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.

Gene Editing Correction of a Urea Cycle Defect in Organoid Stem Cell Derived Hepatocyte-like Cells

Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While individually rare, there is a large number of other genetic-based liver diseases. The approach described here could be applied to a broad range and a large number of patients with these hepatic diseases where it could serve as an in vitro model, as well as identify successful strategies for corrective cell-based therapy.

Detection of some metabolic disorders in suspected neonates admitted at Assiut University Children Hospital

Background Inborn errors of metabolism are genetically inherited diseases which can lead to accumulation of toxic metabolites in the body. Inborn errors of metabolism have a high morbidity and mortality in neonates. Many inborn errors of metabolism are amenable to treatment with early diagnoses. Till now, more than 500 metabolic disorders have been detected. Although individual metabolic disorders are rare, the incidence of overall metabolic disorders is high. Results It was found that 70/200 cases (35 %) had confirmed inborn errors of metabolism, and another 8 cases (4%) suspected to have inborn errors of metabolism; 15/200 (7.5%) cases had mild elevation of phenylalanine level, while 107/200 (53.5%) had another diagnosis rather than metabolic disorders. Urea cycle defect was diagnosed in 20/70 (28.5%), maple syrup urine disease in 18/70 (25.7%), organic acidemia in 15/70 (21.4%), and non-ketotic hyperglycinemia in 1/70 (1.4 %) case. Also, 15/70 (21.4 %) cases had fatty acid oxidation defect. Lastly, one female case (1.4 %) was diagnosed to have disorder of pyrimidine deficiency. Conclusion Diagnosis of inborn errors of metabolism was confirmed in 35% of neonates, and 4% was suspected to have metabolic disorders. These results showed that inherited metabolic disorders are not rare. The development of a nationwide screening program for metabolic disorders is mandatory for early detection of these potentially treatable disorders.

Recurrent encephalopathy and hyperammonemia in new born: case of arginosuccinic aciduria

Urea cycle disorders result from defects in the metabolism of waste nitrogenous compounds derived from the breakdown of proteins and other nitrogen-containing molecules. Argininosuccinic aciduria is a rare autosomal recessive heterogeneous urea cycle disorder, which leads to the accumulation of argininosuccinic acid in the blood and urine. It is caused by defect in the argininosuccinate lyase (ASL) gene, which regulates the breakdown of argininosuccinate to fumarate and arginine in the urea cycle. They are a heterogeneous group of disorders which are associated with hyperammonemia resulting in severe neurological dysfunction like encephalopathy, seizures, developmental and psychomotor delay. The severe central nervous system dysfunction is by alteration of amino acid and neurotransmitters pathways and interference with normal cerebral energy metabolism and oxidative stress. Ammonium toxicity to the brain provokes irreversible damage due to cortical atrophy, edema, and demyelination, resulting in seizures, coma, and even death. We report such a case of urea cycle defect in a newborn that presented with recurrent encephalopathy with hyperammonemia precipitated by minor infections. Detailed investigations including genetic analysis lead to the diagnosis of argininosuccinic aciduria.

Liver Transplantation in an Adult with Citrullinaemia Type 2

Citrullinaemia is a urea cycle defect that results from a deficiency of the enzyme arginosuccinate synthetase. Type 1 disease is diagnosed in childhood, whereas Type 2 disease is adult onset. We report the outcome of a patient with citrullinemia Type 2 who received a liver transplant at our center and the implications of this diagnosis in liver transplantation.