Phenylalanine hydroxylase (PAH)

595862CANXXX10.1177/1941406415595862Infant, Child, & Adolescent NutritionInfant, Child, & Adolescent Nutrition research-articlexxxx ICAN: Infant, Child, & Adolescent Nutrition October 2015 Evidence Based Practice Reports Phenylalanine Hydroxylase Deficiency Hospitalizations A Novel Approach to Nutritional Management Emily Barr, MS, RD, CSP, Mary Sowa, MS, RD, CSP, CNSC, Monica Boyer, RN, MSN, CPNP, and Richard Chang, MD Abstract: Phenylalanine hydroxylase (PAH) deficiency is a metabolic disorder that requires lifelong diet adherence for optimal neurodevelopmental and psychological outcomes. Maintaining phenylalanine (Phe) levels within the desired range (120-360 µmol/l) can be increasingly difficult as children grow older, gain more autonomy, and are affected by social influences. After exhausting outpatient intervention measures with 5 patients with severe PAH deficiency, hospitalization was pursued. Phe levels rapidly decreased in all cases. Despite the inability for 3 of the 5 patients to maintain optimal dietary adherence after hospitalization, the information gained regarding the patients protein tolerance was invaluable. Our clinic has found this approach to be a useful tool in the ongoing management of patients with PAH deficiency and will continue to consider hospitalization for our patients who are failing outpatient management. Keywords: phenylalanine hydroxylase deficiency; dietary adherence; hospitalization; protein tolerance; blood phenylalanine levels Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU), is a rare inborn error of metabolism affecting phenylalanine (Phe) metabolism. Patients with PAH deficiency have an impaired ability to convert Phe to tyrosine (Tyr), which results in elevated blood Phe levels and decreased synthesis of Tyr. Elevated Phe is neurotoxic as evidenced by magnetic resonance imaging findings (white matter changes), which have been attributed to elevated and variable Phe levels over time. 1,2 The natural history of untreated PAH deficiency includes mental retardation, seizures, behavioral problems, stunted growth, eczema, microcephaly, and a musty odor. 3 Newborn screening (NBS) has allowed for early identification and treatment of patients with PAH deficiency and has changed the natural history of this disorder. Severe intellectual disability can be avoided when blood Phe levels are well controlled in infancy and early childhood; however, a relaxed diet later in life corresponds with poor clinical outcomes including impaired executive functioning, increased impulsivity, suboptimal school performance, and Newborn screening (NBS) has allowed for early identification and treatment of patients with PAH [phenylalanine hydroxylase] deficiency and has changed the natural history of this disorder. psychiatric symptoms (anxiety, depression, and phobias). 1,4 Maternal PAH deficiency presents additional challenges during pregnancy. It has been reported that approximately 65% of PAH-deficient mothers are not under good metabolic control prior to conception and therefore expose their fetus to the teratogenic effects of elevated Phe (mental retardation, microcephaly, congenital heart disease, intrauterine growth restriction). 4 Theoretically, the treatment plan for PAH deficiency is not complicated; but in DOI: 10.1177/1941406415595862. From CHOC Children s, Orange, California. Address correspondence to Emily Barr, MS, RD, CSP, CHOC Children s, 1201 W La Veta Ave, Orange, CA 92868; e-mail: ebarr@choc.org. For reprints and permissions queries, please visit SAGE s Web site at http://www.sagepub.com/journalspermissions.nav. Copyright 2015 The Author(s) 262

