Phenylketonuria (PKU) is a single-gene disorder that was discovered in 1934 when a Norwegian dentist, Asbjörn Folling noticed an odor in the urine of his two intellectually disabled children. He assumed correctly that the odor was related to the disorder so he had their urine analyzed. High levels of phenyl pyruvic acid were found in both samples. Eventually, Folling discovered other intellectually disabled children who had abnormally high levels of urinary phenyl pyruvic acid and so he concluded that this subpopulation of intellectually disabled children suffered from the same disorder. Aside from intellectual disability, other symptoms of PKU include vomiting, seizures, hyperactivity, irritability, and brain damage (Strisciuglio & Concolino, 2014). The pattern of transmission of PKU through the family trees of the afflicted individuals indicates that it is a single gene mutation. There is a general estimated low incidence rate of PKU in a population so a small number of people in a population are likely to carry the PKU gene. Since, this gene is recessive, PKU develops only in homozygous individuals- which are individuals who inherited the PKU gene from both their father and mother. The biochemistry of PKU turned out to be reasonably straightforward and seems correct. This is because it is discovered that PKU homozygotes lack phenylalanine hydroxylase, an enzyme required for the conversion of the amino acid phenylalanine to tyrosine. As a result, the phenylalanine accumulates in the body and so, the levels of dopamine, a neurotransmitter normally synthesized from tyrosine becomes low. The consequence is an abnormal brain development. Similar to other behavioral traits, the behavioral symptoms of PKU result from interactions between genetic and environmental factors especially the interaction between the PKU gene and diet (Rohde et al., 2014). This is where Rohde and his companions came together and conducted a research to see the relationship of the PKU gene with diet including fruits and vegetables.
Objective of the Research
According to the article, the objective of the research was to investigate the micronutrient supply in Phenylketonuria (PKU) patients on a relaxed diet. PKU is one of the most common inborn metabolic disorders caused by a deficient activity of phenylalanine hydroxylase in most tissues predominantly in the liver. Children with untreated PKU suffer from severe physical and mental disability. Postnatal diagnosis through newborn screening shows that immediate initiation of a lifelong phenylalanine (Phe) restricted diet alongside a supplementation of a phenylalanine-free amino-acid mixture (AAM) could result in a normal cognitive development. Individual daily phenylalanine tolerance depends on the residual phenylalanine hydroxylase activity and so varies significantly between patients. The necessary AAM dosage depends on the individual Phe tolerance, age and body weight. In order to account for the metabolic imbalances and potential absorption deficiencies of amino acids from the AAM, it is generally suggested to provide an additional surplus of about 20% of the recommended protein supply. In order to also avoid micronutrient deficiencies, as the patients’ choice of natural food is sure to be limited, the AAM contains significant amounts of vitamins, minerals and trace elements. Patients with a mild course of the disease who follow a relaxed diet would get only a small amount of AAM. Consequently, these patients are at a risk of insufficient micronutrient supply.
Subjects and Method
The subjects were sixty-seven patients in number between the ages of 6-45 years with a phenylalanine tolerance of 600mg/day. From a 3-day diet record, protein supply as well as consumption of essential amino acids and several micronutrients were assessed and compared with the current recommendations and data for the healthy population. Anthropometric data such as weight, height, body mass index of the patients was collected. The patients were asked to give a detailed 3-day diet record including all food, beverages and the AAM. From the records, nutritional analysis was performed according to age, body weight and gender. In order to analyze the micronutrient intake and its relationship to PKU, the patients were divided to two groups: Group 1 which represents patients who do not use AAM in this research while Group 2 were patients receiving AAM. Group 2 was further divided to two subgroups according to their calculated total protein intake: Group 2a with more than 120% protein intake while Group 2b with less than 120% protein intake of the recommendations.
When analyzing the data below, patients with sufficient micronutrient supply appeared to consume protein from an AAM at a dose of 0.05 per kg body weight or more. To test the hypothesis, the supply with micronutrients according to this threshold was calculated and indeed, patients with a protein intake from AAM of at least 0.5kg per kg body weight showed significantly higher intake of vitamin D, calcium, iron, iodine, folic acid, vitamin B1, B2 and B12 than the patients with a protein intake of less than 0.5g from AAM per kg body weight. Also, the supply of micronutrients exceeded the recommendations in those patients with at least 0.5g protein per kg body weight from AAM and vice versa. However, these patients showed a significantly better supply of micronutrients compared to patients who consumed no AAM.
