Abstract
The effectiveness of a phenylalanine-restricted diet to improve the outcome of individuals with phenylalanine hydroxylase deficiency (OMIM no. 261600) has been recognized since the first patients were treated 60 years ago. However, the treatment regime is complex, costly, and often difficult to maintain for the long term. Improvements and refinements in the diet for phenylalanine hydroxylase deficiency have been made over the years, and adjunctive therapies have proven to be successful for certain patients. Yet evidence-based guidelines for managing phenylalanine hydroxylase deficiency, optimizing outcomes, and addressing all available therapies are lacking. Thus, recommendations for nutrition management were developed using evidence from peer-reviewed publications, gray literature, and consensus surveys. The areas investigated included choice of appropriate medical foods, integration of adjunctive therapies, treatment during pregnancy, monitoring of nutritional and clinical markers, prevention of nutrient deficiencies, providing of access to care, and compliance strategies. This process has not only provided assessment and refinement of current nutrition management and monitoring recommendations but also charted a direction for future studies. This document serves as a companion to the concurrently published American College of Medical Genetics and Genomics guideline for the medical treatment of phenylalanine hydroxylase deficiency.
Genet Med 16 2, 121–131.
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Main
Nutrition therapy, first introduced 6 decades ago, remains the primary treatment for phenylalanine hydroxylase (PAH) deficiency.1,2,3 The goals of lifelong nutrition therapy include normal physical growth and neurocognitive development, maintenance of adult health, and normal gestational outcomes in pregnant women with PAH deficiency. Knowledge of metabolism, the pathophysiology of PAH deficiency, and the role of nutrition has led to new and improved treatment options, modified low-protein foods, and medical foods that provide protein equivalents and other nutrients when intact protein food sources must be limited. Table 1 contains definitions of modalities used in the nutrition treatment of aminoacidopathies, including PAH deficiency. Lifelong treatment is recommended because of the negative association between elevated blood phenylalanine (PHE) and neurocognition, yet national nutrition recommendations for PAH deficiency are lacking. The goals of the present evidence- and consensus-based recommendations are to translate current knowledge to patient care, foster more harmonious clinical practices, and promote healthy eating, with the ultimate goal of ensuring better outcomes for individuals with PAH deficiency. This document serves as a companion to the concurrently published American College of Medical Genetics and Genomics (ACMG) guideline for the medical treatment of PAH deficiency.4
Materials and Methods
Recommendations were developed by a cooperative effort among Genetic Metabolic Dietitians International, the Southeast Regional Genetics Collaborative, and dietitians from the Diet Control and Management and Maternal PKU Workgroups from the National Institutes of Health Phenylketonuria Scientific Review Conference2 held in February 2012. The evidence for these recommendations represents the synthesis of information from the National Institutes of Health 2000 (ref. 2) and Agency for Healthcare Research and Quality 2012 (ref. 1) reviews and the literature review completed by the National Institutes of Health Phenylketonuria Scientific Review Conference workgroups. PubMed was the primary database for the National Institutes of Health Phenylketonuria Scientific Review Conference scientific literature searches. Search terms were specific to each question (as described in the ACMG guideline4), but inclusion and exclusion criteria were the same for all questions.
Consensus-based tools used to support these recommendations were the National Institutes of Health expert panel summary (described in the companion paper), a PAH Deficiency Delphi survey,5 and an Inborn Errors of Metabolism (IEM) survey (D.M. Frazier, S.C. van Calcar, et al., personal communication). The Delphi process is a component of the guideline development model that uses accepted methods for evidence analysis, with the addition of consensus techniques to address clinical practice issues for which research is lacking.6 The Delphi survey, an online survey in which participants indicated their level of agreement or disagreement with practice statements, was answered by 17 experts from the seven Health Resources and Services Administration Regional Genetics and Newborn Screening Collaboratives. When the level of agreement was 80% or greater, the information was added to the evidence summaries in these recommendations. The IEM survey, also online, was conducted following the National Institutes of Health–sponsored Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism Workshop that was held in December 2011. Information about the use of nutritional treatments and supplements by metabolic specialists managing individuals with PAH deficiency was collected from 82 survey respondents.
