Efficacy of Phenylalanine- and Tyrosine-Restricted Diet in Alkaptonuria Patients on Nitisinone Treatment: Case Series and Review of Literature

<b><i>Introduction:</i></b> Nitisinone used in alkaptonuria (AKU) can result in keratopathy due to strongly increased tyrosine levels. <b><i>Methods:</i></b> This study aimed to investigate nutritional status and changes in plasma tyrosine and phenylalanine and urinary homogentisic acid (u-HGA) levels in 8 adult AKU patients (mean age, 56.3 ± 4.7 years) who were on tyrosine/phenylalanine-restricted diet together with 2 mg/day nitisinone. <b><i>Results:</i></b> The treatment period was 23.4 ± 6.9 months. Daily dietary protein intake was restricted to 0.8–1.0 g/kg/day. Daily tyrosine intake was restricted to 260–450 mg/day for females and 330–550 mg/day for males. Tyrosine/phenylalanine-free amino acid supplements accounted for an average of 56.1% of daily protein intake. The following assessments were performed: anthropometric and plasma tyrosine level measurements every 2 months; ophthalmological examination every 6 months, and nutritional laboratory analyses and measurements of plasma amino acids and u-HGA once in a year. It was targeted to keep the plasma tyrosine level &#x3c;500 μmol/L. The plasma tyrosine level was &#x3c;100 μmol/L before the treatment in all patients and around a mean of 582.5 ± 194.8 μmol/L during the treatment. The diet was rearranged if a plasma tyrosine level of &#x3e;700 μmol/L was detected. The u-HGA level before and after the 1st year of treatment was 1,429.3 ± 1,073.4 mmol/mol creatinine and 33.6 ± 9.5 mmol/mol creatinine, respectively. None of the patients developed keratopathy or experienced weight loss and protein or micronutrient deficiency. <b><i>Conclusion:</i></b> AKU patients should receive tyrosine/phenylalanine-restricted diet for reducing plasma tyrosine level to the safe range. Tyrosine/phenylalanine-free amino acid supplements can be safely used to enhance dietary compliance. Keratopathy and nutrient deficiency should be frequently monitored.

Preventive use of nitisinone in alkaptonuria

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.

Tyrosine Supplementation A Nutraceutical Approach to Counter Heat Stress Induced Cognitive Decline

Supplementation of tyrosine, non-essential amino acid, and precursor of catecholamine was found to ameliorate the heat-induced alterations in latencies of event-related potential P300 and contingent negative variation. Here we present the effect of tyrosine supplementation on heat stress (exposure to ambient temperature 45 oC and relative humidity 30 %) induced alterations in behavior (attention, mood) and levels of plasma monoamines. Ten healthy male participants received a placebo food bar or tyrosine-containing food bar (6.5 g in 50 g) 90 min before heat stress exposure of 90 min. Plasma and urine samples were assayed for catecholamine levels, their precursor, and metabolites using high-performance liquid chromatography. A computer-based automated test battery was used to assess attention and mood by profile of mood states questionnaire. A significantly higher plasma tyrosine (p<0.001) leading to an increased norepinephrine (p<0.05) levels in the tyrosine supplemented group was observed. Selective (p<0.001) and sustained attention (p<0.02) in the tyrosine group were significantly better compared to the placebo group. Reaction time and anger scores decreased (p<0.001) with tyrosine supplementation. It may be concluded that tyrosine supplementation improves heat stress-induced decrement in attention by maintaining the synthesis and turnover of norepinephrine.

Subchronic Tolerance Trials of Graded Oral Supplementation with Phenylalanine or Serine in Healthy Adults

Phenylalanine and serine are amino acids used in dietary supplements and nutritional products consumed by healthy consumers; however, the safe level of phenylalanine or serine supplementation is unknown. The objective of this study was to conduct two 4-week clinical trials to evaluate the safety and tolerability of graded dosages of oral phenylalanine and oral serine. Healthy male adults (n = 60, 38.2 ± 1.8y) completed graded dosages of either phenylalanine or serine supplement (3, 6, 9 and 12 g/d) for 4 weeks with 2-week wash-out periods in between. Primary outcomes included vitals, a broad spectrum of circulating biochemical analytes, body weight, sleep quality and mental self-assessment. At low dosages, minor changes in serum electrolytes and plasma non-essential amino acids glutamine and aspartic acid concentrations were observed. Serine increased its plasma concentrations at high supplemental dosages (9 and 12 g/day), and phenylalanine increased plasma tyrosine concentrations at 12 g/day, but those changes were not considered toxicologically relevant. No other changes in measured parameters were observed, and study subjects tolerated 4-week-long oral supplementation of phenylalanine or serine without treatment-related adverse events. A clinical, no-observed-adverse-effect-level (NOAEL) of phenylalanine and serine supplementation in healthy adult males was determined to be 12 g/day.

