Tyrosine Metabolism

Inherited disorders of tyrosine catabolism have been identified at five of the six enzymatic steps. Under normal conditions tyrosine concentrations are regulated by its synthetic enzyme (phenylalanine hydroxylase) and especially the first catabolic enzyme (tyrosine aminotransferase). Acquired or inherited deficiency of the second catabolic enzyme (4-hydroxyphenylpyruvate dioxygenase) also results in hypertyrosinemia. Tyrosine is mainly degraded in the liver but to a minor extent also in the kidney. In tyrosinemia type I, the primary defect is in the last enzyme of the pathway, accumulation of toxic metabolites are seen, and the hypertyrosinemia results from secondary deficiency of 4-hydroxyphenylpyruvate dioxygenase, which also is found in severe liver disease in general and in the immature liver. Generally, there is no common phenotype to the different disorders of tyrosine degradation. The occurrence of corneal and skin lesions, as seen in tyrosinemia type II, is a direct effect of high tissue tyrosine. Cognitive impairment is common in tyrosinemia type II, probably common in type III, and increasingly reported in type I. The liver and kidney diseases of tyrosinemia type I are caused by accumulation of toxic metabolites (fumarylacetoacetate and its derivatives) and can be prevented by an inhibitor (nitisinone) of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase. Whether maleylacetoacetate hydrolase that essentially gives the same metabolic features as tyrosinemia type I results in clinical features is unclear. In alkaptonuria there is no increase in tyrosine level, and the degradation of tyrosine proceeds at a normal rate to produce homogentisate. Upon oxidation, homogentisate forms reactive intermediates and pigment, which is deposited in various tissues particularly in joints and connective tissue. In hawkinsinuria, a very rare condition, data suggest that an aberrant metabolism of 4-hydroxyphenylpyruvate in some cases may lead to failure to thrive, acidosis, and excretion of a characteristic metabolite pattern.</p

Tyrosine Metabolism

Inherited disorders of tyrosine catabolism have been identified at five of the six enzymatic steps. Under normal conditions tyrosine concentrations are regulated by its synthetic enzyme (phenylalanine hydroxylase) and especially the first catabolic enzyme (tyrosine aminotransferase). Acquired or inherited deficiency of the second catabolic enzyme (4-hydroxyphenylpyruvate dioxygenase) also results in hypertyrosinemia. Tyrosine is mainly degraded in the liver but to a minor extent also in the kidney. In tyrosinemia type I, the primary defect is in the last enzyme of the pathway, accumulation of toxic metabolites are seen, and the hypertyrosinemia results from secondary deficiency of 4-hydroxyphenylpyruvate dioxygenase, which also is found in severe liver disease in general and in the immature liver. Generally, there is no common phenotype to the different disorders of tyrosine degradation. The occurrence of corneal and skin lesions, as seen in tyrosinemia type II, is a direct effect of high tissue tyrosine. Cognitive impairment is common in tyrosinemia type II, probably common in type III, and increasingly reported in type I. The liver and kidney diseases of tyrosinemia type I are caused by accumulation of toxic metabolites (fumarylacetoacetate and its derivatives) and can be prevented by an inhibitor (nitisinone) of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase. Whether maleylacetoacetate hydrolase that essentially gives the same metabolic features as tyrosinemia type I results in clinical features is unclear. In alkaptonuria there is no increase in tyrosine level, and the degradation of tyrosine proceeds at a normal rate to produce homogentisate. Upon oxidation, homogentisate forms reactive intermediates and pigment, which is deposited in various tissues particularly in joints and connective tissue. In hawkinsinuria, a very rare condition, data suggest that an aberrant metabolism of 4-hydroxyphenylpyruvate in some cases may lead to failure to thrive, acidosis, and excretion of a characteristic metabolite pattern.</p

Tetrahydrobiopterin treatment in phenylketonuria:A repurposing approach

In phenylketonuria (PKU) patients, early diagnosis by neonatal screening and immediate institution of a phenylalanine-restricted diet can prevent severe intellectual impairment. Nevertheless, outcome remains suboptimal in some patients asking for additional treatment strategies. Tetrahydrobiopterin (BH4) could be one of those treatment options, as it may not only increase residual phenylalanine hydroxylase activity in BH4-responsive PKU patients, but possibly also directly improves neurocognitive functioning in both BH4-responsive and BH4-unresponsive PKU patients. In the present review, we aim to further define the theoretical working mechanisms by which BH4 might directly influence neurocognitive functioning in PKU having passed the blood-brain barrier. Further research should investigate which of these mechanisms are actually involved, and should contribute to the development of an optimal BH4 treatment regimen to directly improve neurocognitive functioning in PKU. Such possible repurposing approach of BH4 treatment in PKU may improve neuropsychological outcome and mental health in both BH4-responsive and BH4-unresponsive PKU patients

