Introducing a granule based protein substitute to the diet of a child with phenylketonuria to address reluctance to ingest phenylalanine-free protein substitute: A case report

Abstract

Phenylalanine (Phe)-free protein substitutes are used within the management of phenylketonuria (PKU). However, adherence to the Phe-restricted diet is often challenging. A child (age 4.5 years) with PKU rejected the Phe-free protein substitutes used within her therapeutic diet, causing stress for herself and family at mealtimes. Switching to a new Phe-free protein substitute that can be mixed into other foods [PKU GOLIKE^® (3–16)] provided an alternative strategy that was acceptable to the child. Good control of blood Phe was maintained. Newer Phe-free protein substitutes may provide a strategy for maintaining the therapeutic diet for PKU where the patient has difficulty doing so on standard substitutes. Here, the use of a Phe-free protein substitute with improved palatability and ease of use supported maintenance of the Phe-restricted diet for a child with PKU who struggled to maintain the diet on standard substitutes.

Introduction

Phenylketonuria (PKU) is an inborn error of metabolism that results in a toxic build-up of Phe in the brain which, if untreated, almost always causes devastating developmental problems (National Health Service, 2020). Early, continuous lifelong intervention with a Phe-restricted diet is recommended (van Wegberg et al., 2017). Many patients find the Phe-restricted diet burdensome: adherence is often poor, and food neophobia can inhibit intake of new foods and promote unhealthy food choices (MacDonald et al., 2012; Cazzorla et al., 2018; Tonona et al., 2019). Newer Phe-free amino acid substitutes are designed for improved palatability and convenience. We present a case of the application of a prolonged-release amino acid supplement [‘PKU GOLIKE^® Plus (3–16 years)’, referred to henceforth as “the newer amino acid substitute”] for a young child (referred to henceforth as “the case study”) who demonstrated great reluctance to ingest a standard amino acid supplement, with considerable stress for the family at mealtimes.

Case presentation

Written informed consent was provided by the case study's Guardian for the use of her anonymized data.

The case study was diagnosed with PKU on newborn screening (blood Phe was 940 µmol/L on day 5, and 1143 µmol/L on day 10; corresponding blood Tyr levels were 41 µmol/L and 12 µmol/L, respectively). She was initially bottle-fed with a Phe-free specialist infant formula for PKU. Once blood Phe was <1000 µmol/L, dietary Phe was reintroduced at 50 mg/kg. Dietary Phe tolerance was low (150 mg/day). At 6 months she transitioned to a semi-solid second-stage Phe free protein substitute. At age 1 year, the diet plan consisted of:

• 200 mg Phe/day with food, spread evenly over three main meals;

• 3 semi-solid second-stage protein substitutes (30 g protein equivalent; 3 times/day before main meals);

• Phe-free foods;

• Low-protein prescribed food (milk, bread, pasta, flour, rice).

The protein substitute at this time was suitable for infants ≤5 years and we explored different options at age 4.5 years. She was becoming fussy about taking protein substitutes, with considerable stress for the family. Following discussion of options available, the parents requested a trial of the newer amino acid substitute, largely because it could be mixed into food/drinks.

The diet plan at 4.5 years was:

• 175 mg Phe/day with food spread evenly over three main meals;

• 4 semi-solid second-stage protein substitutes – 3 times/day before main meals (40 g protein equivalent);

• Phe free foods;

• Low protein prescribed food (milk, bread, pasta, flour, rice, pizza base);

• Total protein was 2.8 g/kg/day.

The newer amino acid substitute replaced the previous substitute gradually over 3-months:

Step 1: x 1 sachet (15 g protein equivalent) + semi-solid second stage protein substitute (25 g protein equivalent)

Step 2: x 2 sachets (30 g protein equivalent + semi-solid second stage protein substitute (15 g protein equivalent)

Step 3: x 3 sachets (45 g protein equivalent)

Essential fatty acid supplementation was introduced (100 mg DHA and 200 mg AA), as the new protein substitute does not contain this. Her current diet plan is as per Step 3, plus Phe-free foods and the low-protein prescribed food.