vol. 7 no. 5 ICAN: Infant, Child, & Adolescent Nutrition Table 1. NBS Screening and Recall. Patient State NBS Program Initial Phe Recall Phe 1 Oklahoma 723 1244 2 California 412 1273 3 California 412 806 4 California 432 841 5 Washington Abbreviations: NBS, newborn screening; Phe, phenylalanine. a Results (umol/l). practice, it is challenging and requires a lifelong special diet. Phe intake is limited in the diet, and a supplemental metabolic formula (containing Phe-free protein) is required to prevent nutritional deficiencies. The lifelong task of dietary adherence with the goal of maintaining Phe levels within the optimal range (120-360 µmol/l) is difficult, especially for individuals with severe forms of PAH deficiency that result in low Phe tolerance. 4 Some of the challenges that affect diet compliance include increased time for food preparation, availability of low-protein foods, lack of variety in diet, family stressors, and the parent s education level. 5-7 Often, there is a decline in treatment adherence as patients approach school age and adolescence. During this time, adolescents have to contend with peer pressure and deal with diet fatigue as they struggle in their march to autonomy. 1,4 Throughout a patient s lifetime, fluctuations along the spectrum of adherence to noncompliance are often the norm rather than the exception. 5 There are a number of strategies that have been recommended to improve adherence. 5 Education that is individualized for the patient has been shown to improve knowledge and Phe levels. 8 Other successful strategies include the use of simplified diet plans, convenient food choices, and transfer of a diet responsibility to encourage autonomy in the emerging adolescent. 5 Methods Although hospitalization is not routinely used for patients with PAH deficiency, it has been previously reported. 9 In our clinic, we have advocated for inpatient hospitalization for 5 nonadherent or noncompliant patients with severe PAH deficiency who have markedly elevated Phe levels (>600 µmol/l) for an extended period of time. Authorization for a 3- to 7-day inpatient hospitalization is requested for the primary purpose of establishing Phe control, quantifying protein tolerance, extensive nutrition counseling, and, in a select group of patients, to evaluate response to pharmacotherapy (Kuvan). Patient 1 Patient 1 transferred to our clinic at 16 months of age. His NBS results were consistent with severe PAH deficiency 1 (Table 1). He was followed in the metabolic clinic routinely until 7 years of age at which time he was admitted to the hospital due to elevated Phe levels and maternal reports of formula nonadherence. During his hospitalization, the Phe prescription was estimated as the patient s Phe tolerance was unknown. 10 The patient was prescribed a low-protein diet order of 5 grams of protein per day a from foods and metabolic formula providing 45 grams of Phe-free protein per day (Table 2). Strategies were put in place to improve the patient s formula compliance and extensive diet education was provided (Tables 3 and 4). Patients 2 and 3 Patients 2 and 3 are siblings that were identified by the NBS Program with elevated Phe levels found to be consistent with severe PAH deficiency 1 (Table 1). They were followed by another metabolic center before transferring to our clinic at 14 years and 11 years of age, respectively. The patients had monthly Phe levels obtained and were seen in clinic every 2 months, but the patients report of Phe intake and diet records were not consistent with Phe results. The mean Phe levels for the 6 months prior to admit were 1064 µmol/l for patient 2 and 795 µmol/l for patient 3. After 1 year of failed outpatient interventions including findings of deficits in neuropsychological testing and white matter changes on magnetic resonance imaging, the patients were admitted. The focus of the admission was extensive diet education to increase autonomy (Table 4) and assessment of protein tolerance. The patients were prescribed 8 grams of protein per day from foods and 50 grams of Phe-free protein from metabolic formula 10 (Table 2). A 3-day menu was developed with the patients input, and low-protein specialty foods were ordered prior to admission (Tables 3 and 5). Patient 4 Patient 4 was identified by the NBS Program with elevated Phe levels found to be consistent with severe PAH deficiency 1 (Table 1). She was followed intermittently by 2 metabolic centers, and then transferred to our clinic at 11 years of age. Similar to patients 2 and 3, the patient had a history of poor treatment compliance, and her reported diet history was incongruent with measured Phe levels. The patient s mother attributed elevated Phe levels to multiple caregivers (parents divorced), lack of 263