The Table and Figure with explanations
The protein and Phe intake of the different groups are shown in the table below. Total protein intake was not significantly different for groups 1 and 2. However, Phe intake was significantly lower in group 2 illustrating the patients’ need for protein intake with AAM.
This table illustrates the protein and Phe supply of PKU patients on a relaxed diet, grouping according to total protein supply and AAM intake.
In the figure below, despite a sufficient supply of protein and essential amino acids, group 1 showed an insufficient supply with all investigated micronutrients, as compared with the current recommendations except B12. In general, patients in group 1 consumed small amounts of all micronutrients. In group 2, the intake of most micronutrients exceeded the current recommendations. Further analysis shows that between the group 2 subdivisions, group 2a was sufficiently provided with all micronutrients. Differences between children and adults could not be detected. Generally, the micronutrient supply correlated with protein intake from AAM in g per kg body weight.
In contrast, group 2b had an insufficient supply of most micronutrients. However, the differences were not significantly different except for vitamin B12 when compared with the recommendations. There were similarly no differences between children and adults. A positive correlation between the intake of protein from AAM in g per kg body weight and the intake of micronutrients could be detected for most micronutrients. Between groups 2a and 2b, 2a had a higher intake of all micronutrients except for vitamin C and zinc. This was especially significant in vitamin D, calcium, iron, iodine, folic acid, vitamin B1, B2 and B12.
A PKU patient following a relaxed diet is a patient who is not strictly following the procedures recommended by the doctor in order to live a healthy life. From the patients in the research, diet records from three consecutive days were analyzed to evaluate the mean supply of protein, essential amino acids and several micronutrients. The intake of the essential micronutrients exceeded the current recommendations in all the patients which was independent of any AAM intake. In contrast, the supply of micronutrient was determined by the dietary regime. It is common in PKU treatment to provide 120% of the protein supply recommended for healthy children to avoid potential metabolic imbalances and provide sufficient micronutrients. However, based on the research, it is false. Patients not consuming any AAM were insufficiently supplied with micronutrients regardless of a protein supply 150% over the recommendations. Patients also receiving less than 120% of the recommended protein intake and less than 0.5g protein per kg body weight from AAM are at risk of micronutrient deficiencies and vice versa. Patients with tetrahydrobiopterin (BH4)- sensitive PKU undergoing the relatively new and successful cofactor therapy with tetrahydrobiopterin (BH4) will be at a risk of continuous micronutrient deficiencies with long-term consequences especially because of the expected number of PKU patients on a relaxed diet without AAM in the coming years. These eating habits develop during childhood and remain stable throughout life. This is where specialized dieticians play an important role in the care of a PKU patient. This is because ending the AAM supplement needs careful consideration, dedicated dietary counselling and close follow-up as lack of AAM as seen in the research, means deficiency in protein, vitamin C. calcium and vitamin D which are important for the well-being any PKU patient. However, vitamin B12 shows adequate supply irrespective of AAM intake and so it is an unreliable indicator for this research yet it is still recommended for PKU patients. In conclusion, a daily routine of detailed records of food intake in addition to follow-up visits to the hospital with nutritional counselling and supplementing deficient components could at least temporarily help a relaxed diet PKU patient live a reasonably healthy life.
• Rohde, C., Mütze, U., Schulz, S., Thiele, A. G., Ceglarek, U., et al. (2014). “Unrestricted fruits and vegetables in the PKU diet”: A 1-year follow-up. European Journal of Clinical Nutrition, 68, 401–403.
• Rohde, C., et al. “PKU patients on a relaxed diet may be at risk for micronutrient deficiencies.” European journal of clinical nutrition 68.1 (2014): 119.
• Strisciuglio, P., & Concolino, D. (2014). New strategies for the treatment of phenylketonuria (PKU). Metabolites, 4, 1007–1017.