Appendix 7Dietary Treatment for Phenylketonuria

1. Current Dietary Treatment

Dietary restriction of phenylalanine (Phe) has been the mainstay of treatment for PKU in Canada for more than 40 years, since the introduction of neonatal screening for the disease. Two recent new treatment strategies are now in limited use;³¹ large neutral amino acids (LNAA) and tetrahydrobiopterin (BH₄). However, they are not targeted to the whole patient population, and are often used as an adjunct to dietary treatment.

2. Goals of Dietary Treatment

a)

To maintain plasma Phe concentrations within the recommended treatment ranges²⁷ by:

• Controlled restriction of natural protein intake:

  • Exclusion of high-protein foods (e.g., meat, fish, poultry, eggs, milk, most dairy products, nuts, soy, and legumes) from the diet.
  • Daily allowance of dietary Phe from measured quantities of lower protein foods (e.g., cereals, vegetables, and fruit), allowed within Phe tolerance.

    –

    Phe tolerance varies widely from individual to individual, depending on the variant of PKU,³² and in the same individual, depending on age,³³ adequacy of energy, protein intakes, and state of health.

• Supplementation of the diet with a medical food (i.e., synthetic protein consisting of Phe-free L-amino acids, and additional nutrients).

  • The optimal dose of medical food has not been determined, but it usually provides 52% to 80% of total dietary protein.³⁴
  • Consumption of protein substitute should be evenly spread throughout the day to optimize protein utilization for anabolism, and to control plasma Phe concentrations.³⁵
  • The distribution and dosage of the protein supplement are probably the most important determinants of plasma Phe concentrations in individuals with PKU on diet.^36,37
  • Historically, patient compliance with protein substitutes is poor,³⁸ but palatability and presentation have improved in recent years. Many new novel protein substitutes have been introduced and short-term studies have demonstrated improved compliance.^39,40
  • Glycomacropeptide (GMP) can also be used as an alternative to synthetic amino acids as it is dietary protein that contains no Phe. It occurs naturally in the whey fraction of bovine milk; does not contain aromatic amino acids, Phe, tryptophan, and tyrosine; and contains concentrations that are higher in isoleucine and threonine. In general, GMP medical foods are acceptable as an alternative to the synthetic amino acid diets, and increase variety, satiety, and palatability.⁴¹
  • There is the potential for LNAA to help lower blood and brain Phe levels as they competitively inhibit (using the four L-system transporters) the transportation of Phe across the blood—brain barrier and intestinal mucosa. LNAA has been prescribed (either alone or in combination with the low-Phe diet) for adults who either cannot adhere to or have a hard time adhering to the Phe-restricted diets. However, evidence of its efficacy is lacking; therefore, additional research is required before its implementation in everyday practice.⁴¹

b)

To ensure that the diet meets requirements for Phe (an essential amino acid), total protein (natural plus synthetic), energy, fat, carbohydrate, and micronutrients (vitamins, minerals, trace elements, essential fatty acids):

• Provision of special low-protein foods (e.g., breads, pastas, baked goods, milk substitutes, cheese, vegetable burgers, scrambled egg mix, mashed potato mix), in order to meet energy requirement and/or relieve the monotony of the diet.
• Supplementation of the diet with micronutrients (e.g., vitamins, minerals, and trace elements) if the prescribed intake of medical food is not anticipated to meet estimated requirements.

c)

To support normal growth and development in children and optimal health (physical and mental) in adults

d)

To achieve micronutrient biochemical status that is ideal

e)

To ensure that the diet is palatable, flexible, and compatible with a modern-day lifestyle:

Despite continued improvements, the diet remains highly restrictive, socially and financially burdensome, and time-consuming to manage;⁴² hence, leading to poor adherence.

3. Dietary Adherence

Dietary adherence is determined by plasma Phe concentrations: patients are expected to provide routine blood samples for this purpose. However, in children older than 10 years, plasma Phe concentrations above the age-related treatment goals, and frequency of blood testing below recommendations, are the norm.^19,21

Patients often have to wait days to weeks to obtain the results of a blood Phe test. However, a portable Phe monitoring device (currently in development) has the potential to improve dietary adherence, by allowing patients to monitor blood Phe levels in real time.³¹

4. Harms of the Phe-Restricted Diet

a)

Deficiency of micronutrients (vitamins, minerals, trace elements):

• Vitamin B12 deficiency has been reported on a number of occasions and is most probably secondary to noncompliance with the medical food,⁴³ the only source of vitamin B12 in the diet (apart from a multivitamin and mineral supplement), if intake of high-protein foods of animal origin is avoided.
• Individuals with PKU are at risk for suboptimal plasma levels of iron, zinc, and vitamin A, despite adequate intake.⁴⁴

b)

Deficiency of essential fatty acids:

The diet, often low in fat and essential fatty acids (especially alpha-linolenic acid), puts children at risk of deficiencies in long-chain polyunsaturated fatty acids (LCPUFA),⁴⁵ especially in docosahexaenoic acid (DHA).⁴⁶

c)

Impaired growth in children:

There have been a number of reports of impaired growth, but this has not been a universal observation.⁴⁷

d)

Reduced bone mass:

Reduction in peak bone mass has been described in adults with PKU⁴⁸ but the etiology (diet and/or disease) has yet to be elucidated.

e)

Obesity:

• Children with PKU have been reported to be at risk of obesity, despite energy intakes that appeared to be less than recommended.⁴⁹
• Investigators have suggested that PKU patients with poor metabolic control may be subject to dysregulation of their neuroendocrine system, secondary to high plasma Phe levels.⁵⁰

5. Current Practices in Managing Phenylketonuria in Canada

There are approximately 21 treatment centres in Canada: three devoted to adults and the remainder to individuals of all ages. A survey of metabolic dietitians across Canada was conducted in 2009. The response rate of the survey was approximately 50%. Of the 10 centres that responded, two followed fewer than 20 patients, five between 20 and 50 patients, two between 51 and 100 patients, and one between 101 and 150 patients. Nine of the 10 centres reported that they each had about 20 patients who were inactive, and the remaining centre between 51 and 100 patients. Five of the nine centres reported that they attempt to maintain contact with inactive patients.

There is currently an initiative underway by a physician to try to achieve more comprehensive information than that which was collected in the above-mentioned 2009 survey. There was general agreement among the respondents of the survey in terms of the frequency with which patients are expected to attend clinic visits and to provide blood samples (to monitor Phe concentrations). The majority of the respondents (six out of nine) indicated that their patients had to visit the hospital to provide a blood draw: patients in the remaining centres (three out of nine responses) were able to send in blood spots. The majority of respondents (seven out of nine) indicated that their treatment centre does a BH₄ loading test, before initiation of diet therapy in an infant with a positive newborn screen for PKU.

On the contentious issue of whether diet therapy is indicated for mild hyperphenylalaninemia,⁵¹ six respondents (out of 10) indicated that their treatment centres initiate the Phe-restricted diet, if blood Phe concentration is more than 360 µmol/L, and another respondent if it is more than 240 µmol/L. The remaining three respondents (out of 10) indicated that their institutions do not initiate the Phe-restricted diet unless blood Phe concentration is more than 600 µmol/L; i.e., unless the newborn has PKU. In general, there was consensus among the 10 respondents regarding target blood Phe concentrations,²⁷ and they all indicated that their treatment centres recommend “diet for life.”