Preventive use of nitisinone in alkaptonuria

Abstract Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2–2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications

Communication of an Abnormal Metabolic New-Born Screening Result in The Netherlands:The Parental Perspective

In the Netherlands, abnormal New-Born Screening (NBS) results are communicated to parents by the general practitioner (GP). Good communication and consequential trust in professionals is of the utmost importance in the treatment of phenylketonuria (PKU). The aim of this study was to assess parental satisfaction regarding the communication of an abnormal NBS result for PKU in the Netherlands. An email containing the link to a web-based questionnaire was sent by the Dutch PKU Association to their members. Responses to open questions were categorized, data of both open and closed questions were analysed with descriptive statistics and the Chi-Square test using SPSS. Out of 113 parents of a child with PKU (born between 1979 and 2020), 68 stated they were overall unsatisfied with the first communication of the NBS result. Seventy-five parents indicated that wrong or no information about PKU was given. A significant decrease was found in the number of parents being contact by their own GP over the course of 40 years (p < 0.05). More than half of all parents were overall unsatisfied with the first communication of the abnormal NBS result for PKU. Further research on how to optimize communication of an abnormal NBS results is necessary

Dietary Liberalization in Tetrahydrobiopterin-Treated PKU Patients:Does It Improve Outcomes?

Purpose: this systematic review aimed to assess the effects of dietary liberalization following tetrahydrobiopterin (BH4) treatment on anthropometric measurements, nutritional biomarkers, quality of life, bone density, mental health and psychosocial functioning, and burden of care in PKU patients. Methods: the PubMed, Cochrane, and Embase databases were searched on 7 April 2022. We included studies that reported on the aforementioned domains before and after dietary liberalization as a result of BH4 treatment in PKU patients. Exclusion criteria were: studies written in a language other than English; studies that only included data of a BH4 loading test; insufficient data for the parameters of interest; and wrong publication type. Both within-subject and between-subject analyses were assessed, and meta-analyses were performed if possible. Results: twelve studies containing 14 cohorts and 228 patients were included. Single studies reported few significant differences. Two out of fifteen primary meta-analyses were significant; BMI was higher in BH4-treated patients versus controls (p = 0.02; standardized mean difference (SMD) (95% confidence interval (CI)) = −0.37 (−0.67, −0.06)), and blood cholesterol concentrations increased after starting BH4 treatment (p = 0.01; SMD (CI) = −0.70 (−1.26, −0.15)). Conclusion: there is no clear evidence that dietary liberalization after BH4 treatment has a positive effect on anthropometric measurements, nutritional biomarkers, or quality of life. No studies could be included for bone density, mental health and psychosocial functioning, and burden of care

Gut-microbiome composition in response to phenylketonuria depends on dietary phenylalanine in BTBR Pah^enu2 mice

Phenylketonuria (PKU) is a metabolic disorder caused by a hepatic enzyme deficiency causing high blood and brain levels of the amino acid Phenylalanine (Phe), leading to severe cognitive and psychological deficits that can be prevented, but not completely, by dietary treatment. The behavioral outcome of PKU could be affected by the gut-microbiome-brain axis, as diet is one of the major drivers of the gut microbiome composition. Gut-microbiome alterations have been reported in treated patients with PKU, although the question remains whether this is due to PKU, the dietary treatment, or their interaction. We, therefore, examined the effects of dietary Phe restriction on gut-microbiome composition and relationships with behavioral outcome in mice. Male and female BTBR Pah(enu2) mice received either a control diet (normal protein, “high” Phe), liberalized Phe-restricted (33% natural protein restriction), or severe Phe-restricted (75% natural protein restriction) diet with protein substitutes for 10 weeks (n = 14 per group). Their behavioral performance was examined in an open field test, novel and spatial object location tests, and a balance beam. Fecal samples were collected and sequenced for the bacterial 16S ribosomal RNA (rRNA) region. Results indicated that PKU on a high Phe diet reduced Shannon diversity significantly and altered the microbiome composition compared with wild-type animals. Phe-restriction prevented this loss in Shannon diversity but changed community composition even more than the high-Phe diet, depending on the severity of the restriction. Moreover, on a taxonomic level, we observed the highest number of differentially abundant genera in animals that received 75% Phe-restriction. Based on correlation analyses with differentially abundant taxa, the families Entereococacceae, Erysipelotrichaceae, Porphyromonadaceae, and the genus Alloprevotella showed interesting relationships with either plasma Phe levels and/or object memory. According to our results, these bacterial taxa could be good candidates to start examining the microbial metabolic potential and probiotic properties in the context of PKU. We conclude that PKU leads to an altered gut microbiome composition in mice, which is least severe on a liberalized Phe-restricted diet. This may suggest that the current Phe-restricted diet for PKU patients could be optimized by taking dietary effects on the microbiome into account