ICAN: Infant, Child, & Adolescent Nutrition October 2015 Table 2. Admission Diet Orders a. Patient Age (Gender) (yrs) Weight (kg) Metabolic Formula (kcals) Phe-Free Protein (g) Tyrosine (g) Protein From Foods (g) 1 7 4/12 (male) 45.1 480 45 5.2 5 2 15 11/12 (male) 69.4 785 50 5.4 8 3 12 9/12 (female) 51.6 785 50 5.4 8 4 13 2/12 (female) 57 583 45 4.6 8 5 11 3/12 (female) 29 628 40 4.8 10 Abbreviation: Phe, phenylalanine. a All patients took metabolic formula divided into 3 servings per day. Table 3. Hospitalization Strategies. Patient Strategies 1 Sticker chart to reinforce completion of formula and nutrition activities Egg timer to assist with finishing formula in goal time of 15 minutes Included grandparents in education session as they were found to be preparing majority of food 2 and 3 Admission over winter break Shared room for siblings Patients made formula in room and stored in refrigerator 3-Day menu was developed with patient prior to admission 4 All caregivers present for admission (mom, dad, grandma, and neighbor) Favorite foods brought from home for meals and education sessions 5 Daily education directed to patient to increase ownership/responsibilities of diet management All patients Meal planning with patient/family prior to admission Consulted Psychology and Child Life Full access to play room and teen room Daily schedule provided to organize day and optimize mealtimes, formula consumption, teaching opportunities and laboratory testing Provided basket of free foods to snack on between meals supervision, and diet fatigue. Patient was noted to have anxiety, but did not follow-up with psychology as recommended. She was also noted to be a non-responder to Kuvan. After 2 years of suboptimal treatment compliance and elevated Phe levels at our center, we were contacted by the patient s school with concerns of declining school performance (drop in full scale IQ from 90 to 68), and a hospital admission was expedited to rapidly reduce Phe levels and determine the patient s protein tolerance. 264

vol. 7 no. 5 ICAN: Infant, Child, & Adolescent Nutrition Table 4. Low-Protein Diet Education Strategies. Patient Low-Protein Diet Prescription Education Strategies 1 5 grams protein per day General phenylketonuria (PKU) diet/formula importance Measuring foods and liquids Reading food labels Keeping food records 2 and 3 8 grams protein per day Counting grams of protein Meal planning/review of nutrition lessons taught throughout the week Estimating portion sizes for all foods Favorite foods and meal planning Transition of care model 11 4 4 grams protein per day and free fruits and vegetables Estimate actual protein intake ~7 grams protein per day Simplified method of counting extrapolated from the USDA MyPlate 12 (Figure 5) Counting grams of protein in all foods, except fruits and vegetables* *Exceptions potatoes, corn, green beans, and peas 5 10 grams protein per day Reviewed education similar to patient 1 During the hospitalization, the patient was prescribed 8 grams of protein per day from foods and 45 grams of Phe-free protein from metabolic formula 10 (Table 2). A simplified diet education plan was implemented. Patient 5 Patient 5 was identified and diagnosed with PAH deficiency by NBS. Her care was transferred to our metabolic center at the age of 5 years. The patient initially did well and was able to maintain Phe levels within the desired treatment range on a protein-restricted diet. As the patient entered preadolescence, her Phe control was suboptimal, and a Kuvan trial was proposed. At 11 years of age, the patient was electively admitted for a Kuvan trial in a controlled hospital setting where a validated treatment response could be obtained. Orders for a low-protein diet of 10 grams per day and metabolic formula providing 40 grams of Phe-free protein per day were placed (Table 2). A protein-free supplement was also ordered to provide additional calories to improve her weight and body mass index status. Diet education was provided throughout the admission, with the goals of increasing the patient s autonomy (Tables 3 and 