Abstract
Alkaptonuria (AKU) is caused by homogentisate 1,2‐dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone‐treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone‐treated AKU mice were fed tyrosine/phenylalanine‐free and phenylalanine‐free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre‐nitisinone, post‐nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700 μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine‐free amino acid supplements. Elevated tyrosine (813 μmol/L) was significantly reduced in nitisinone‐treated AKU mice fed a tyrosine/phenylalanine‐free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3, 274.8, and 144.3 μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine‐free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine‐free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 μmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone‐induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.
Highlights
Alkaptonuria (AKU; OMIM #203500) is an autosomal recessive, multisystem disease caused by mutations in the homogentisate 1,2-dioxygenase (HGD) enzyme (EC 1.13.11.5).[1]
Numerous reports and studies document impaired cognitive function in hereditary tyrosinemia type 1 (HT-1) patients that have been treated long-term with nitisinone and protein restriction.[9,14,15]. These neurodevelopmental effects could be due to either nitisinone-induced tyrosinemia or severe liver failure experienced before diagnosis and subsequent initiation of nitisinone treatment
The treatment of AKU with the homogentisic acid (HGA)-lowering drug nitisinone has proven to be effective at reducing HGA.[24]
Summary
Alkaptonuria (AKU; OMIM #203500) is an autosomal recessive, multisystem disease caused by mutations in the homogentisate 1,2-dioxygenase (HGD) enzyme (EC 1.13.11.5).[1]. The association of tyrosinemia with neural cognition is another important consideration, as tyrosine is a precursor to neurotransmitters such as dopamine, adrenaline and noradrenaline. Metabolites of these neurotransmitters have previously been shown to significantly alter with nitisinone treatment in AKU patients.[13] numerous reports and studies document impaired cognitive function in HT-1 patients that have been treated long-term with nitisinone and protein restriction.[9,14,15] These neurodevelopmental effects could be due to either nitisinone-induced tyrosinemia or severe liver failure experienced before diagnosis and subsequent initiation of nitisinone treatment. We provide proof-ofconcept that mechanisms reducing uptake of dietary tyrosine into the bloodstream would be effective
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