ABSTRACT
Tyrosinemia type I is a recessive inborn error of metabolism caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme in the metabolism of tyrosine. This renders FAH nonfunctional and without treatment, toxic metabolites accumulate causing liver and kidney damage. Introduction of the drug NTBC in 2002 offered a treatment which inhibits an upstream enzyme, preventing the production of the toxic metabolites. There is now a long-term survival rate of greater than 90 % in children, but there are reports of lower cognitive function and IQ as well as schooling and behavioral problems in these children. We studied a mouse model of tyrosinemia type I to gain insight into the effects of tyrosinemia type I and treatment with NTBC on mouse learning, memory, and behavior. In the Barnes maze, visual and spatial cues can be used by mice to remember the location of a dark escape box. The primary time, distance, and strategy taken by the mice to locate the escape box is a measure of learning and memory. Our findings show that mice with tyrosinemia type I were slower to learn than wild-type mice treated with NTBC and made more mistakes, but were capable of learning and storing long-term memory. After learning the location of the target hole, mice with tyrosinemia type I respond differently to a change in location and were less flexible in learning the new target hole location. Our findings suggest that this slower learning and cognitive difference is caused by tyrosinemia type I and not by the treatment with NTBC.
