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Phenylketonuria is an inherited metabolic disorder that results in an increased blood concentration of the amino acid phenylalanine (1). It was the first inborn error of metabolism newborn screening test and was developed in the 1960’s (2, 3). Phenylketonuria is characterized by a deficiency in the enzyme phenylalanine hydroxylase that prevents phenylalanine from sufficiently being converted into tyrosine (1). Because phenylalanine cannot be converted, it accumulates in the blood and brain, becomes toxic, and results in cognitive impairment and mental retardation (1, 4). If phenylalanine levels are controlled from birth through childhood, intellectual disability does not occur (2, 3). When phenylalanine levels stay elevated, such as when patients go off the low-phenylalanine diet, adverse effects such as depression, anxiety, and phobias can occur (2). These can take a heavy toll and affect one’s education, the capability to make a living, and ability to return to metabolic control (2). Treatment for phenylketonuria is lifelong and consists of maintaining phenylalanine blood levels between 120 and 360 µmol/L (3). To achieve this, a low-phenylalanine diet and an amino acid-based medical formula that provides all necessary amino acids except for phenylalanine, macronutrients, and micronutrients needed for growth and development must be strictly followed (1).
Adhering to a low-phenylalanine diet can be very difficult for many reasons: lack of access of modified low protein foods, poor flavors of formulas and medical foods, cost, and the strictness of dietary protein intake (5). Due to these issues, many adults with phenylketonuria stop adhering to the diet, resulting in elevated blood levels of phenylalanine (3). These high levels can be detrimental as they cause executive function deficits and slow neurological processing speed, which can make it difficult for patients to count phenylalanine intake (5).
According to one study done by the National PKU Alliance (6), in which they surveyed its members to determine their current health status and interest in new phenylketonuria treatments, 51.7% reported having difficulty managing a phenylalanine restricted diet. Children in another study reviewing metabolic control (7) reported that they only sometimes adhere to the low phenylalanine diet due to its burden. Many parents also report that the most substantial issue they face when trying to help their child with phenylketonuria is managing the diet (8).
Not only do those with phenylketonuria have a difficult time adhering to the diet, but they also face other complications. Due to the strict diet, quality of life diminishes, and it is not uncommon for eating disorders to develop (9). One case-controlled study using insurance claims databases and health claims data (3) in which participants were grouped by age, found that those with phenylketonuria have more neuropsychiatric conditions, including eating disorders, intellectual disabilities, epilepsy, ADD/ADHD, OCD, and autism spectrum disorders, than those in the general population. This was true even after restricting the sample to younger adults, those aged 20-39 years, who had most likely been diagnosed at birth, were treated throughout childhood, and who had opportunities to continue treatment into adulthood (3). However, the youngest cohort, those aged 20-39 years, had a lower prevalence of the neuropsychiatric comorbidities than the older cohorts (3). These findings show why it is so essential for those with phenylketonuria to keep a low intake of phenylalanine in their diet: to live life with the least complications, patients need to continue treatment throughout life (3). In another study involving multiple centers (10), surveys were completed with phenylketonuria families to determine their attitudes towards the disorder as it has been found that the attitudes of patients and their caregivers determine if and how recommendations are followed (10). The researchers found that parents are reluctant to let their children choose their diet appropriate foods, which increased their feelings of shame and helplessness (10). Many adolescents also felt embarrassed due to having to follow a different diet than others (10).
Many people with phenylketonuria have difficulty tracking and adhering to the low phenylalanine diet (5). Instead of having to count phenylalanine from foods, they can use the Simplified Diet, which will also help maintain blood phenylalanine levels in the treatment range of 120 and 360 µmol/L (5). While this diet has previously been used in many clinics in the United States as the Low Protein Diet, others are now only starting to use it to help manage phenylketonuria (5). This diet allows patients with phenylketonuria to consume foods with low phenylalanine content without counting or tracking them and low protein foods that include less than 20 milligrams of phenylalanine per serving (5). It has been designed to help lessen the burden of phenylalanine counting, to increase flexibility, and to promote healthier foods (5).
