Corticosteroid-induced hyperammonaemic encephalopathy in a woman with late-onset ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is a rare, X linked disorder that can manifest in late adulthood in heterozygous females as severe hyperammonaemia following environmental stressors. We present a case of hyperammonaemic encephalopathy that was triggered by glucocorticoid administration in an adult woman with heterozygous OTCD with clinical response to haemodialysis, ammonia scavengers and a high-calorie, low-protein diet.

Sensory ataxic polyneuropathy unmasking late-onset urea cycle defect.

A 63-year-old man with type 2 diabetes mellitus, alcohol consumption in moderation, and three episodes of hepatic encephalopathy presented with symmetrical lower limb distal weakness, sensory ataxia, thickened palpable nerves, mood disturbances for seven years, and a family history of schizophreniform disorders. Nerve conduction studies showed demyelinating sensorimotor polyradiculoneuropathy. CSF analysis showed mild albumino-cytological dissociation. MRI brain and lumbosacral plexus showed thickened fifth cranial nerves and lumbosacral roots. He was treated with steroids for a provisional diagnosis of chronic inflammatory polyneuropathy and became encephalopathic. EEG showed triphasic waves. Serum ammonia was 201 micrograms/dL. Further evaluation suggested ornithine transcarbamylase (OTC) deficiency. The patient underwent hemodialysis with a low protein diet, rifaximin, and sodium benzoate, with subsequent recovery.

Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation.

Hyperammonemia is a rare and often fatal complication following the conditioning therapy in autologous and allogeneic stem cell transplant recipients. It is characterized by anorexia, vomiting, lethargy and coma without any other apparent cause. The diagnosis is often delayed because symptoms can be subtle and ammonia is usually not included among the routine analyzes. Previous reports have not identified the molecular mechanisms behind hyperammonemia in stem cell transplant recipients. Urea cycle disorders (UCDs) are inborn errors of metabolism leading to hyperammonemia that usually presents in early childhood, whereas first presentation in adults is less common. Here we describe an adult woman with hyperammonemia following autologous stem cell transplantation for multiple myeloma. No apparent cause of hyperammonemia was identified, including portosystemic shunting, liver dysfunction or recent hyperammonemia-inducing chemotherapy. Hyperammonemia, normal blood glucose as well as anion gap and a previous history of two male newborns that died early after birth, prompted biochemical and genetic investigations for a UCD. A heterozygous variant in the X-linked gene encoding ornithine transcarbamylase (OTC) was identified and was regarded as a cause of UCD. The patient improved after treatment with nitrogen scavengers and high caloric intake according to a UCD protocol. This case report suggests that UCD should be considered as a possible cause of hyperammonemia following stem cell transplantation.

Acute onset of ornithine transcarbamylase deficiency after total anomalous pulmonary venous connection repair to a 2-day-old neonate.

Ornithine transcarbamylase deficiency is an X-linked disorder which results in the accumulation of ammonia causing irritability and vomiting. Acute hyperammonemia requires rapid and intensive intervention. However, as those clinical features are non-specific and commonly seen in peri-operative situation, ornithine transcarbamylase deficiency could be difficult to diagnose prior to and post-emergency cardiac surgery. We report a 2-day-old male neonate who was diagnosed with ornithine transcarbamylase deficiency presenting hyperammonemia and severe heart failure after total anomalous pulmonary venous connection repair.

Late-Onset Ornithine Transcarbamylase Deficiency Complicated with Extremely High Serum Ammonia Level: Prompt Induction of Hemodialysis as the Key to Successful Treatment.

