterozygotes with OTCD. We retrospectively identified female patients who underwent plasma amino acid analysis at the National Center for Child Health and Development, using data from electronic medical records from March 2002 to September 2021. We extracted patient age, medical history, and biochemical data, including plasma amino acid levels. Patients were categorized into several groups according to their underlying diseases; those with underlying diseases that could potentially affect plasma amino acid levels, such as mitochondrial disease or short bowel syndrome, were excluded, except for untreated OTCD. Biochemical values were compared between OTCD patients and others using the Mann-Whitney U test. The receiver operator characteristic analysis was performed to assess the diagnostic capability for detecting OTCD in each subject. For patients with multiple test data, the most recent of the measurement dates was used in the analysis. The data sets of 976 patients were included. There were significant differences in values of glutamine, citrulline, arginine, and ammonia, but the diagnostic capacity of each alone was inadequate. By contrast, the (glutamine + glycine)/(citrulline + arginine) ratio was appropriate for discriminating heterozygous female patients with OTCD, with a sensitivity of 100% and specificity of 98.6% when the cutoff level was 15.8; the AUC for this discrimination was 0.996 (95% confidence interval, 0.992 to 1.000). These findings could help identify heterozygous female patients with OTCD before the onset of clinical disease.

ODP284 Hyperinsulinism-Hyperammonaemia syndrome: a dive into the rare presentation and diagnostic challenges encountered in adults

Abstract Background Hyperinsulinemic-hyperammonemia, a rare form of congenital hyperinsulinemia, can seldom present in adulthood if failed to be diagnosed during infancy, enabling it to be difficult to identify, and predisposing affected individuals to neurological complications. Case A 20-year-old female with intellectual disability, seizure disorder and ornithine transcarbamylase deficiency was admitted for recurrent episodes of asymptomatic hypoglycemia. Her medications included risperidone, fluoxetine, levetiracetam, lacosamide, ferrous sulphate and acetaminophen. Physical examination including vital signs was unremarkable. Relevant labs included a fasting glucose of 46mg/dl [70-99]. Further work up of hypoglycemia revealed an IGF-1 of 215ng/dl [85-350] and AM Cortisol of 6.5mcg/dl [5-25]. Given a low AM cortisol level under stress, an ACTH stimulation test was done with appropriate response of cortisol of 24 following cosyntropin administration, ruling out adrenal insufficiency. The patient continued to have h ypoglycemia noted on several glucometer checks every 4 hours where she remained asymptomatic. She was further evaluated with a mixed meal study where no hypoglycemia was noted. A 72 -hour fast was performed which was terminated based on a venous blood sample glucose reading of 50 mg/dl confirmed after hypoglycemia was noted on a glucometer check. The labs showed elevated C-peptide levels of 4ng/ml [0.4-2], insulin of 4mIU/L [<25] and proinsulin level of 2.3pmol/l [3-20]. Levels of insulin and proinsulin were noted to be inappropriately normal in the setting of hypoglycemia. Beta hydroxybutyrate was low at 0.1mmol/L [<0.5] and glucagon inappropriately normal at 36pg/ml [50-100]. Sulfonylurea, meglitinide and autoimmune antibody screen were negative. CT abdomen and pelvis was negative for pancreatic abnormality. In the absence of evidence for acquired causes of hyperinsulinemic hypoglycemia, congenital cases were investigated. Based on that, further labs were obtained including ammonia levels which was elevated at 177.2 u/dl [15-45]. Accordingly, GLUD-1 gene mutation was sent, given high suspicion for hyperinsulinemic hyperammonemia syndrome, which resulted positive and confirmed the diagnosis. She was started on a protein restricted diet and diazoxide which regulated her blood glucose levels effectively. Discussion Hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism caused by activating mutations of the GLUD 1 gene which encodes Glutamate Dehydrogenase, a key enzyme in the beta cell pathway of amino acid-stimulated insulin secretion. The resultant syndrome is characterized by fasting and protein induced hypoglycemia, elevated serum ammonia levels without typical hyperammonemic symptoms. Management includes effective blood glucose control with an insulin inhibitor such as diazoxide and a protein restricted diet with consideration to predominantly include carbohydrates and fat. Conclusion Hyperinsulinemia hyperammonemia is a rare form of congenital hyperinsulinemia typically diagnosed during infancy and should be considered as a possible differential diagnosis in patients presenting with new onset hypoglycemia, as timely diagnosis and intervention can prevent forthcoming neurological complications. Presentation: No date and time listed

Excretion of excess nitrogen and increased survival by loss of SLC6A19 in a mouse model of ornithine transcarbamylase deficiency.