Blood PHE and Tyrosine (TYR) Control
Target blood PHE
Blood PHE has been used to monitor metabolic status and determine appropriate dietary PHE intake and has been shown to be a reliable predictor of clinical outcomes.7 The companion ACMG PAH deficiency treatment guideline supports a lifelong target blood PHE of 120–360 µmol/l for optimal cognitive outcome.4 Eighty percent of Delphi respondents supported 120–360 µmol/l as a goal blood PHE for individuals with PAH deficiency of all ages, yet there was recognition that the goal is difficult to achieve and may not apply in all cases.5 Regular blood PHE monitoring is key to the management of PAH deficiency. During infancy, early childhood, and pregnancy, more frequent monitoring is necessary to assess the increased dietary PHE needs of anabolism3 ( Table 2 ). The British Medical Research Council guidelines recommend measuring PHE concentrations at a standard time3; there was a consensus that blood samples be collected at the same time of day, preferably 2–3 hours after a meal.5 It is recommended that medical food be consumed throughout the day to maintain stable concentrations of blood PHE.8
Target blood TYR and PHE:TYR ratio
Because both endogenous production of TYR and intact protein intake are greatly limited in PAH deficiency, monitoring is necessary to ensure that supplementation is adequate to maintain the blood TYR in the normal range. Some clinicians routinely monitor blood PHE:TYR ratios.9 There are reports of impairments in executive function among individuals with high PHE:TYR ratios.9,10 However, at this time the clinical relevance of PHE:TYR as a routine biomarker requires further study.
Recommendations
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Maintain blood PHE between 120 and 360 μmol/l throughout the life span for optimal outcome.
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Monitor blood PHE most frequently during times of increased anabolism: infancy, childhood, and pregnancy.
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Monitor blood PHE at a consistent time during the day, preferably 2–3 hours after eating.
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Maintain blood TYR in the normal range.
The Influence of Genotype on Nutrition Treatment
As described in the ACMG guideline,4 individuals with PAH deficiency have been categorized by phenotype (PHE tolerance and blood PHE concentrations) and genotype.4 PHE tolerance is defined as the amount of dietary PHE (mg/day) an individual with PAH deficiency can consume while maintaining blood PHE in the treatment range.11 Although individuals with PAH deficiency are represented by a spectrum of residual enzyme activity, some practitioners find practical utility in referring to the older categories: “classic/severe,” “moderate,” “mild,” and “mild hyperphenylalaninemia not needing PHE restriction.”
Treatment by phenotype and PHE tolerance
In clinical practice, PHE tolerance can often be determined by 2–5 years of age.12 However, because PHE tolerance can change during periods of rapid growth or changes in lifestyle, it is important to reassess PHE tolerance periodically by assessing dietary PHE intake with blood PHE.11,13 Predicting PHE tolerance may be useful when communicating expectations to families, assessing responsiveness to adjunctive therapy,14 and planning dietary prescriptions.
Those with little residual PAH activity (“classic PKU”) will require the most medical food as their primary source of protein equivalents.15 Modified low-protein foods should be introduced early to meet critical energy needs and maintain metabolic control in this group. For individuals with mild or moderate PAH deficiency, less medical food and/or modified low-protein food is needed to maintain blood PHE control.16 Such individuals are also more likely to respond to sapropterin, which has the potential for allowing liberalization of the diet. The need to treat individuals with very mild hyperphenylalaninemia remains under debate.17
Even with classification by genotype or phenotype, additional factors can affect the management of PAH deficiency. Individualized treatment plans must reflect the patient’s unique genetic makeup, general health, intercurrent illness, growth requirements, activity level, pregnancy/lactation status, and access to care.
Nutrient Requirements, Sources, and Monitoring
Nutrient requirements for individuals with PAH deficiency do not differ from those of the general population, except for PHE, TYR, and protein ( Table 3 ).3,18,19,20 Concern about the nutritional adequacy of the diet arises because the severe restriction of foods containing intact protein necessitates lifelong reliance on semisynthetic medical foods, from which some nutrients may not be as well absorbed. In addition, nonadherence to medical food consumption, or reliance on nutritionally incomplete medical foods, increases the risk of multiple nutrient deficiencies. Therefore, monitoring of nutrient intake and laboratory indexes of nutritional adequacy is recommended ( Table 2 ).
