Date of Award
Master of Science (MS)
Luis R. Cruz-Vera
Inborn errors of metabolism., Genetic disorders.
Hereditary Tyrosinemia Type 1 (TTI) is an autosomal recessive disorder that is characterized by the deficiency of the fumarylacetoacetase (FAH) enzyme in the tyrosine catabolic pathway, resulting in the elevation of tyrosine and its byproducts in the blood, cerebrospinal fluid (CSF), and tissues. The accumulation of the toxic metabolites succinylacetone and fumarylacetoacetate in the liver and kidneys leads to catastrophic effects and death if not treated. The current treatments available for TTI patients are pharmacotherapy with nitisinone (NTBC) with diet modification and/or a liver transplant, each with its own associated risks. Recently, data has been published showing that TTI patients on long term treatment of NTBC have a decline in their neurocognitive abilities and Intelligence Quotient (IQ). A novel effect of NTBC treatment is an abnormal increase in the amino acid tyrosine, a precursor utilized for catecholamine production. It has been demonstrated that human neurons in vitro treated with NTBC have a 40-fold increase in dopamine release, indicating a potential mechanism for these neurocognitive alterations. Furthermore, FAH knockout and WT mice maintained on NTBC have marked decreases in plasma concentrations of dopamine and serotonin. Additionally, it has been shown that FAH -/- mice on NTBC show a decreased performance in a spatial learning and memory task known as the Barnes' maze. This indicates that NTBC, through disruptions in catecholamine levels, may be responsible for the decrease seen in neurocognitive abilities detailed in the current literature.
Coker, Sarah Bradham, "Cognitive studies on a mouse model of tyrosinemia type I" (2015). Theses. 114.