4). Results Patient 1 had Phe levels collected on admission and daily throughout his stay. The Phe results from day 1 and day 2 represented a Phe reduction of 57%, validating the estimated protein prescription (Figure 1). After discharge, Phe levels initially remained within the desired treatment range, but within 2 months the Phe levels began trending upward (averaging 522.6 µmol/l). At that time it was found that the family was experiencing significant social upheaval and the grandparents were emergently responsible for the patient s meal preparation, but had not received thorough education. Therefore, the patient was readmitted and the grandparents were educated on his diet. Figure 1 includes the results of the second admission, where desirable Phe levels were achieved and maintained for 6 months. The Phe levels for patients 2 and 3 decreased daily during their inpatient stay, confirming that the protein prescription of 8 grams per day was appropriate (Figure 2). At the time of discharge, patient 2 had a Phe level of 425 µmol/l, which increased to 1570 µmol/l 1 week after discharge. Similarly, patient 3 had a Phe level of 230 µmol/l at discharge, which 265

ICAN: Infant, Child, & Adolescent Nutrition October 2015 Table 5. Sample Daily Hospital Menu for Patients 2 and 3. Breakfast increased to 918 µmol/l 1 week after discharge. Both patients were unable to maintain Phe levels within the desired treatment range after hospitalization and continued with poor metabolic control for the next 6 months (Figure 2). Patient 4 Phe levels demonstrated a 36% reduction (Table 3 and 4). Phe levels remained above the desired treatment range at the time of discharge (Figure 3), and the patient s protein prescription was further reduced to 7 grams per day on the day of discharge. 2.3 Grams Protein Maddy s Crackels 2 cups 0.4 Cantaloupe 1/2 cup 0.7 Oranges 1 (cut in wedges) 1.2 Apple juice 4 oz 0 Lunch Grilled cheese sandwich 2.5 Grams Protein Low protein bread 2 slices 0.2 Low protein cheese 2 slices 0.8 Grapes 1½ cups 0.9 Strawberries 1/2 cup 0.5 Gatorade 1 0 Low-protein sugar cookie 3 0.1 Dinner Spaghetti 3.1 Grams Protein Low-protein pasta 62 grams (dry) 0.8 Tomato sauce 2 tbsp 1 Tossed green salad 1 cup 0.6 Ranch salad dressing 2 tbsp 0.4 7-up 0 Low-protein brownie 0.3 After discharge, Phe levels were obtained frequently for 3 months and demonstrated another 39% decrease, eventually achieving the desired treatment range (Figure 3). Patient was then lost to follow-up. Patient 5 demonstrated a good response to Kuvan with a 95% reduction in Phe levels from hospital day 1 to day 7, and the patient was able to increase her protein intake by 20% over the following month. Post hospitalization, Phe levels were monitored frequently over 6 months and stayed within the desired treatment range (Figure 4). Discussion Prior to their elective hospital admissions, our patients had struggled with diet adherence and had not achieved optimal metabolic control for quite some time. During their admissions, the controlled hospital environment allowed for strict dietary compliance, which enabled us to accurately quantify the patient s protein tolerance and demonstrate improved Phe levels in all of our patients. With patient 1, we also identified the need for the extended family to be involved in the patient s nutrition education and new strategies were implemented to ensure formula compliance at home. For patients 2, 3, and 4, the hospital goals focused on increasing autonomy and a simplified protein counting system to improve patient knowledge and adherence. An obvious shortfall of their hospitalization was the inability to maintain optimal Phe levels outside the hospital environment. For patient 5, we determined that she was a Kuvan responder and we were able to increase her protein prescription. Opting for an elective hospitalization is a difficult decision to make for patients with metabolic disorders that have poor diet adherence. However, an inpatient admission allows for focused, uninterrupted patient education that is often not available in the outpatient clinic setting. Additionally, despite the inability for all patients to maintain optimal dietary adherence post hospitalization, the information gained regarding the patient s protein tolerance was invaluable for present treatment and could potentially aid in the critical dietary management with maternal PAH deficiency. Our clinic has found this approach to be a useful tool to achieve the aforementioned goals and will continue to be considered for our patients with PAH deficiency who are failing outpatient management. 266

