Guideline sources The following summarized guidelines for the evaluation and management of phenylketonuria are prepared by our editorial team based on guidelines from the American College of Obstetricians and Gynecologists (ACOG 2020), the European Society for Phenylketonuria and Allied Disorders (ESPKU 2017), the Genetic Metabolic Dietitians International (GMDI/SERC 2016), the American College of Medical Genetics (ACMG 2014), and the U.S. Preventive Services Task Force (USPSTF 2008). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Screening in newborns: As per ACMG 2014 guidelines: Obtain screening for phenylalanine hydroxylase deficiency in newborns by tandem mass spectrometry. E Recognize that a prenatal diagnosis of phenylalanine hydroxylase deficiency can only be established using deoxyRNA-based methods. E As per USPSTF 2008 guidelines, obtain screening for phenylketonuria in newborns. A https://web.pathway.md/diseases/recwbfqGToOKtkOUx 1/7 6/29/23, 11:09 PM Phenylketonuria Pathway 2. Diagnostic investigations Blood amino acid analysis: obtain quantitative blood amino acid measurement in newborns with positive screening results. E Pterin analysis: As per ESPKU 2017 guidelines, obtain measurement of blood or urine pterins and dihydropteridine reductase activity in dried blood spots to exclude tetrahydrobiopterin deficiencies in the differential diagnosis of patients with hyperphenylalaninemia of any degree. B As per ACMG 2014 guidelines, obtain additional testing, including analysis of pterin metabolism, to define the cause of hyperphenylalaninemia. E Genetic testing: Provide ongoing genetic counseling to patients with phenylalanine hydroxylase deficiency and their families. E Obtain PAH genotyping for improved therapy planning. E Mental health assessment: Recognize that: intelligence in patients with optimally treated phenylalanine hydroxylase deficiency is in the normal range but lower than sibling controls the incidence of nonintellectual psychological symptoms, especially impairment in executive function, is increased in phenylalanine hydroxylase deficiency the risk for neurocognitive or psychological symptoms in phenylalanine hydroxylase deficiency is related to the age of onset of therapy, lifelong phenylalanine levels, and adherence to treatment. E Show 2 more 3. Medical management Indications for treatment: As per ESPKU 2017 guidelines, consider classifying patients with phenylalanine hydroxylase deficiency as either not requiring treatment or requiring diet or tetrahydrobiopterin, or both, to maintain blood phenylalanine concentrations in the recommended range. C Show 4 more As per GMDI 2016 guidelines, initiate treatment in patients with phenylketonuria with blood phenylalanine levels > 360 mcmol/L. B As per ACMG 2014 guidelines, consider initiating treatment in patients with late or untreated phenylalanine hydroxylase deficiency. E Show 2 more Treatment targets: As per ESPKU 2017 guidelines: Set target phenylalanine concentrations of 120-360 mcmol/L in < 12 years old patients with phenylketonuria. B https://web.pathway.md/diseases/recwbfqGToOKtkOUx 2/7 6/29/23, 11:09 PM Phenylketonuria Pathway Set target phenylalanine concentrations of 120-600 mcmol/L in > 12 years old patients with phenylketonuria. B As per GMDI 2016 guidelines: Maintain lifelong blood phenylalanine level in the range of 120-360 mcmol/L. B Minimize elevation of blood phenylalanine levels during illness by treating the underlying illness, meeting protein and energy needs, and preventing dehydration and electrolyte imbalance. E As per ACMG 2014 guidelines, maintain a treated phenylalanine concentration in the range of 120-360 mcmol/L in all patients of all ages. E Tetrahydrobiopterin: As per GMDI 2016 guidelines, obtain a phenylalanine challenge to determine maximal dietary phenylalanine tolerance when sapropterin response brings blood phenylalanine to within control range, or to clarify a sapropterin response when historical blood phenylalanine is already within control range. B Show 2 more As per ACMG 2014 guidelines, consider initiating sapropterin to reduce phenylalanine levels in responsive patients with phenylalanine hydroxylase deficiency. E Show 2 more Combination therapy: As per GMDI 2016 guidelines, offer combined treatment with sapropterin (when indicated) and diet therapy to improve blood phenylalanine levels and/or clinical status, and develop individualized therapy plans to provide the best outcome. B As per ACMG 2014 guidelines, consider offering individualized combination therapies to facilitate improvement in blood phenylalanine levels. E 4. Nonpharmacologic