Protein catabolism ultimately yields toxic ammonia, which must be converted to urea by the liver for renal excretion. In extrahepatic tissues, ammonia is temporarily converted primarily to glutamine for subsequent hepatic extraction. Urea cycle disorders (UCDs) are inborn errors of metabolism causing impaired ureagenesis, leading to neurotoxic accumulation of ammonia and brain glutamine. Treatment includes dietary protein restriction and oral "ammonia scavengers." These scavengers chemically combine with glutamine and glycine to yield excretable products, creating an alternate pathway of waste nitrogen disposal. The amino acid transporter SLC6A19 is responsible for >95% of absorption and reabsorption of free neutral amino acids in the small intestine and kidney, respectively. Genetic SLC6A19 deficiency causes massive neutral aminoaciduria but is typically benign. We hypothesized that inhibiting SLC6A19 would open a novel and effective alternate pathway of waste nitrogen disposal. To test this, we crossed SLC6A19 knockout (KO) mice with spfash mice, a model of ornithine transcarbamylase (OTC) deficiency. Loss of SLC6A19 in spfash mice normalized plasma ammonia and brain glutamine and increased median survival in response to a high protein diet from 7 to 97 days. While induced excretion of amino acid nitrogen is likely the primary therapeutic mechanism, reduced intestinal absorption of dietary free amino acids, and decreased muscle protein turnover due to loss of SLC6A19 may also play a role. In summary, the results suggest that SLC6A19 inhibition represents a promising approach to treating UCDs and related aminoacidopathies.

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Pathogenic variants of ornithine transcarbamylase deficiency: Nation-wide study in Japan and literature review.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked disorder. Several male patients with OTCD suffer from severe hyperammonemic crisis in the neonatal period, whereas others develop late-onset manifestations, including hyperammonemic coma. Females with heterozygous pathogenic variants in the OTC gene may develop a variety of clinical manifestations, ranging from asymptomatic conditions to severe hyperammonemic attacks, owing to skewed lyonization. We reported the variants of CPS1, ASS, ASL and OTC detected in the patients with urea cycle disorders through a nation-wide survey in Japan. In this study, we updated the variant data of OTC in Japanese patients and acquired information regarding genetic variants of OTC from patients with OTCD through an extensive literature review. The 523 variants included 386 substitution (330 missense, 53 nonsense, and 3 silent), eight deletion, two duplication, one deletion-insertion, 55 frame shift, two extension, and 69 no category (1 regulatory and 68 splice site error) mutations. We observed a genotype–phenotype relation between the onset time (neonatal onset or late onset), the severity, and genetic mutation in male OTCD patients because the level of deactivation of OTC significantly depends on the pathogenic OTC variants. In conclusion, genetic information about OTC may help to predict long-term outcomes and determine specific treatment strategies, such as liver transplantation, in patients with OTCD.

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.

Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice

Hydrodynamic tail vein injection (HTV) is the "gold standard" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of spf ash mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene. HRII resulted in a transfection efficiency below 1%, 100-fold lower than HTV. While HRII induced minimal liver toxicity compared with HTV, overexpression of luciferase by both methods, but not of a natural liver-specific enzyme, elicited an immune response that led to the elimination of luciferase expression. Further testing of MC vectors delivered via HRII in spf ash mice did not result in sufficient therapeutic efficacy and needs further optimization and/or selection of the corrected cells. This study reveals that luciferase expression is toxic for the liver. Furthermore, physical delivery of MC vectors via the bile duct has thepotential to treat defects restricted to periportal hepatocytes, which opens new doors for non-viral liver-directed gene therapy.

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.

Clinical findings of patients with hyperammonemia affected by urea cycle disorders with hepatic encephalopathy.

Urea cycle disorders (UCD) are a group of genetic diseases caused by deficiencies in the enzymes and transporters involved in the urea cycle. The impairment of the cycle results in ammonia accumulation, leading to neurological dysfunctions and poor outcomes to affected patients. The aim of this study is to investigate and describe UCD patients' principal clinical and biochemical presentations to support professionals on urgent diagnosis and quick management, aiming better outcomes for patients. We explored medical records of 30 patients diagnosed in a referral center from Brazil to delineate UCD clinical and biochemical profile. Patients demonstrated a range of signs and symptoms, such as altered levels of consciousness, acute encephalopathy, seizures, progressive loss of appetite, vomiting, coma, and respiratory distress, in most cases combined with high levels of ammonia, which is an immediate biomarker, leading to a UCD suspicion. The most prevalent UCD detected were ornithine transcarbamylase deficiency, followed by citrullinemia type 1, hyperargininemia, carbamoyl phosphate synthase 1 deficiency, and argininosuccinic aciduria. Clinical symptoms were highly severe, being the majority developmental and neurological disabilities, with 20% of death rate. Laboratory analysis revealed high levels of ammonia (mean ± SD: 860 ± 470 μmol/L; reference value: ≤80 μmol/L), hypoglycemia, metabolic acidosis, and high excretion of orotic acid in the urine (except in carbamoyl phosphate synthetase 1 [CPS1] deficiency). We emphasize the need of urgent identification of UCD clinical and biochemical conditions, and immediate measurement of ammonia, to enable the correct diagnosis and increase the chances of patients' survival, minimizing neurological and psychomotor damage caused by hepatic encephalopathy.

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.