BACKGROUND Ornithine transcarbamylase deficiency (OTCD) is an X-linked semi-dominant disorder, causing possible fatal hyperammonemia. Late-onset OTCD can develop at any time from 2 months after birth to adulthood, accounting for 70% of all OTCDs. CASE REPORT A 35-year-old man with chronic headaches stated that since childhood he felt sick after eating meat. Fourteen days before hospital admission, he began receiving 60 mg/day of intravenous prednisolone for sudden deafness. The prednisolone was stopped 5 days before hospital admission. Four days later, he was transferred to our hospital because of confusion. On admission, he had hyperammonemia of 393 µmol/L. Because he became comatose 7 hours after admission, and his serum ammonia increased to 1071 µmol/L, we promptly started hemodialysis. Because his family history included 2 deceased infant boys, we suspected late-onset OTCD. On day 2 of hospitalization, we began administering ammonia-scavenging medications. Because he gradually regained consciousness, we stopped his hemodialysis on day 6. After his general condition improved, he was transferred to the previous hospital for rehabilitation on day 32. We definitively diagnosed him with late-onset OTCD due to the low plasma citrulline and high urinary orotic acid levels found during his hospitalization. CONCLUSIONS Clinicians should suspect urea cycle disorders, such as OTCD, when adult patients present with marked hyperammonemia without liver cirrhosis. Adult patients with marked hyperammonemia should immediately undergo hemodialysis to remove ammonia, regardless of causative diseases.

Psychological Stress Triggers a Hyperammonemia Episode in Patient with Ornithine Transcarbamylase Deficiency.

An 18-year-old male motorcycle racer, who was a participant in the FIM Road Racing World Championship and had a history of Ornithine Transcarbamylase deficiency, developed nausea and dizziness while driving his motorcycle and became unconscious right after he stopped at the box. He was rapidly attended to by the medical personnel of the circuit, and once he recovered consciousness, he was taken to the local hospital where the blood analysis showed hyperammonemia (307 µg/dL) and excess alkalosis. The patient was properly following the prescribed treatment, and there were no environmental stressors. Hence, psychological stress and its somatization due to the risky task that the patient was performing could have triggered the episode. Stress must be considered as a potential cause, triggering strenuous metabolic stress that leads to hyperammonemia.

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.

Liver transplantation in rare late-onset ornithine transcarbamylase deficiency with central nervous system injury: A case report and review of the literature.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) is a genetic metabolic disease. Its clinical manifestations are mainly central nervous system dysfunction caused by high blood ammonia. Late-onset OTCD combined with central nervous system injury has a poor therapeutic response, which is one of the main factors affecting the prognosis and quality of life of patients. liver transplantation (LT) has gradually become a radical treatment for OTCD, which has achieved good results. However, there is no consensus on the timing of LT and problems of nervous system damage and repair. METHODS: We report the development of late-onset OTCD with central nervous system injury in an 11-year-old child who received liver transplantation at our transplant center. His first symptoms were nonprojectile vomiting, followed by irritability and disturbance of consciousness, after which the disease progressed rapidly and finally resulted in a coma. After liver transplantation, the child's consciousness returned to normal, muscle strength of the limbs gradually recovered from grade 0 to grade 4, and muscle tone gradually recovered from grade 4 to grade 1, suggesting that the motor nerves had gradually recovered. However, the child is currently mentally retarded, and the language center has not yet fully recovered.At the same time, we made a literature review of OTCD. CONCLUSION: For OTCD patients with central nervous system injury, liver transplantation can fundamentally solve the problem of ammonia metabolism in the liver and avoids further damage to the central nervous system caused by hyperammonemia. At the same time, children's nervous systems are in the developmental stage when neuroplasticity is greatest. If liver transplantation is performed as soon as possible, nerve repair is still possible.

A promoter variant in the OTC gene associated with late and variable age of onset hyperammonemia.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn error caused by loss of function variants in the OTC gene typically associated with severe neonatal hyperammonemia. Rare examples of late-onset OTCD have also been described. Here, we describe an OTC promoter variant, c.-106C>A, in a conserved HNF4a binding site, identified in two male siblings in Family 1 whose first and only recognized episodes of severe hyperammonemia occurred at ages 14 and 39 years, respectively. We identified the same OTC variant segregating in a large family with late-onset OTCD with variable expressivity (Family 2). We show that this OTC promoter variant reduces expression >5-fold in a dual-luciferase assay that tests promoter function. Addition of an upstream OTC enhancer increases expression of both the wild type and the c.-106C>A variant promoter constructs >5-fold with the mutant promoter still about fourfold lower than the wild type. Thus, in both contexts, the promoter variant results in substantially lower OTC expression. Under normal demand on urea cycle function, OTC expression in hemizygous males, although reduced, is sufficient to meet the demand for waste nitrogen excretion. However, in response to severe metabolic stress with attendant increased requirements on urea cycle function, the impaired promoter function results in inadequate OTC expression with resultant hyperammonemia. In the absence of precipitating events, hemizygotes with this allele are asymptomatic, explaining the late age of onset of hyperammonemia in affected individuals and the incomplete penetrance observed in some individuals in Family 2.