interventions Protein and phenylalanine intake: adjust intact protein intake to meet the patient's recommended phenylalanine intake (for anabolism and maintaining an appropriate blood phenylalanine concentration). B Show 3 more Breast milk: Encourage the use of breast milk, when possible, either from direct breastfeeding or the use of expressed breast milk, as the source of phenylalanine (and intact protein) in infants. B Initiate gradual introduction of solid food to replace the equivalent amount of phenylalanine/intact protein in infant formula or breast milk when the infant is developmentally ready (usually at 4-6 months of age). B Medical foods: provide medical foods to meet recommended nutrient intake and achieve optimal adherence. Ensure that vitamin, mineral, energy, and/or fat intake is supplemented from other sources when choosing incomplete medical foods. B Show 2 more https://web.pathway.md/diseases/recwbfqGToOKtkOUx 3/7 6/29/23, 11:09 PM Phenylketonuria Pathway Tyrosine supplementation: administer supplemental tyrosine if blood tyrosine concentrations are consistently below the normal range. B Large neutral amino acid supplementation: consider administering large neutral amino acid supplementation in adult patients with phenylketonuria unable to achieve metabolic control with diet or other adjunctive therapy. C Show 2 more 5. Specific circumstances Pregnant patients (pre-pregnancy counseling): provide pre-pregnancy consultation with a maternal-fetal medicine specialist and genetic counseling, as well as ensure co-management with a metabolic geneticist or specialist involved in the patient's care, in all reproductive-aged patients with phenylalanine hydroxylase deficiency. Provide information on reproductive options and family planning as well as management of maternal phenylalanine hydroxylase deficiency before, during, and after pregnancy. E Pregnant patients, fetal assessment: As per ACOG 2020 guidelines: Obtain a detailed anatomic survey and fetal growth assessments for the detection of fetal anomalies and growth restriction in pregnant patients with phenylalanine hydroxylase deficiency. E Obtain fetal echocardiography to evaluate for congenital heart defects in pregnant patients with phenylalanine hydroxylase deficiency. E As per ACMG 2014 guidelines: Obtain close monitoring of fetal growth and assessment for fetal congenital heart defects by a high-risk obstetrics group in the routine prenatal care of patients with phenylketonuria, as elevated blood phenylalanine levels in the first 8-10 weeks of gestation are associated with an increased risk of congenital heart defects and poor fetal growth. E Recognize that there is a linear relationship between maternal phenylalanine levels > 360 mcmol/L throughout gestation and lower IQ of the developing fetus. E Pregnant patients, treatment targets: As per ACOG 2020 guidelines, achieve phenylalanine levels < 360 mcmol/L for at least 3 months before becoming pregnant and maintain at 120-360 mcmol/L during pregnancy. E As per ESPKU 2017 guidelines: Set target phenylalanine concentrations of 120-360 mcmol/L in pregnant patients treated for phenylketonuria. B Do not initiate treatment to lower blood phenylalanine before or during pregnancy in patients with untreated blood phenylalanine concentrations < 360 mcmol/L. D As per SERC/GMDI 2016 guidelines, maintain blood phenylalanine levels in the range of 120-360 mcmol/L before, during, and after pregnancy. B As per ACMG 2014 guidelines, achieve maternal phenylalanine levels < 360 mcmol/L before becoming pregnant as fetal development is optimal when maternal phenylalanine levels are < 360 mcmol/L before conception. E https://web.pathway.md/diseases/recwbfqGToOKtkOUx 4/7 6/29/23, 11:09 PM Phenylketonuria Pathway Pregnant patients, diet: As per ACOG 2020 guidelines, offer lifelong dietary restriction and therapy to improve the quality of life in patients with phenylalanine hydroxylase deficiency. E As per SERC/GMDI 2016 guidelines: Provide a diet meeting the nutritional needs of pregnancy and promoting adequate weight gain. B Facilitate access to psychosocial support as necessary to maintain dietary therapy in pregnancy. E Pregnant patients, large neutral amino acids: As per SERC/GMDI 2016 guidelines, avoid using large neutral amino acid monotherapy during pregnancy. D As per ACMG 2014 guidelines, do not use large neutral amino acids during pregnancy. D Pregnant patients, tetrahydrobiopterin: As per SERC/GMDI 2016 guidelines, consider initiating sapropterin during pregnancy on a case-by-case basis, especially in patients with mild-to-moderate forms of phenylketonuria