vol. 7 no. 5 ICAN: Infant, Child, & Adolescent Nutrition Figure 1. Patient 1 s Phenylalanine (Phe) Levels for Average 6 Months Prior to Admission (6 mo PA), Hospital Days (HD) 1 to 5 During First Admission, Between Admissions (BA), HD 1 to 4 During Second Admission, and 6 Months After Discharge (6 mo AD). 1200 Phe Levels (umol/l) 1000 1010 800 721.7 600 580 522.6 400 383 364 200 227 117 243 234 276 183.6 0 6 mo PA (n=23) HD1 HD2 HD3 HD4 HD5 BA (n=6) HD1 HD2 HD3 HD4 6 mo AD (n=10) Figure 2. Phenylalanine (Phe) Levels for Patients 2 and 3 Average 6 Months Prior to Admission (6 mo PA), Hospital Days (HD) 1 to 4, and Average 6 Months After Discharge (6 mo AD). Phe Levels (umol/l) 1200 1000 1064 1086 894 800 795 600 664 569 Pa ent 2 400 200 437 314 422 425 250 230 Pa ent 3 0 6 mo PA (n=8) HD1 HD2 HD3 HD4 6 mo AD (n=7) 267

ICAN: Infant, Child, & Adolescent Nutrition October 2015 Figure 3. Patient 4 s Phenylalanine (Phe) Levels 2 Year Average (2 yr avg) Prior to Hospitalization, During Each Hospital Day (HD) During Admission and then Post Hospitalization Discharge Days (DC). 1200 Phe Levels (umol/l) 1000 800 600 993 1010 896 777 647 703 618 400 502 449 200 251 0 2 yr avg (n=7) HD1 HD2 HD3 HD4 DC1 DC2 DC3 DC6 DC16 Figure 4. Patient 5 s Phenylalanine (Phe) Levels for Average 6 Months Prior to Admission (6 mo PA), Response to Kuvan Initiation (Hospital Days [HD] 1 to 7), and Phe Level 6 Months After Discharge (6 mo AD) Post Kuvan Initiation. 1400 Phe Levels (umol/l) 1200 1170 1000 1020 800 758 600 400 200 0 6 mo PA (n=26) 569.3 622 HD1 HD2 HD3 HD4 HD5 HD6 HD7 6 mo AD (n=23) 435 145 59 316.2 268

vol. 7 no. 5 ICAN: Infant, Child, & Adolescent Nutrition Figure 5. Metabolic Vegetarian Plate Adapted From USDA myplate.gov 12. Author Note The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article. References 1. Vockley J, Andersson H, Antshel K, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16:188-200. 2. Hood A, Antenor-Dorsey J, Rutlin J, et al. Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria. Mol Genet Metab. 2015;114:19-24. 3. Walter J, Lachmann R, Burgard P. Hyperphenylalanemia. In: Saudubray J, Berghe G, Walter J, eds. Inborn Metabolic Diseases. 5th ed. New York, NY: Springer; 2012:252-264. 4. Singh R, Rohr F, Frazier D, et al. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16:121-131. 5. MacDonald A, Gokmen-Ozel H, Rinj MN, Burgard P. The reality of dietary compliance in the management of phenylketonuria. J Inherit Metab Dis. 2010;33:665-670. 6. Cotugno G, Nicolo R, Cappelletti S, Goffredo BM, Dionisi Vici C, Di Ciommo V. Adherence to diet and quality of life in patients with phenylketonuria. Acta Paediatr. 2011;100:1144-1149. 7. Bilginsoy C, Waitzman N, Leonard C, Ernst S. Living with phenylketonuria: Perspectives of patients and their families. J Inherit Metab Dis. 2005;28:639-649. 8. Gleason L, Michals K, Matalon R, Langenberg P, Kamath S. A treatment program for adolescents with phenylketonuria. Clin Pediatr (Phila). 1992;31:331-335. 9. Duran G, Rohr F, Slonim A, Guttler F, Levy H. Necessity of complete intake of phenylalanine-free amino acid mixture for metabolic control of phenylketonuria. J Am Diet Assoc. 1999;99:1559-1563. 10. Acosta P, Yannicelli S. Protocol 1-phenylketonuria (PKU). In: Acosta P, Yannicelli S, eds. The Ross Metabolic Formula System, Nutrition Support Protocols. 4th ed. Columbus, OH: Ross Products/Abbott Laboratories; 2001:1-32. 11. Cristine M. Trahms Program for Phenylketonuria Seattle. PKU selfmanagement timeline. http://depts. washington.edu/pku/resources/timeline. html Copyright 2008. Accessed December 12, 2014. 12. US Department of Agriculture. MyPlate. http://www.choosemyplate.gov/about. html. Published June 2, 2011. Accessed May 18, 2013. 269