In a cross-over study involving fourteen children aged 2 to 10 years (9), two groups were assigned to continue a diet either consisting of restricted consumption of fruits and vegetables or to start on a diet of free fruits and vegetables. These two groups then switched over to the other type of diet for an additional two weeks (9). Study results showed that those on the unrestricted fruits and vegetables diet did not increase their intake of fruits and vegetables (9). Instead, these participants used the amount of phenylalanine they usually count in fruits and vegetables to increase their consumption of other phenylalanine-containing foods such as potatoes, cereals, dairy products, meats, or sweets, increasing their total phenylalanine consumption by 58 mg per day (9). However, the free intake of fruits and vegetables did not have an impact on metabolic control (9). The unrestricted intake of fruits and vegetables is also expected to help prevent eating disorders as this is one food group that patients do not have to track (9).
In a different study involving the observation of nine patients with classical phenylketonuria over three years (11), patients were able to freely eat fruits and vegetables with a phenylalanine concentration of less than 75 mg. Results showed patients increased their phenylalanine tolerance and maintained good metabolic control despite having increased phenylalanine intake by an average of 83 mg from not having to count the amounts from fruits and vegetables (11). It is thought that the lower absorption of protein from the high fiber content of fruits and vegetables or the decreased bioavailability of amino acids from plant proteins are possible reasons for the consistently good metabolic control of patients despite their increased intakes of phenylalanine (11).
Another study involved 80 individuals with phenylketonuria in which 73 started the study on a classical phenylalanine-restricted diet and 7 started on a simplified diet (12). However, during the study 50 patients switched to the simplified diet while 23 remained on the classical restricted diet (12). This study investigated the effect of the simplified diet, or the intake of fruits and vegetables containing phenylalanine less than 100 mg/100 g, on blood phenylalanine levels over a period of three years (12). Results of the study indicated that intake of fruits and vegetables containing phenylalanine less than 100 mg/100 g had no adverse effects on blood phenylalanine levels in patients with phenylketonuria, regardless of the severity of the disorder or the age at which they switch their diet (12). These results increase the independence of the patients in choosing foods, can improve their quality of life, and provide evidence that the simplified diet is safe in the long-term for controlling phenylalanine blood levels (12).
In a different three-part, open, prospective crossover study conducted at the homes of 15 participants with either moderate or severe phenylketonuria (13), the free use of fruits and vegetables containing differing amounts of phenylalanine was studied: 0-50 mg/100 g, 51-75 mg/100 g, and 76-100 mg/100 g. Results found that participants increased their daily intake of phenylalanine by 51 mg during weeks 4-8 and 39 mg during weeks 9-15 (13). However, this unrestricted consumption of fruits and vegetables containing phenylalanine 51 – 100 mg/100 g did not adversely affect metabolic control (13).
There is growing evidence that a simplified diet can drastically improve phenylketonuria patients’ lives by simplifying their eating habits, allowing them to include more nutrients from fruits and vegetables, and by providing them with more options to eat foods containing small amounts of protein. These diet changes will hopefully increase the compliance of phenylketonuria patients and help them keep their blood phenylalanine levels within treatment range throughout their lives.
Patients with poor compliance who have elevated phenylalanine levels and are solely counting phenylalanine levels of food, when switched to a simplified diet, will improve their compliance and lower their phenylalanine blood levels within treatment range, or 120 and 360 µmol/L.
For this study evaluating the efficacy of switching to a simplified diet for improving compliance and blood phenylalanine levels in patients with phenylketonuria, participants will be recruited from the LeBonheur Children’s Hospital Genetics Clinic in Memphis, TN, from January 2019 to April 2019. This clinic sees patients who have inborn errors of metabolism, including phenylketonuria, maple syrup urine disease, medium chain acyl-CoA dehydrogenase deficiency, and urea cycle disorders, and assists families in managing disorders that are treated using medications and diet (14).
