Altered myelination as a proposed mechanism for neurocognitive dysfunction observed in mice with Tyrosinemia type 1
Date of Award
Master of Science (MS)
Tyrosinosis., Cognition disorders., Myelination., Inborn errors of metabolism.
The exact mechanism behind the recent reports of impaired neurocognitive function in individuals with the rare genetic disorder Hereditary Tyrosinemia Type I (HT1) has yet to be determined. This disorder stems from lack of expression of the gene fumarylacetoacetate hydrolase (FAH), which is responsible for tyrosine catabolism. This subsequently leads to a buildup of tyrosine and associated harmful metabolites that will cause sever liver dysfunction and cancer if treatment is not provided. The drug 2-[2-nitro-4-(trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC) has proven to be effective in stopping the negative consequences on the liver and kidneys by inhibiting an enzyme upstream in the metabolic pathway. Although this treatment has allowed for prolonged survival in HT1 individuals, it remains unknown if NTBC has any negative effects on brain function. Studies on mice have illustrated that the disease process causes altered social behavior and cognition, mimicking the effects observed in patients with the disorder. Additionally, mice with HT1 displayed changes in myelination of the cerebral cortex. These results suggest that the neuropsychological problems observed in individuals with HT1 stem from the disease process, and that the glial cells responsible for myelination could provide a source for the increased myelination and abnormal social behavior observed in mice with HT1.
Moore, Marissa E., "Altered myelination as a proposed mechanism for neurocognitive dysfunction observed in mice with Tyrosinemia type 1" (2018). Theses. 240.