Protein and amino acids
Because medical food is the primary source of protein equivalents in the diet for PAH deficiency, it is a critical component of the diet throughout life. Recommendations for total protein intake exceed age- and sex-specific Dietary Reference Intakes because l-amino acids found in most medical foods are absorbed and oxidized more rapidly than amino acids in intact protein.21,22 Traditionally, l-amino acids (without PHE) have been the source of protein equivalents in medical foods, but more recently, glycomacropeptide (GMP), an intact protein that is low in PHE, has been used as a protein source in combination with limiting l-amino acids.23 l-Amino acid–based or GMP-based medical foods provide ~85% of the protein needs of individuals with a severe form of PAH deficiency.24 Large neutral amino acids (LNAAs) can also be used as the medical food for some individuals with PAH deficiency in conjunction with a more relaxed protein restriction.
Normal protein status, assessed by monitoring plasma amino acids and prealbumin, is achievable when total protein is provided in appropriate amounts.18,21 Prealbumin is an acceptable measure of protein status in individuals with PAH deficiency.25 Mild protein insufficiency, as indicated by a prealbumin concentration of <20 mg/dl, has been associated with decreased linear growth.26
TYR is conditionally essential in PAH deficiency and must be added to the diet to maintain blood concentrations in the normal range. By itself, TYR supplementation does not improve neurological outcomes.27 All medical foods for the treatment of PAH deficiency are supplemented with TYR;15 therefore, individuals who do not adhere to their prescribed intake of medical food may have inadequate blood concentrations of TYR. In addition, TYR has a low solubility and may settle out of prepared medical foods during storage.15 Most clinicians monitor blood TYR routinely in individuals with PAH deficiency,9 and low plasma TYR has been documented among individuals treated with diet.28 One cause could be a diurnal variation in blood TYR.29 Supplementation beyond that provided by medical food with TYR is indicated only if blood TYR concentrations are consistently below the normal range. Fewer than 20% of clinicians in the IEM survey (D.M. Frazier, S.C. van Calcar, et al., personal communication) routinely prescribe TYR supplementation.
Energy
Because energy expenditure varies from person to person, energy requirements must be individually assessed. Most evidence suggests that energy requirements are not increased in PAH deficiency, and carbohydrate and fat intakes are within established recommendations.30,31
Essential fatty acids
With adequate fat intake, children with PAH deficiency are found to have normal essential fatty acid (EFA) status.32 Medical foods supplemented with sources of long-chain polyunsaturated fatty acids increase blood concentrations of EFA.33 When a fat-free medical food is provided or the diet contains inadequate sources of linoleic and α-linolenic acid, EFA status should be monitored.5 Both the IEM survey (D.M. Frazier, S.C. van Calcar, et al., personal communication) and the Delphi survey5 suggest that supplementation with precursor EFA, or with preformed docosahexaenoic acid (DHA), may be necessary in these individuals. In infancy, including breast milk or standard formulas containing DHA and arachidonic acid, as well as medical foods that contain DHA/arachidonic acid, can help ensure adequacy.
Micronutrients
Most medical foods available in the United States are supplemented with vitamins and minerals to provide micronutrients in amounts that meet recommendations. When a medical food does not contain adequate amounts of micronutrients or an individual’s intake is inadequate, a vitamin and mineral supplement should be included in the treatment plan. Additional biochemical monitoring ( Table 2 ) is indicated when there is a question about inadequate or excessive intake.
Minerals, including copper, manganese, and zinc,34 as well as selenium,35 have been reported as being deficient in the diet for PAH deficiency. However, these minerals are now added to most medical foods. Iron deficiency (without anemia) has been reported among individuals with PAH deficiency, and routine evaluation of iron status is recommended.36,37
Vitamin B12, as well as B6, deficiency may occur if there is inadequate consumption of medical food or animal protein.38 Severe megaloblastic anemia has been reported in adolescents and adults with PAH deficiency who are off-diet.39 Because B12 deficiency can cause neurological deficits,40 including memory loss, such symptoms could be erroneously attributed to high blood PHE. Supplementation is indicated if B12 markers remain low.40 In addition, higher than normal plasma B12 levels have been reported in some on-diet individuals with PAH deficiency.41 Both excessive and inadequate intakes of the fat-soluble vitamins A and D are possible with inappropriate medical food intake. Monitoring for clinical signs with subsequent biochemical testing is warranted.