unable to maintain blood phenylalanine levels in the recommended treatment range for pregnancy. E As per ACMG 2014 guidelines, consider initiating sapropterin (pregnancy category C) during pregnancy following a discussion of the benefit and risks to mother and fetus. E Pregnant patients, monitoring: As per ACOG 2020 guidelines, monitor pregnant patients with phenylalanine hydroxylase deficiency or hyperphenylalaninemia in consultation with physicians familiar with phenylalanine hydroxylase deficiency, with close follow-up with a metabolic geneticist and healthcare providers with experience in managing high-risk pregnancy. E As per SERC/GMDI 2016 guidelines, monitor weight gain, dietary intake, and biochemical parameters to ensure nutrient adequacy and metabolic control during pregnancy. B Pregnant patients (special circumstances): modify phenylketonuria therapy and collaborate with other caregivers to support the nutritional and metabolic needs of patients with multiple pregnancies, gestational diabetes, and other special circumstances. B Pregnant patients, postnatal care: As per ACOG 2020 guidelines, advise that breastfeeding is safe for infants born to patients with phenylalanine hydroxylase deficiency provided the infants do not have phenylalanine hydroxylase deficiency. E As per SERC/GMDI 2016 guidelines, encourage patients with phenylketonuria to maintain dietary therapy after pregnancy and to breastfeed their infants. B As per ACMG 2014 guidelines: Advise that patients with phenylalanine hydroxylase may safely breastfeed. E Encourage patients with phenylalanine hydroxylase deficiency to maintain a phenylalanine- restricted diet, including the use of medical foods, postpartum for optimal maternal/infant outcomes. E https://web.pathway.md/diseases/recwbfqGToOKtkOUx 5/7 6/29/23, 11:09 PM Phenylketonuria Pathway 6. Patient education General counseling: Encourage all patients to follow treatment recommendations throughout their lives, including patients who have relaxed their diet restrictions and patients who have never been treated. Recognize and address individual barriers impeding success. B Adopt clinic procedures enhancing adherence to the nutritional recommendations of "diet for life" by providing individualized educational strategies, referrals to appropriate social service and mental health professionals, age-appropriate group activities, and a plan for the transition from pediatric to adult clinical services. B 7. Follow-up and surveillance Serial clinical and laboratory assessment: As per ESPKU 2017 guidelines, obtain lifelong, systematic follow-up in specialized metabolic centers in all adult patients with phenylketonuria because of specific risks that might occur during adulthood. B Show 3 more As per GMDI 2016 guidelines, monitor dietary records to assess the adequacy of nutrient intake in supporting appropriate growth and nutritional status. Modify individual dietary recommendations and counseling to improve adherence if nutritional intake is suboptimal. B Show 5 more Clinical findings Symptoms Past medical history Abnormal behavior Attention deficit hyperactivity disorder Intellectual disability Autism spectrum disorder Learning difficulties in school Congenital heart disease Musty body odor Depression Musty breath odor Developmental delay Personality or behavioral changes Epilepsy Seizure Neurological exam Skin rash Social isolation Cognitive impairment Parkinsonism Past obstetric history Lab findings Recurrent miscarriages serum phenylalanine Integument exam serum phenylalanine-to- tyrosine ratio Hypopigmentation serum tyrosine Imaging findings https://web.pathway.md/diseases/recwbfqGToOKtkOUx 6/7 6/29/23, 11:09 PM Phenylketonuria Pathway Microcephaly Genetic testing References 1. Jerry Vockley, Hans C Andersson, Kevin M Antshel et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014 Feb;16 2 188 200. Open 2. Singh RH, Cunningham AC, Mofidi S et al. Updated, web-based nutrition management guideline for PKU An evidence and consensus based approach. Mol Genet Metab. 2016 Jun;118 2 72 83. Open 3. ACOG Committee. Management of Women With Phenylalanine Hydroxylase Deficiency Phenylketonuria): ACOG Committee Opinion, Number 802. Obstet Gynecol. 2020 Apr;135 4):e167- e170. Open 4. Francjan J van Spronsen, Annemiek Mj van Wegberg, Kirsten Ahring et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. 2017 Sep;5 9 743 756. Open 5. US Preventive Services Task Force. Screening for phenylketonuria PKU US Preventive Services Task Force Reaffirmation recommendation. Ann Fam Med. 2008 Mar-Apr;6 2 166. Open https://web.pathway.md/diseases/recwbfqGToOKtkOUx 7/7