Patients with phenylketonuria visit the clinic in order to have blood work drawn so their phenylalanine and tyrosine levels can be monitored, and how often they visit is determined by their resulting blood phenylalanine levels, severity of disease, and their age. Because it is imperative that infants maintain their phenylalanine levels within the treatment range of 120 to 360 µmol/L (or 2.0 to 6.0 mg/dL), they must visit the clinic frequently, and this can be as often as once weekly. Older children, however, tend to have appointments once every two weeks, monthly, or every few months, and adults, depending on their phenylalanine levels and interest in attending clinic visits, may only visit the clinic yearly.
Every time patients visit the clinic, they are asked to bring a 3-day food record that includes all foods and drinks consumed over the last three days and the amount of each, whether items are measured using scales, fluid ounces, household measurements, or an estimation of any of these, such as using their hand to show how much was eaten. The patients are mailed a detailed letter including information from their appointment, food record, lab data, recommendations by the dietitian, and a 3-day food record recording sheet after every visit to the clinic in which they can use to record their intakes. However, if a patient forgets to bring the food record to the appointment, the dietitians will ask the patient to email or fax it to the office, and they will also ask for a 24-hour food and drink recall. 3-day food records tend to be very detailed, and a 24-hour recall tends to provide inadequate detailed information needed to accurately assess nutrition intake. Food records represent how a patient typically eats and are analyzed in a web-based nutrient analysis software program called MetabolicPro for different information depending on the metabolic disorder (15). MetabolicPro breaks down the amino acid content, energy, macronutrients, and micronutrients of each food and drink entered into the system (15). However, MetabolicPro does not have an extensive list of foods or drinks, and not every item on a patient’s food record may be found in the program. This causes the dietitian to have to manipulate MetabolicPro items to correctly match the food record items in nutritional value or the phenylalanine or protein levels patients may have recorded on their food records to try to be as accurate as possible. For phenylketonuria, food records are analyzed for the patients’ intake of phenylalanine, tyrosine, protein, and calories. The food records allow the dietitians to see how well patients have been following their diet prescriptions, which consist of the daily amount of phenylalanine or natural protein a patient is allowed. If phenylalanine levels come back significantly raised, the food records will be examined to determine if a patient is eating too much phenylalanine or protein or if something else might be going on, such as an illness the patient is suffering from. The patient will then be counseled on any changes they might need to make to their diet, and the patient will be asked to return to the clinic within the next couple of weeks for a recheck.
Criteria for participation in this study include a diagnosis of phenylketonuria or hyperphenylalaninemia, the ability to switch from counting phenylalanine daily to a simplified diet, the ability to either send in blood samples or to have blood drawn from LeBonheur’s outpatient clinic at least once each month depending on age from January to April, and a 3-day food record completed three days before each blood sample is taken. At each visit serum levels of phenylalanine will be measured. Because patients’ levels of phenylalanine will increase if sick, they will have to have labs drawn when they are healthy. If a patient is sick during their scheduled visit, then they will have to reschedule or have labs drawn again when they are no longer sick. Patients will be excluded if they do not comply with their daily protein allowance on the simplified diet.
Patients who are eighteen years and older and the legal guardians of patients younger than eighteen or of patients who have intellectual disabilities will be called to discuss if they would be interested in switching over to the simplified diet to participate in this study. If interested, they will come in for an appointment to go over the simplified diet in detail.