Late-onset ornithine transcarbamylase deficiency mimicking a focal opercular syndrome.

A previously healthy 27-year-old man was brought to hospital after been found late at night confused, agitated and talking incoherently. He represented 12 days later with focal seizures, progressing to anarthria and encephalopathy. MR scan of brain showed diffuse cerebral oedema and his plasma ammonia was >2000 µmol/L (12-55 µmol/L). He developed refractory status epilepticus and subsequently died. Genetic analysis identified an ornithine transcarbamylase (OTC) gene mutation on the X chromosome. We discuss this atypical presentation of OTC deficiency as a rare but treatable cause of hyperammonaemic encephalopathy.

In Silico Analysis of a De Novo OTC Variant as a Cause of Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common X-linked hereditary disorder of urea cycle disorders that is caused by neonatal hyperammonemia. OTC gene sequence variations are common causes of OTCD. The current study presents a 28-month-old baby girl proband with phenotypical characteristics of OTCD such as irritability, somnolence, intermittent vomiting, and high levels of serum ammonium. Whole-exome sequencing revealed a de novo c.275G>A p.(Arg92Gln) variant within the OTC gene. In silico analysis revealed a possible differential affinity between wild-type and mutant OTCase, while Arg92Gln decreases the binding ability of OTCase to the substrate, which can disrupt the urea cycle and explains the molecular pathogenicity of clinical hyperammonemia. In light of the fact that the genotype and phenotype correlation of OTCD is still uncertain, the present in silico analysis outcome can enhance our knowledge on this complicated, rare, and severe genetic disorder.

Late-onset of ornithine transcarbamylase deficiency: A rare medical examiner case.

Ornithine Transcarbamylase (OTC) is an enzyme of the urea cycle, which converts ammonia into urea in the liver cells. OTC plays a crucial role in the breakdown and removal of nitrogen in the body. OTC deficiency is a rare X-linked recessive disorder that classically presents in early life with signs of hyperammonemia and progressive central nervous system involvement resulting in seizures, coma, and death. Sentinel presentation in adulthood is quite rare. A 29-year-old man developed altered mental status after receiving an epidural steroid injection 3 days earlier for back pain. He presented to the emergency department severely agitated, and his workup revealed an elevated ammonia level of 125 µmol/L. He refused admission and was discharged against medical advice. The following day, his mentation deteriorated, he developed status epilepticus, and was transported to another emergency department. He was admitted with worsening hyperammonemia (levels rising to over 700 µmol/L). His clinical condition progressive deteriorated, and he developed encephalopathy and diffuse cerebral edema. Liver function testing indicated progressive liver damage, and amino acids were detected in his blood and urine. Clinical and laboratory findings suggested undiagnosed OTC enzyme deficiency. He died 2 days after admission. An autopsy showed an 1890 g liver with diffuse yellow discoloration and softening. Histology and electron microscopy revealed findings suggestive of urea cycle disorder, such as microvesicular steatosis, apoptosis, and scattered mitosis, clusters of clear hepatocytes at the PAS stain, and mitochondria abnormalities. Genetic analysis revealed a hemizygous pathogenic variant of the OTC gene (c.622G>A). OTC deficiency should be suspected in subjects with hyperammonemic encephalopathy. If a genetic mutation is identified in the deceased, surviving family members should be screened to prevent potential life-threatening complications.

Bivalirudin for the prevention of hepatic artery thrombosis in pediatric liver transplantation.