Figure 1 and Table 1 show blood Phe during the introduction of the new protein substitute. Between Step 1 and Step 2, we increased overall protein intake to provide 45 g protein equivalent (3 g/kg) as blood Phe exceeded her target range of 120–360 µmol/L. Her Phe levels tended to exceed the recommended range if she was not on this level of protein intake. One low blood Phe value (Step 2) was due to skipping a dietary Phe exchange. A high blood Phe value during Step 3 was associated with intercurrent illness. Overall, average blood Phe remained well controlled.

Figure 1.

Blood Phe and Tyr levels. Dotted lines show the upper and lower bounds of guideline targets for blood Phe in the management of PKU (120–360 μmol/L). Blood Tyr could be measured down to a minimum of 20 μmol/L. Values shown at this level for blood Tyr (solid grey squares) should be interpreted as “<20 μmol/L”. Steps 1–3 are alterations to the use of the newer amino acid substitute (see text). The time axis is shown as an arbitrary scale in months without specific dates to help preserve anonymisation of the case.

Table 1.

Blood Phe levels over the last 11 months since being on the above diet plan.

	Blood Phe level (µmol/L)	Comment
Average blood Phe level	317	In range (120–360 µmol/L)
Max blood Phe level	590	Due to an intercurrent illness
Min blood Phe level	75	Due to not completing all Phe exchanges in school lunches.

Blood Tyr levels are not a primary biomarker of metabolic control in PKU (van Wegberg et al., 2017). These were generally contained within the usually quoted reference range of 30–120 μmol/L (Adnan and Puranik ). Further work with the family will be aimed at identifying and rectifying the reasons for occasional dips in blood Tyr to <20 μmol/L.

The case study tracked along the 9^th percentile for weight (15.2 kg and 15.7 kg at the start and end of the follow-up period, respectively). Height was measured at the end of the study period only and this was also on the 9^th percentile (1.02 m). The protein substitute was well tolerated without gastrointestinal tolerability issues.

Discussion

The case study has had good control of her PKU according to current guidelines (van Wegberg et al., 2017) since the introduction of the newer amino acid substitute as the main protein substitute. Careful adjustment of overall protein intake is key to achieving such an outcome. Absorption of amino acids from the new protein substitute is prolonged relative to immediate-release amino acid mixtures and occurs over a time frame similar to absorption of amino acids from natural protein (Giarratana et al., 2018; Scheinin et al., 2020, 2021). This may avoid liberation of Phe from endogenous proteins catabolised for energy during fasting (MacDonald et al., 2020). The composition of this new product has been formulated to meet the nutritional needs of people with PKU within this age range during administration of the low-protein diet.

Her parents report that the battle to get her to take her protein substitutes no longer occurs, and that mealtimes are much more relaxed. The technology used in the manufacture of the protein substitute described here leads to masking of the smell and flavour of the amino acids, which likely helped here. A key to ensuring success and compliance with this product is to introduce the granules gradually, which may help to diminish food neophobia. The ability to add the newer amino acid substitute to food distinguishes it from other PKU protein substitutes available in the UK, which are either a powder made into a drink/paste, or a ready-to-drink pouch. The case study's parents experimented with different recipes for delivering the product: pasta sauce, stir fry, and smoothies were especially successful. These will have been unique to this child and each parent or guardian will need to explore how best to deliver the protein substitute to meet the needs and palate of their individual child, taking advantage of the flexibility provided by being able to add this protein substitute to favourite foods.

This report focuses on metabolic control in the short term (6 months) after the switch to protein substitute. The future diet prescription will be adjusted based on Phe levels, growth and age, with the goal of bringing her blood Phe levels more firmly under control. Indeed, establishing a proper growth trajectory will be key to longer term evaluation of its success. For now, getting the child to consume adequate calories within a formal PKU diet plan, without deterioration of weight status, is a major step forward for this family. Later, she may need to switch to an alternative formulation of the newer amino acid substitute designed for age 16 + years as this contains more protein equivalent (20 g) than the version for age 3–16 years described in this report (15 g protein equivalent), still enabling ingestion of a single sachet three-times-daily to meet her protein requirements as she grows. Future adjustment to the diet will include measures aimed at preventing episodes of low blood Tyr.

This case report illustrates the potential of a newer, prolonged release protein substitute to support adherence to the low-Phe diet for a child with PKU who rejected her previous protein substitute. This increased the quality of life for the patient and her family while maintaining good blood Phe control.