The two most recent food records and their analyses in MetabolicPro, the diet prescription, and the progress note written by the dietitian of patients deemed eligible for participation will be reviewed. Depending on the participants’ diagnosed severity, the significance of their phenylalanine levels, their previous diet prescriptions, and their ages, their allowed maximum protein consumption will be determined for the simplified diet. The participants will come in for a visit in either December or early January to discuss the simplified diet and everything it entails. Participants will be told how much protein they can eat daily and that foods with low phenylalanine and protein content, such as fruits and vegetables, do not need to be counted. Participants will also be given a handout of low protein foods and a simplified diet booklet to assist them in switching over to the simplified diet. After this initial appointment, they will begin using the simplified diet.
Participants will be scheduled for their first appointment and blood work after beginning the simplified diet in January 2019. Participants will be called a week before their appointment to remind them to bring in their 3-day food record. They will come in at least once monthly depending on their age and phenylalanine levels, and they will see the dietitian each time to discuss any issues they might be having and to discuss their food record. After each appointment when lab values have been received, their phenylalanine, protein, tyrosine, and calorie levels will be assessed. If phenylalanine levels are not within the treatment range of 120 to 360 µmol/L (or 2.0 to 6.0 mg/dL), the participant will be called to discuss any changes they might need to make to ensure they are following the simplified diet appropriately. This information will be reinforced in the detailed letter sent home after every appointment and at the next appointment. The final collection period for this study will be in April 2019, and participants will also be asked the following questions to determine what they thought of the simplified diet:
- Was it easier to count phenylalanine levels or to follow the simplified diet?
- Do you think you are more likely to count phenylalanine levels in foods and drinks or follow the simplified diet on a daily basis?
- Would you prefer to stay on the simplified diet, or would you rather go back to counting phenylalanine levels? Why?
- What do you think of the simplified diet?
The outcome measures of this study will be determined using a linear regression model. Each participant will be evaluated individually based on their dietary intakes of protein and phenylalanine from the 3-day food record in relation to their phenylalanine serum levels. Independent Samples t Tests will also be used to compare patients’ two most recent lab values of phenylalanine levels against their first two lab values of phenylalanine levels after beginning the simplified diet. Linear regressions will be run through Excel using the XLSTAT add-on software, and the Independent Samples t Tests will be run through SPSS software.
The budget will consist of numerous items. Twenty low protein food handouts will be printed at 0.25¢ per handout for a total of $5, and twenty simplified diet booklets will be purchased at $5.00 per booklet for a total of $100. Both the low protein food handouts and the simplified diet booklets will be paid for by the University of Tennessee Medical Genetics Clinic. Patients traveling to appointments will receive mileage reimbursement from the National Organization for Rare Disorders (NORD) at 54.5¢ per mile. While this will vary depending on the patient, the average mileage is about twenty miles. Reimbursing twenty patients at 54.5¢ per mile for an average of twenty miles will cost a total of $218. While at each appointment, patients will also need to get blood work drawn, and these costs will be covered by the patients’ insurances or by NORD. Because patients’ food records will have to be analyzed through MetabolicPro, its annual membership cost, $150.00, must also be included in the budget. Because the dietitians involved in the patients’ care would be seeing these patients regularly regardless of the study, they will not be compensated extra for the purpose of this study.
NORD is an organization that provides the primary source of information and support for families who have rare diseases (16). They provide materials such as fact sheets, free webinars, and infographics to patients and caregivers to help them better understand and manage their disorders (16). They also assist patients with insurance premiums and co-pays, receiving medications and diagnostic testing, and traveling for consultations with disease specialists or clinical trials (16).
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- University of Tennessee Health Science Center. Newborn Screening and Inborn Errors of Metabolism Team. Internet: https://www.uthsc.edu/bcdd/services/clinical/metabolism.php (accessed 1 December 2018).
- Genetic Metabolic Dietitians International. MetabolicPro. Internet: https://www.metabolicpro.org/ (accessed 1 December 2018).
- National Organization for Rare Disorders. Patient and Caregiver Resource Center. Internet: https://rarediseases.org/for-patients-and-families/information-resources/patient-and-caregiver-resource-center/ (accessed 5 December 2018).
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