There may be concerns with bone density that are unique to PAH deficiency. Decreased bone mineral density and bone mineral content, indicated by dual-energy X-ray absorptiometry, have been noted.42,43 Osteopenia, defined as bone mineral density one or more SDs from normal reference for age and sex, is also seen44 but cannot be attributed to vitamin D concentrations alone. Some reports indicate that bone density is associated with adherence to nutrition therapy,45 whereas others note decreased density across groups, stratified by calcium and phosphorus intakes42 and/or as compared with controls without PAH deficiency.43 Aberrant findings in protein markers, correlating to bone resorption or absorption, have also been reported.46,47 Further research is warranted to look at the effects of PAH deficiency itself, PAH deficiency management, and nutrient intake on bone density.
Anthropometrics
With adequate nutrient intake, appropriate growth can be expected for individuals with PAH deficiency.18,19 Impaired linear growth has been noted in children with PAH deficiency who had low plasma prealbumin concentrations.26 There is conflicting evidence as to whether or not the rates of overweight and obesity in children with PAH deficiency are similar to those of the general population.30,48
Clinical indicators
Physical findings associated with poorly controlled PAH deficiency include osteopenia45 and dermatological problems.49 Asthma, recurrent headache, eczema, neurological signs, hyperactivity, and/or lethargy have all been reported in adults with PAH deficiency who discontinued dietary treatment.50 Psychological symptoms include phobias and depression.51 The majority of physical signs and symptoms of PAH deficiency reported in the literature resolved when blood PHE concentrations were reduced to the treatment range.
Recommendations
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Provide the same nutrient intakes as those of the general population, except for PHE, TYR, and protein.
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Assess the need for vitamin/mineral supplementation when a medical food without complete vitamins and minerals is used or when there is insufficient adherence with medical food intake.
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Monitor nutrition status by assessing anthropometrics, clinical signs and symptoms, nutrient intake, and laboratory indexes of metabolic control and nutrition adequacy ( Table 2 ).
Nutrition Strategies for Management of Individuals with PAH Deficiency
Selecting medical food
Medical foods provide necessary protein equivalents in the diets of individuals with PAH deficiency, and selecting the appropriate medical food can affect both dietary compliance and nutritional status. There are more than 30 medical foods available for the treatment of PAH deficiency, and they can be classified by the age for which they are intended and by macronutrient composition ( Table 4 ). Infant medical foods typically lack only PHE. Products designed for children, adolescents, and adults vary widely in protein, fat, vitamin, and mineral content to meet individual taste and nutrient needs, but many are nutritionally incomplete. The macro- and micronutrient profiles of many medical foods for IEM are available at http://www.gmdi.org. Medical food should be consumed throughout the day and divided into at least three servings because more frequent consumption of medical foods is associated with better PHE tolerance13 and improved plasma PHE concentrations.8
Medical foods are available in a variety of flavors and in different forms (i.e., powders, ready-to-drink liquids, tablets, and bars). Convenience packaging and alternative forms of medical foods typically cost more than the powdered forms. Although insurance coverage of medical foods is mandated in some states, there are exceptions and limitations. Therefore, access to medical food is not guaranteed in the United States, and obtaining coverage can be an arduous process.52 This is due, in part, to the fact that medical foods are not prescription medications but have a unique classification by the Food and Drug Administration that was intended to promote the development of more products for PAH deficiency and other orphan diseases.53 The classification allows a less costly regulatory process necessary to get medical foods to market.