Clinical Characteristics of Pediatric Patients with Urea Cycle Disorders

Objective: Urea cycle disorders (UCDs) are inherited deficiencies of the enzymes or transport molecules involved in the cellular excretion of excess ammonia produced during protein metabolism. The aim of this study was to evaluate the clinical characteristics and long-term outcome of pediatric patients with UCDs. Material and Methods: Our research was conducted between September 2020-March 2021 in Dr. Sami Ulus Maternity and Child Health Training and Research Hospital. Clinical characteristics in 16 patients with UCDs [carbamoyl phosphate synthetase I deficiency (n=1), N-acetylglutamate synthase deficiency(n=1), argininosuccinate lyase deficiency (n=4), argininosuccinate synthetase deficiency (n=4), arginase deficiency (n=2), ornithine transcarbamylase deficiency (n=2), hyperammonemia hyperornithinemia homocitrullinuria syndrome (n=2)] were defined. The term “neonatal-onset” UCD was used if symptoms occurred within 28 days of life, and “late-onset” if symptoms started after the neonatal period. Results: Eight patients presented with acute metabolic crisis during newborn period. Core clinical phenotype in neonatal-onset UCDs included sepsis-like findings, whereas epilepsy and mental retardation was predominant in lateonset UCDs. For patients with neonatal-onset UCDs, hyperammonemia was more severe at the initial period. Conclusion: Despite evolving treatment opportunities, still high mortality rates were found in neonatal-onset UCD. UCDs should be suspected in pediatric patients with hyperammonemia and metabolic investigations should be performed immediately to enlighten diagnosis. Neonatal-onset UCD usually present with symptoms of acute hyperammonemia, while moresubtle neurological manifestations are frequent initial findings in the late onset UCD.

Moving towards a novel therapeutic strategy for hyperammonemia that targets glutamine metabolism.

Patients with urea cycle disorders intermittently develop episodes of decompensation with hyperammonemia. Although such an episode is often associated with starvation and catabolism, its molecular basis is not fully understood. First, we attempted to elucidate the mechanism of such starvation-associated hyperammonemia. Using a mouse embryonic fibroblast (MEF) culture system, we found that glucose starvation increases ammonia production, and that this increase is associated with enhanced glutaminolysis. These results led us to focus on α-ketoglutarate (AKG), a glutamate dehydrogenase inhibitor, and a major anaplerotic metabolite. Hence, we sought to determine the effect of dimethyl α-ketoglutarate (DKG), a cell-permeable AKG analog, on MEFs and found that DKG mitigates ammonia production primarily by reducing flux through glutamate dehydrogenase. We also verified that DKG reduces ammonia in an NH4 Cl-challenged hyperammonemia mouse model and observed that DKG administration reduces plasma ammonia concentration to 22.8% of the mean value for control mice that received only NH4 Cl. In addition, we detected increases in ornithine concentration and in the ratio of ornithine to arginine following DKG treatment. We subsequently administered DKG intravenously to a newborn pig with hyperammonemia due to ornithine transcarbamylase deficiency and found that blood ammonia concentration declined significantly over time. We determined that this effect is associated with facilitated reductive amination and glutamine synthesis. Our present data indicate that energy starvation triggers hyperammonemia through enhanced glutaminolysis and that DKG reduces ammonia accumulation via pleiotropic mechanisms both in vitro and in vivo. Thus, cell-permeable forms of AKG are feasible candidates for a novel hyperammonemia treatment.

Variable disease manifestations and metabolic management within a single family affected by ornithine transcarbamylase deficiency

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency.

Considerations for prenatal and postpartum management of a female patient with ornithine transcarbamylase deficiency

We report on pregnancy management and outcomes in a 27-year-old female patient with ornithine transcarbamylase (OTC) deficiency, the most common inherited enzyme deficiency in the urea cycle. Our patient was diagnosed during childhood after hyperammonemia associated with surgery and steroid treatment and was well-controlled with nitrogen scavenger treatment, low-protein diet, and L-citrulline supplementation. OTC gene sequencing identified a variant of unknown significance that has more recently been classified as likely pathogenic. Women with OTC deficiency are at increased risk of hyperammonemia during pregnancy and the postpartum period, therefore monthly follow up and laboratory assessments are critical in management decision making. Our patient was maintained on glycerol phenylbutyrate, L-citrulline and essential amino acid supplements, along with restricted protein intake during pregnancy. A multidisciplinary approach with the obstetrics, prenatal genetics, high risk obstetric, and anesthesia teams was also necessary for optimal management during pregnancy, throughout labor and delivery, and during the postpartum period. After successful childbirth and discharge, our patient experienced a hyperammonemic crisis related to poor enteral nutrition, and acute management protocols were implemented to stabilize her. For her newborn son, acute hyperammonemia protocols were on standby, and newborn screening and laboratory testing were expedited to assess his risk. He was healthy and did not experience symptoms of concern. In this case report, we emphasize the importance of close collaboration with maternal-fetal medicine team members during and immediately after pregnancy to ensure successful management of a female patient with OTC deficiency and her newborn.