Abstract
Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in the tyrosine degradation pathway. Neurocognitive deficiencies have been described in TT1 patients, that have, among others, been related to changes in plasma large neutral amino acids (LNAA) that could result in changes in brain LNAA and neurotransmitter concentrations. Therefore, this project aimed to investigate plasma and brain LNAA, brain neurotransmitter concentrations and behavior in C57 Bl/6 fumarylacetoacetate hydrolase deficient (FAH−/−) mice treated with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and/or diet and wild-type mice. Plasma and brain tyrosine concentrations were clearly increased in all NTBC treated animals, even with diet (p < 0.001). Plasma and brain phenylalanine concentrations tended to be lower in all FAH−/− mice. Other brain LNAA, were often slightly lower in NTBC treated FAH−/− mice. Brain neurotransmitter concentrations were usually within a normal range, although serotonin was negatively correlated with brain tyrosine concentrations (p < 0.001). No clear behavioral differences between the different groups of mice could be found. To conclude, this is the first study measuring plasma and brain biochemistry in FAH−/− mice. Clear changes in plasma and brain LNAA have been shown. Further research should be done to relate the biochemical changes to neurocognitive impairments in TT1 patients.
Highlights
Tyrosinemia Type 1 (TT1; McKusick 27670) is an inborn error of tyrosine metabolism caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH)
The experimental diet and normal AIM-93 diet were well tolerated by the mice and the total food intake during the experiment did not differ between the different group of mice (p = 0.513)
Neurotransmitter concentrations in FAH−/− were mostly normal, especially serotonin concentrations were negatively correlated with brain tyrosine concentrations
Summary
Tyrosinemia Type 1 (TT1; McKusick 27670) is an inborn error of tyrosine metabolism caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) Due to this deficiency, toxic products such as fumarylacetoacetate, maleylacetoacetate, succinylacetoacetate and succinylacetone (SA) accumulate proximal to the enzymatic defect, mainly causing acute liver failure, development of hepatocellular carcinoma at a young age, renal tubulopathy and/or porphyria like syndrome. Nutrients 2019, 11, 2486 tyrosine concentrations, making dietary restriction of tyrosine and its precursor phenylalanine again necessary [1,2,3] With this combined treatment, most clinical problems could be prevented in TT1 patients. The pathophysiological mechanisms underlying these neurocognitive and behavioral problems in TT1 patients are not fully understood, biochemical differences and treatment with the herbicide NTBC potentially play a central role. The nine large neutral amino acids (LNAA), including tyrosine and phenylalanine, are transported across the blood-brain barrier in a competitive way [5]
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