Glycomacropeptide
GMP is an intact whey protein low in PHE, TYR, histidine, leucine, tryptophan, and arginine. All except PHE must be added as free l-amino acids to provide an appropriate protein source for PAH deficiency.54 Although long-term efficacy and growth studies are lacking, a short-term inpatient study found no safety concerns when GMP products replaced amino acid–based medical food.54 Various markers pointed to improved protein utilization,54 and lower ghrelin concentrations suggested improved satiety when GMP products replaced each subject’s usual amino acid–based medical food as the protein source.55 Medical food products incorporating GMP are an alternative to PHE-free amino acid formulas. Because GMP contains a small amount of PHE (2–5 mg PHE per gram of protein),54 the allowance of PHE from food may need to be reduced to maintain PHE intake within PHE tolerance limits.23
Large neutral amino acids
The theory behind LNAA use as a medical food is described in the ACMG guideline.4 LNAAs are not recommended for young children or pregnant women but should be considered for adults with PAH deficiency who are not in good metabolic control and do not adhere to other treatment options.5 LNAA therapy has been shown to improve executive function in some adults.56 When using LNAAs, 25–30% of total protein needs are provided by LNAAs, with the remaining 70–75% coming from dietary protein sources.57 Protein intake and plasma amino acids should be monitored to prevent essential amino acid deficiencies. It is difficult to monitor the success of LNAA therapy because blood PHE remains high, and measurement of PHE concentration in the brain is impractical. Blood and urine melatonin have been suggested as surrogate markers for serotonin and may be useful in monitoring treatment.58 Serotonin has been shown to be deficient in individuals with PAH deficiency who exhibit executive function defects.58
Providing dietary PHE
Because PHE is an essential amino acid, limited amounts from intact protein must be provided for anabolic processes regardless of the medical food chosen. For infants, the source of PHE can be either breast milk59 or infant formula (containing DHA/arachidonic acid). A variety of strategies for introducing breast milk have been described.59 Although there is little consensus about the best way to incorporate breast milk into the diet of an infant with PAH deficiency, there is agreement that feeding at the breast, as well as feeding expressed breast milk by bottle, results in good metabolic control.60 Later in the first year, breast milk or infant formula is slowly removed in exchange for limited amounts of intact protein from solid foods containing an equivalent amount of PHE.
Tracking dietary PHE
There is little consensus about the best method for tracking dietary PHE intake. As long as data are available on the PHE content of individual food items, the most precise method of tracking PHE intake is counting milligrams of PHE. An exchange system (1 exchange = 15 mg PHE) is easier for some patients and families. Those with higher PHE tolerance may be able to achieve good PHE control by counting grams of protein. This has the advantage of allowing the use of food labels as a guide. A more liberal approach of allowing “free” consumption of fruits, vegetables, and low-PHE foods (<100 mg PHE/100 g) allows for similar blood PHE control to that of other tracking methods.61 This system has been used by clinics in Europe with good success but is not common practice in the United States.5
Modified low-protein foods
Individuals with severe forms of PAH deficiency and low PHE tolerance often rely on modified low-protein foods to provide energy and variety in their diets.15 Modified low-protein foods, including low-protein breads and pasta, use the starch portion of the grain rather than the higher-protein flour.62 It is important to note that these products do not have the usual vitamin enrichment found in regular grain products. As a source of energy, these products can help to prevent weight loss, catabolism, and the resulting elevated blood PHE.15 Third-party reimbursement for modified low-protein foods is not universally available.52
Sapropterin (tetrahydrobiopterin) therapy
Sapropterin dihydrochloride (sapropterin) is the pharmaceutical form of tetrahydrobiopterin, a cofactor required for PAH activity. Given in therapeutic doses, sapropterin appears to enhance PAH activity in certain individuals with PAH deficiency.63 The ACMG PAH deficiency guideline recommends a trial of sapropterin therapy for all individuals.4 The benefits of response fall into two categories: for individuals who are nonadherent or unable to maintain diet restriction and medical food intake, sapropterin may lower blood PHE without further diet modification; and for individuals who maintain blood PHE within the therapeutic range by dietary adherence, sapropterin may allow liberalization of dietary PHE and less medical food intake.64
Although sapropterin therapy may support significant dietary liberalization, it seldom allows individuals to maintain appropriate blood PHE without some PHE restriction and medical food. Regular monitoring of blood PHE, dietary adequacy, and nutritional status continue to be essential. Individualized patient counseling includes planning and calculating the diet with a higher PHE or protein allowance, choosing appropriate natural protein sources, reading labels, distributing high-PHE/intact protein foods throughout the day, meeting micronutrient/vitamin requirements when the medical food prescription is decreased, and understanding the importance of consistent sapropterin dosing.65,66 Longer-term follow-up will be necessary to determine whether individuals with PAH deficiency remain adherent to sapropterin and dietary recommendations and if there is an impact on outcome.
