Primary urea cycle disorders Urea Cycle reactions Ah

Primary urea cycle disorders

Urea Cycle reactions (Ah Mew et al. , in Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015)

Urea Cycle Disorders (UCDs) • Complete or partial deficiencies of any of these six enzymes or the two amino acid transporters • prevalence of 1: 30, 000 to 1: 46, 000 live births • clinical manifestations due to hyperammonemia • clinical signs may depend on severity and location of the defect with more proximal defects being more severe • mild, episodic symptoms to profound neurologic morbidity & mortality

Causes • Inborn errors of metabolism • inherited in an autosomal recessive manner, except OTC deficiency, which is X-linked • CPS) deficiency & OTC deficiency most common Hyperammonemia ATP production reduced Brain damage

Symptoms • Depend on the degree of molecular dysfunction & the hyperammonemia Symptoms may be slight, • failure to thrive • episodic hyperammonemia • intellectual disability to more severe manifestations • developmental disabilities • altered mental status • coma and even death

Diagnosis is based on • Clinical examination • Biochemical estimations • The family history • Enzymatic assays, and • Molecular analyses.

Treatment May encompass any or a combination of the following: • Dietary protein restriction • Pump driven dialysis for acute management • Supplementation with arginine or citrulline or oral sodium phenylbutyrate as alternative pathway therapy • Additional treatment with conjugating agents • Liver transplantation

Current Research • Due to the rarity of the conditions, international collaborative efforts such as the NIH-UCD Consortium (UCDC) have been vital in developing evidence-based consensus guidelines for the diagnosis, therapy, procedures and management of UCDs. • Current research in the field is focused on • Knowledge of protein structure • Expression systems and animal models • Experimental therapies including hypothermia, hepatocyte transplantation and enzyme replacement or gene therapy

Urea cycle defects