Brain Myo-inositol and Glutamine Levels as a Predictor of Neurotoxicity in Ornithine Transcarbamylase Deficiency

The urea cycle is a mechanism of the hepatic detoxification of ammonia, which accumulates within the body as a result of protein metabolism. It also is responsible for de novo synthesis of arginine (Scaglia & Lee, 2006). There are eight known deficiencies in the urea cycle (six enzymes and two transporters) that impair ureagenesis, the most common being ornithine transcarbamylase (OTC) deficiency. (CHECK: some reports said 6 known causesCongenital defects of enzymes within this cycle impair the conversion of ammonia to urea, and result in the accumulation of toxic intermediate metabolites. Inborn genetic defects in the metabolism of ammonia can lead to rapid hyperammonemia, which is characterized by symptoms of unexplained lethargy, headaches, seizures, hypoventilation, vomiting, coma, and psychomotor retardation (Ah Mew et al., 2015).Neurotoxicity can result from a number of mechanisms, such as the accumulation of glutamine (Gln) in astrocytes leading to cellular swelling and cerebral edema (Gropman et al., 2008). As gln levels increase, myo-inositol (mI), an osmolyte, has a tendency to exit the cells in order to maintain astrocyte homeostasis (Gropman et al., 2008). Decreased mI is associated with injury to the deep white matter in the brain, and therefore may be an indicator of changes on the chemical level that may be evident even in clinically asymptomatic patients (Gropman et al., 2008). This present study, a part of an ongoing 10-year research project, focused on patients with OTC deficiency and the elevated levels of brain glutamine during hyperammonemic events, the suspected catalyst of neurotoxicity. Magnetic resonance spectroscopy (MRS) was used to investigate whether the ratio of glutamine to myo-inositol (mI) can be used as a predictor for cytotoxic edema, impairment of white matter tracts, and subsequent cell loss.The results of this neuroimaging study were generally consistent with previous research findings, indicating that a lower gln and higher mI was correlated with reduced hospitalizations for hyperammonemic episodes and a milder clinical presentation in patients with OTC deficiency. Conversely, most symptomatic individuals showed an elevated gln with a compensatory decrease in mI levels. In patients with an elevated gln and mI, the clinical manifestations appear to be less severe, perhaps due to protective functions of the preserved mI.