Nutrition counseling and education
Nutrition counseling and education involve teaching individuals with PAH deficiency and/or their caregivers the importance of the diet in maintaining appropriate blood PHE, normal growth, and health maintenance while ensuring that they have the necessary skills to adhere to the diet throughout the life span. Education techniques and materials must be appropriate for the individual’s learning style,67 access to care, acceptance of the diet, and/or readiness for change. Research into effective education and counseling strategies for PAH deficiency is lacking.
Recommendations
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Evaluate individual nutritional needs, ability to adhere to recommendations, and access to treatment options when choosing appropriate interventions (medical food, modified low-protein food, sapropterin, and LNAAs) to achieve blood PHE in the target range.
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Provide counseling and education specific to the needs of the individual with PAH deficiency (and/or his/her caregivers) to help maintain appropriate blood PHE throughout the life span.
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Recommend that medical food be consumed throughout the day for optimal metabolic control.
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Include breast milk and/or infant formula as sources of PHE in the diet of an infant with PAH deficiency.
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Track PHE intake by any of several methods, including counting milligrams or exchanges of PHE or grams of protein.
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Consider use of LNAAs in adults with PAH deficiency who are not in good metabolic control and not able to adhere to other treatment options.
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Individualize the diets of responders to sapropterin with appropriate PHE, medical foods, or modified low-protein food intake and/or vitamin/mineral supplementation to ensure adequate nutrient intake.
Treatment in Special Circumstances
Pregnancy in women with PAH deficiency
High maternal blood PHE is associated with poor outcomes in offspring, including low birth weight, microcephaly, congenital heart defects, and intellectual disability. Maintaining maternal blood PHE between 120 and 360 μmol/l before and during pregnancy results in the best outcome for offspring.2 However, 30% of clinics surveyed recommend 120–240 μmol/l as the target range for maternal blood PHE.5
Most studies have not evaluated the effect of nutrition (beyond maternal blood PHE) on outcomes. In the Maternal PKU Collaborative Study, maternal protein intake and energy were significantly and negatively correlated with blood PHE throughout the entire pregnancy.68 Women with low protein intake secondary to inadequate consumption of medical food also had low overall nutrient intake and a higher incidence of congenital anomalies in their offspring.69 Adequate energy and fat intake, as well as adequate weight gain, have all been associated with better pregnancy outcomes.68 Control of nausea and vomiting, especially in early pregnancy, is key to preventing catabolic weight loss and elevated PHE levels. Neither TYR intake nor blood TYR has been reported to be associated with outcomes in maternal PAH deficiency.70 Fat and essential fatty acid intakes may be very low in individuals with PAH deficiency when their medical food contains no fat. DHA supplementation of 200–300 mg/day should be provided to all pregnant women with PAH deficiency.5 Specific monitoring recommendations during pregnancy for women with PAH deficiency are outlined in Table 2 . The use of adjunctive therapies in managing blood PHE during pregnancy is a matter of debate. LNAA monotherapy is not recommended, because it does not result in adequate control of blood PHE. Because sapropterin can lower blood PHE, its use should be considered on a case-by-case basis.5 Women are encouraged to continue the diet in the postpartum period and can breast-feed their non–PAH-deficient infant regardless of maternal blood PHE levels.
Recommendations
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Maintain blood PHE between 120 and 360 μmol/l before conception and throughout pregnancy.
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Monitor dietary intake of pregnant women with PAH deficiency to ensure nutrient adequacy.
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Consider sapropterin use on a case-by-case basis for pregnant women who have difficulty adhering to the diet.
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Do not recommend LNAAs for use in pregnant women with PAH deficiency.