Oral Tyrosine Supplementation Facilitates Conditions for the Preferential Transport of Tyrosine Across the Blood-Brain Barrier in Anorexia Nervosa: a Case Study Series

Background: Anorexia nervosa is a severe and complex illness associated with a lack of efficacious treatment. Ongoing tyrosine administration has been proposed as a possible treatment through increasing blood tyrosine sufficiently to facilitate brain catecholamine synthesis. Saturation with the noradrenergic precursor tyrosine could alleviate noradrenergic dysregulation with subsequent reduction in dietary restraint and eating, weight and shape concern. The effects of tyrosine supplementation in adolescents with anorexia nervosa remain to be tested. This feasibility study aimed to explore whether an oral tyrosine dosage raises plasma tyrosine sufficiently in adolescents with anorexia nervosa and healthy peers and is sustained over time to allow conditions for the preferential transport across the blood-brain barrier. Case Presentation: The first stage of this study explored the pharmacological response to a single, oral tyrosine load in adolescents (aged 12-15 years) with anorexia nervosa (n=2) and healthy peers (n=2). The second stage explored the pharmacological and psychological response to ongoing tyrosine administration in adolescents with anorexia nervosa. Peak tyrosine levels occurred at approximately two-three hours and approached baseline levels by eight hours. Blood tyrosine elevation was maintained over time in participants with anorexia nervosa. Some improvements in participant psychological tests were evident. There were no measured side effects. Conclusions: The considerable blood tyrosine increase appeared sufficient to facilitate conditions for the preferential transport of tyrosine across the blood-brain barrier which has the potential to improve noradrenergic brain function in people with anorexia nervosa. Further exploration of tyrosine as an adjunct treatment in anorexia nervosa is warranted.

Tissue-specific FAH deficiency alters sleep–wake patterns and results in chronic tyrosinemia in mice

Fumarylacetoacetate hydrolase (FAH) is the last enzyme in tyrosine catabolism, and mutations in the FAH gene are associated with hereditary tyrosinemia type I (HT1 or TYRSN1) in humans. In a behavioral screen of N-ethyl-N-nitrosourea mutagenized mice we identified a mutant line which we named “swingshift” (swst, MGI:3611216) with a nonsynonymous point mutation (N68S) in Fah that caused age-dependent disruption of sleep–wake patterns. Mice homozygous for the mutation had an earlier onset of activity (several hours before lights off) and a reduction in total activity and body weight when compared with wild-type or heterozygous mice. Despite abnormal behavioral entrainment to light–dark cycles, there were no differences in the period or phase of the central clock in mutant mice, indicating a defect downstream of the suprachiasmatic nucleus. Interestingly, these behavioral phenotypes became milder as the mice grew older and were completely rescued by the administration of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione], an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, which is upstream of FAH. Mechanistically, the swst mutation had no effect on the enzymatic activity of FAH, but rather promoted the degradation of the mutant protein. This led to reduced FAH protein levels and enzymatic activity in the liver and kidney (but not the brain or fibroblasts) of homozygous mice. In addition, plasma tyrosine—but not methionine, phenylalanine, or succinylacetone—increased in homozygous mice, suggesting that swst mutants provide a model of mild, chronic HT1.

Hawkinsinuria clinical practice guidelines: a Mexican case report and literature review

Hawkinsinuria is an autosomal dominant disorder of tyrosine metabolism. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene ( HPD) result in an altered HPD enzyme, causing hawkinsin and tyrosine accumulation. Persistent metabolic acidosis and failure to thrive are common features in patients with hawkinsinuria. We present the first known Latin American patient diagnosed with hawkinsinuria, and the tenth reported patient in the literature. We aim to establish clinical practice guidelines for patients with hawkinsinuria. The patient’s plasma tyrosine level was 21.5 mg/dL, which is several times higher than the reference value. Mutation analysis indicated heterozygosity for V212M and A33T variants in HPD. In the case of altered tyrosine levels found during newborn screening, we propose exclusive breastmilk feeding supplemented with ascorbic acid. Amino acid quantification is useful for monitoring treatment response. If tyrosinemia persists, protein intake must be decreased via a low-tyrosine diet. Molecular studies can be used to confirm a patient’s disease etiology. Further reports are required to elucidate new pathogenic and phenotypic variations to enable the development of an appropriate therapeutic approach.