BACKGROUND: Early hepatic artery thrombosis (HAT) after liver transplantation is a serious complication that frequently results in graft loss and the need for retransplantation. Although studies have reported on various operative and endovascular treatment approaches, pharmacologic strategies for the prevention or management of HAT are not well defined. Patients with blood clotting disorders, those with a contraindication to heparin, and those who have previously developed HAT represent unique challenges in management. METHODS: We present the case of a 9-month-old male with a hypercoagulable state who developed early HAT after two liver transplants, despite the use of postoperative therapeutic heparin infusion. RESULTS AND CONCLUSION: The patient successfully underwent a third liver transplant using intraoperative and postoperative bivalirudin infusion, a direct thrombin inhibitor. Rotational thromboelastometry (ROTEM) was used to guide anticoagulation and blood product administration in the perioperative period. At 1.5 years post-transplant, the patient has good graft function with patent hepatic vasculature. This case demonstrates the innovative use of bivalirudin anticoagulant therapy and viscoelastic methodologies to improve outcomes in hypercoagulable liver transplant recipients.

Status epilepticus secondary to hyperammonaemia: a late presentation of an undiagnosed urea cycle defect.

In this report, we describe the diagnosis, investigation and management of a patient presenting with refractory status epilepticus secondary to a previously unrecognised urea cycle defect, ornithine transcarbamylase deficiency, causing a hyperammonaemic encephalopathy. While metabolic disorders will be readily considered in a paediatric population presenting with difficult seizures, it is unusual for such cases to present in adulthood, and maintaining a broad differential in patients with status epilepticus is important. Early recognition and initiation of treatment are vital. Furthermore, the patient had been diagnosed with schizophrenia over a decade previously and more recently started on sodium valproate, a medication known to contribute to hyperammonaemia. This case also emphasises the importance of exclusion of underlying organic disease prior to diagnosis of psychiatric conditions.

Mycobacterium abscessus infection in a patient with ornithine transcarbamylase deficiency and liver transplant.

Rapidly growing mycobacteria, including Mycobacterium abscessus, have become a common cause of post-procedural infections and are notoriously difficult to diagnose and treat. Here, we report a 10-month-old male status post-orthotopic liver transplantation due to ornithine transcarbamylase deficiency who presented with a 4-month history of hypertrophic and friable granulation tissue of surgical wounds refractory to treatment with broad spectrum antibiotics and surgical debridement. Skin biopsy and tissue culture yielded a diagnosis of M abscessus infection that demonstrated excellent clinical response to appropriate antibiotic and surgical treatment.

Valproate-induced fatal acute hyperammonaemia-related encephalopathy in late-onset ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is a genetic disorder of the urea cycle characterised by deficiency in the enzyme OTC, resulting in an accumulation of ammonia. Valproic acid (VPA), a commonly used medication in the treatment of neurologic and psychiatric conditions, has been known to cause episodes of acute hyperammonaemia in patients with OTC deficiency. We present the case of a 29-year-old man with a long history of non-specific psychiatric disorders, who suffered from a hyperammonaemic crisis following the administration of VPA, leading to the diagnosis of OTC deficiency. The patient's hospital course was complicated by progressive cerebral oedema, which resulted in worsening encephalopathy, seizures and death. We discuss the pathophysiology of hyperammonaemia in OTC deficiency, and various management strategies, including lactulose, levocarnitine, scavenger therapy and haemodialysis.

Neuromyelitis Optica Complicated by Ornithine Transcarbamylase Deficiency Treated Safely with Pulse Steroid Therapy.

Steroid administration to patients with urea cycle disorders can cause hyperammonemia. We encountered a 36-year-old woman with neuromyelitis optica (NMO) complicated by ornithine transcarbamylase (OTC) deficiency. By reducing the doses of steroids and adequate infusion management, we were able to administer pulse steroid therapy without any severe complications. This case indicates the safety of steroid treatment in patients with urea cycle disorders.

Acute liver dysfunction with delayed peak of serum aminotransferase levels as a presentation of ornithine transcarbamylase deficiency in females.

We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant.