Julien BARUTEAU, MD, PhD
University College London Great Ormond Street Institute of Child Health, Great Ormond Street Hospital
Cerebral Vulnerability to Hyperammonaemia in Citrin Deficiency
The late phenotype of Adolescent and Adult with Citrin Deficiency (AACD) is associated with repeated hyperammonaemic episodes. Patients with AACD show a high rate of acute neurological complications compared to other urea cycle disorders. Acute therapies for hyperammonaemia do not differ between AACD and urea cycle disorders.
Although citrin is mainly expressed in the liver, we identified its expression in human astrocytes, predominantly compared to its isoform aralar. Astrocytes are essential supporting cells in the brain, which regulate the environment for neurons. One astrocyte can connect to thousands of neurons. It is well-known that astrocytes act as an ultimate cerebral protection in case of hyperammonaemia by buffering ammonia in excess.
In Citrin Deficiency, the disruption of NADH/NAD ratio alters multiple cellular pathways and affects the environment of the cells, both at baseline but particularly in the case of acute cellular stress.
We hypothesise that citrin-deficient astrocytes are dysfunctional, which limits their ability to detoxify ammonia nd provides a rationale for the clinical severity of hyperammonaemic episodes and subsequent neurological sequelae observed in AACD.
In this proposal, we aim to pioneer the description Citrin expression in the human brain, assess the pathophysiology associated with Citrin Deficiency in human astrocytes exposed to hyperammonaemia and screen for therapeutic agents, which could restore hyperammonaemia-related dysregulation and alleviate neurological sequelae in AACD.
