Evaluation of a casein glycomacropeptide-based protein substitute, in the dietary management of NTBC-induced tyrosinaemia in patients with alkaptonuria: A prospective open-label study.

BACKGROUND: 2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) treatment of alkaptonuria (AKU) leads to increased blood tyrosine levels, causing skin issues and potentially sight-threatening corneal keratopathy. Adherence to dietary management of NTBC-induced tyrosinemia, a low-protein diet with or without protein substitutes, can be difficult for patients. This 28-day interventional study evaluated a low tyrosine casein glycomacropeptide (cGMP) protein substitute (TYR sphere)®, a 20 g protein equivalent, cGMP-based protein substitute, in terms of adherence, palatability, usability, comparison to amino acid (AA)-based protein substitutes, gastrointestinal tolerance and metabolic control in adults with NTBC-induced tyrosinaemia. METHODS: Four adults (mean 61.1 years, range 53.3-69.3 years) with AKU and NTBC-induced tyrosinaemia were recruited from the United Kingdom National Alkaptonuria Centre (NAC). The cGMP protein substitute was prescribed based on individual nutritional requirements, replacing ≥1 AA-based protein substitute. Participants recorded product-related data in study diaries, using five-point Likert scales and daily and weekly logs. To determine metabolic control, prestudy blood tyrosine levels were compared to weekly blood spot tests during the study. RESULTS: Median cGMP protein substitute adherence was 98%. Most participants rated palatability and usability positively, and preferred cGMP protein substitute to AA-based products. There were no notable gastrointestinal changes, and metabolic control was maintained. CONCLUSIONS: cGMP protein substitute is a palatable and well-tolerated option in the dietary management of AKU patients with NTBC-induced tyrosinaemia.

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria.

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.

The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma.

BACKGROUND: Alkaptonuria (AKU) is a disorder of tyrosine/protein metabolism leading to accumulation of homogentisic acid. Clinical management historically recommended reducing dietary protein intake, especially in childhood, which has since been discredited in the literature. For the first time, analysis of baseline cross-sectional nutritional surveillance data from a large cohort of AKU patients is presented, which has clinical implications in all aspects of treatment planning. METHOD: Seventy-four patients (mean 55 years) admitted to the National Alkaptonuria Centre (NAC), underwent a global nutritional assessment, which included objective anthropometry, bioimpedance measures, habitual nutritional intake using a 7-day food diary and key nutritional biomarkers, including 24 hours urinary nitrogen, serum albumin, total protein and total 25-hydroxy vitamin D. All data was compared with cohort norms or recommended nutrient intakes for health (RNI). The potential beneficial impact of protein and anti-inflammatory nutrients such as vitamin C, selenium, and zinc were statistically interrogated against the AKU severity score index (AKUSSI)-a validated measure of disease progression stratified by age. RESULTS: Fifty percent of AKU patients reported some level of protein restriction at some point in their lives. In comparison with national data sets, AKU patients present with significantly lower than predicted mid-upper arm circumference, grip strength, BMI, total energy and protein intake, and higher than predicted percentage body fat. They therefore meet the ESPEN criteria as "clinically undernourished." Severity fluctuates over the life course. No statistical association is identified between protein intake, expressed as %RNI or g/kg, or anti-inflammatory nutrients, including vitamin C as a high dose supplement on the severity of the disease, when correlated against the validated AKUSSI score. CONCLUSION: AKU patients are at risk of protein depletion associated with a "perfect storm" of risk factors: historical, poorly evidenced recommendations to reduce total protein intake; limited mobility as the condition progresses, compromising muscle integrity; frequent hospital admissions for major surgery associated with multiple joint replacements, creating pinch points of high metabolic demand and the potential impact of the disease itself. As this is the first time this risk has been identified, the authors consider the dietetic implications of nitisinone treatment, which requires dietary protein control to manage the acquired tyrosinaemia. The lack of statistically significant evidence to support dietary manipulation of any kind to impede disease progression in AKU is demonstrated.

Uniformity of Food Protein Interpretation Amongst Dietitians for Patients with Phenylketonuria (PKU): 2020 UK National Consensus Statements.

In phenylketonuria (PKU), variable dietary advice provided by health professionals and social media leads to uncertainty for patients/caregivers reliant on accurate, evidence based dietary information. Over four years, 112 consensus statements concerning the allocation of foods in a low phenylalanine diet for PKU were developed by the British Inherited Metabolic Disease Dietitians Group (BIMDG-DG) from 34 PKU treatment centres, utilising 10 rounds of Delphi consultation to gain a majority (≥75%) decision. A mean of 29 UK dietitians (range: 18-40) and 18 treatment centres (range: 13-23) contributed in each round. Statements encompassed all foods/food groups divided into four categories based on defined protein/phenylalanine content: (1) foods high in protein/phenylalanine (best avoided); (2) foods allowed without restriction including fruit/vegetables containing phenylalanine ≤75 mg/100 g and most foods containing protein ≤0.5 g/100 g; (3) foods that should be calculated/weighed as an exchange food if they contain protein exchange ingredients (categorized into foods with a protein content of: >0.1 g/100 g (milk/plant milks only), >0.5 g/100 g (bread/pasta/cereal/flours), >1 g/100 g (cook-in/table-top sauces/dressings), >1.5 g/100 g (soya sauces)); and (4) fruit/vegetables containing phenylalanine >75 mg/100 g allocated as part of the protein/phenylalanine exchange system. These statements have been endorsed and translated into practical dietary management advice by the medical advisory dietitians for the National Society for PKU (NSPKU).