ABSTRACT
Hereditary tyrosinemia type I (HT1) is caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, the template for the final enzyme in the tyrosine catabolism pathway. If left untreated this deficiency of functional FAH leads to a buildup of toxic metabolites that can cause liver disease, kidney dysfunction and high mortality. The current treatment with the drug NTBC prevents the production of these metabolites and has consequently increased the survival rate in HT1 children. As a result of this increased survival, long term complications of HT1 are now being observed, including slower learning, impaired cognition and altered social behavior. We studied a mouse model of HT1 to gain insight into the effects of HT1 and treatment with NTBC on social behavior in mice. We showed that mice with HT1 display abnormal social behavior in that they spend more time in the absence of another mouse and do not discriminate between a novel mouse and an already familiar mouse. This altered behavior was due to HT1 and not treatment with NTBC. Quantification of cerebral cortex myelin in mice with HT1 showed a two to threefold increase in myelin expression. Our findings suggest that absence of FAH expression in the brain produces an altered brain biochemistry resulting in increased expression of myelin. This increase in myelination could lead to abnormal action potential velocity and altered neuronal connections that provide a mechanism for the altered learning, social behavior and cognitive issues recently seen in HT1.