Sick days and catabolism
Infection, inflammation, and injury induce a catabolic state, with increased endogenous protein breakdown and impaired anabolism. For individuals with PAH deficiency, this can lead to increased blood PHE; however, there are no published data, nor is there consensus regarding “sick day” management. Specialized parenteral nutrition solutions have been used when adequate enteral intake is not possible.71
Late-treated PAH deficiency
Improvements in behavior and functioning have been documented in previously untreated individuals with PAH deficiency who have been placed on diet therapy.72,73 In children for whom therapy was delayed, improvement in IQ may occur after nutrition therapy is initiated.72,73 Choice of treatment modality should be based on feasibility and effectiveness for the individual patient. Among the concerns are comorbidities, contraindications due to prescribed medications, and limited access to care.
Psychosocial Support
Treatment for PAH deficiency is complex, and adherence to recommendations diminishes with age.74 The companion ACMG PAH deficiency treatment guideline4 discusses the problems and challenges faced by individuals with PAH deficiency as they transition into adulthood.4 Adherence improves if individuals have a social support system; an understanding of the benefits of treatment; access to appropriate care, medical foods and modified low-protein foods; and a belief that PAH deficiency is manageable.75 Special support and advocacy are frequently necessary to secure access to the medical foods required by individuals with PAH deficiency.2,51 Creative approaches for clinic- and community-based programs, such as age-specific educational programs, camps, and other support programs, hold promise for improving adherence and quality of life.
Recommendations
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Ensure access to medical and modified low-protein foods.
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Provide connections to sources of social support, such as camps, mentoring programs, and other support groups.
Conclusion
Nutrition management of PAH deficiency has resulted in remarkable outcomes for individuals who have benefitted from early diagnosis and treatment. These positive outcomes are the sum of dedicated research, clinical attentiveness, and patient adherence. Although much has been learned about providing proper nutrition on a PHE-restricted diet, many aspects of diet and health in individuals with PAH deficiency require further investigation. These include issues such as adequacy of absorption of nutrients from medical foods, bone density, weight status, long-term neurocognitive outcomes, and oxidative stress, as well as the roles of less available nutrients (e.g., menaquinone and vitamin K2) and functional nonnutrients (e.g., nucleosides, nucleotides, pre- and probiotics, and polyphenolic compounds). How to balance nutrition management with other treatments, such as LNAAs, sapropterin, and PEGylated phenylalanine lyase, and the impact of genotype on treatment are still being explored. Continued research should also examine approaches that promote adherence to therapy. The health-care system must ensure that individuals with PAH deficiency have access to the care necessary for optimal outcomes.
These recommendations for the nutrition management of individuals with PAH deficiency reflect the latest in scientific understanding and clinical practice. The workgroup is continuing, with evidence and consensus methodology, to develop comprehensive nutritional management guidelines, resources, and tools for PAH deficiency that will be made available on the Genetic Metabolic Dietitians International and the Southeast Regional Genetics Collaborative websites.
Disclosure
R.H.S., F.R., A.C., S.C.V.C., and J.V. have participated in and/or received research funding for clinical trials related to PAH deficiency. A.C. has participated in and received research funding for studies related to PAH deficiency and is a consultant for and serves on advisory boards for BioMarin Pharmaceuticals and Merck and Company. S.M. serves on the advisory board for the PKU Demographics, Outcomes and Safety Registry (PKUDOS) sapropterin postmarketing patient registry and is a consultant dietitian for BioMarin. The other authors declare no conflict of interest.
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Acknowledgements
We gratefully acknowledge the National Institutes of Health (NIH) for convening the PKU Scientific Review Conference, the contributions of the members of the Diet Control and Management and Maternal PKU Workgroups, and the guidance provided by the NIH Office of Dietary Supplements. We acknowledge members of the Genetic Metabolic Dietitians International PKU Guideline Development Workgroup who provided their expertise in nutrition management of PAH deficiency for this article. Finally, we acknowledge Teresa Douglas and Kathryn Coakley for their assistance in editing. This work was partially supported by a grant from the Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services (grant H46- MC24090).
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Singh, R., Rohr, F., Frazier, D. et al. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med 16, 121–131 (2014). https://doi.org/10.1038/gim.2013.179
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DOI: https://doi.org/10.1038/gim.2013.179
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