Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Phenylketonuria (PKU)
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Phenylalanine hydroxylase (PAH) deficiency has considerable geographic variation. Approximately 1 in 13,500 to 19,000 infants in the United States is born with PAH deficiency. The incidence of PAH deficiency varies based on ethnicity, with a higher prevalence among Native American and Caucasian individuals. It has an estimated an incidence of 1/10,000 live births in Europe with a higher rate in some countries (e.g., 1/4500 in Ireland). Prevalence is particularly high in Turkey, with estimates from 1/2600 to 1/4000.
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Clinical Features
(Signs / symptoms)
PAH deficiency is due to impaired activity of the hepatic enzyme PAH involved in the metabolism of the amino acid phenylalanine (PHE). This deficiency results in increased blood levels of PHE which is toxic to several tissues, particularly the brain. Clinical features of untreated PAH deficiency include: intellectual disability, developmental delay, stunted growth, microcephaly, epilepsy, a musty body odor, decreased skin and hair pigmentation, eczema, behavior problems, emotional disorders, and structural brain changes visible on MRI. Affected individuals also have decreased myelin formation and decreased dopamine, norepinephrine, and serotonin production. Further problems can emerge later in life and include exaggerated deep tendon reflexes, tremor, and paraplegia or hemiplegia, and osteopenia. PAH deficiency presents a spectrum of severity based on the degree of elevated PHE. The most severe cases have complete or near-complete deficiency of PAH activity. These cases are typically referred to as "classic phenylketonuria" or "classic PKU". Untreated, plasma PHE concentrations in classic PKU may be greater than 1200 μmol/L (mean normal level is 60umol/L) with a dietary PHE tolerance of less than 500 mg/day. Without dietary restriction of PHE, most children with classic PKU develop profound and irreversible intellectual disability. Cases that, when untreated, have blood PHE levels greater than normal but less than 1200 umol/L are typically referred to as having hyperphenylalaninemia (HPA). Individuals with HPA are at a much lower risk for cognitive and neuropsychological impairment in the absence of treatment. In addition to these terms, alternative classification schemes have been proposed. PHE is a potent teratogen, and elevated plasma PHE levels in pregnant women will result in a teratogenic syndrome in the offspring, even if the offspring do not have PAH deficiency. Maternal PKU syndrome can cause microcephaly, congenital heart defects, low birth weight, craniofacial abnormalities, and intellectual disability in the child.
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Natural History
(Important subgroups & survival / recovery)
Neonates with PAH deficiency show no physical signs. In the absence of neonatal diagnosis, symptoms develop within a few months of birth and may be very mild to severe. If left untreated, older children with PAH deficiency can develop clinical manifestations associated with PAH deficiency. However, with good control of PHE concentrations neonatally and during early childhood, most affected children have normal development measured at 5 years of age. Adults with classic PKU who had good control as children typically have normal intelligence or mild degrees of intellectual deficit. Historically, children diagnosed with PKU were allowed to relax the dietary restriction of PHE in adolescence. However, it is been demonstrated that increased PHE levels in adulthood have been associated with significant adverse neurocognitive and psychiatric problems, including anxiety, depression, phobias, and deficits in executive functioning.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with PAH deficiency, the following evaluations are recommended:
• Blood PHE concentration and PHE tolerance at the time of diagnosis to classify infants with HPA. The individual's diet should be tailored to calculate PHE tolerance irrespective of genotype
• BH4 loading tests to determine which persons are BH4 responsive and which are not in order to relax or discontinue restriction of dietary PHE in those who are responsive. (Tier 4)
Blood PHE levels should be maintained in the range of 120-360 μmol/l in patients of all ages, where untreated PHE levels are >360umol/L. There is strong evidence that treatment and maintenance of metabolic control throughout life is essential to optimal functioning and quality of life of individuals with PAH deficiency. A variety of adverse neurocognitive and psychiatric outcomes, including deficits in executive functioning and psychiatric symptoms such as anxiety, depression, and phobias can develop later in life when there is relaxation of PHE control. Patients with late or untreated PAH deficiency may benefit from institution of therapy. While it is unlikely that there will be improvement in cognitive abilities even if treatment successfully reduces blood PHE, there is anecdotal evidence suggesting that patients may exhibit improvements in behavior, psychiatric symptomatology, and seizure control. (Tier 2)
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Individuals with non-PKU HPA who have plasma PHE concentrations consistently below 600 μmol/L (10 mg/dL) are not at higher risk of developing intellectual, neurologic, and neuropsychological impairment than are individuals without PAH deficiency. While some specialists debate the advisability of non-treatment, others believe that dietary treatment is unnecessary for the individuals in this class. A study of thirty-one individuals with HPA who were never treated and whose plasma PHE concentrations did not exceed 600 μmol/L had normal cognitive neuropsychological development. (Tier 3)
The mainstay of treatment is dietary restriction of PHE, which results in decreased blood PHE levels. The initiation of dietary treatment depends on the extent of HPA. Most treatment centers initiate treatment at a PHE level of 360 μmol/l or higher, while the effects of treatment in the range of 360 to 600 μmol/l is unclear. Though a threshold for the adverse effects of elevated blood PHE has not been proven, treatment at PHE levels between 120 and 360 μmol/l is not recommended. (Tier 2)
• Information on the effectiveness of dietary treatment in adults diagnosed with PAH deficiency based on incidental or secondary findings were not identified.
• One systematic review assessed the results of RCTs of the low-PHE diet compared to relaxation or termination of dietary restrictions in children. Combined results of 2 studies conducted in young children (n=90) indicated that blood PHE concentrations were significantly lower in participants on the low-PHE diet than those on a less restricted diet (mean difference at 12 months was -751.54, 95% CI: -883.41 to - 619.67). In addition, one study (n=115) reported that participants who continued the low-PHE diet until age 6 achieved a higher IQ than those who discontinued the diet (mean difference at 12 months was 5.00, 95% CI 0.40 to 9.60). All of these studies were conducted in patients who were diagnosed in the neonatal period and started a low PHE diet in early infancy. None of these studies address the implementation of a restricted diet in an individual identified later in life. (Tier 1)
• A crossover RCT of the PHE restricted diet was conducted in a group of 34 adults (aged 21-61 years) who had never been treated and had severe challenging behavior. Only half completed the 60 week study, and significant challenges were encountered in instituting the PHE-restricted diet in this population. While levels of blood PHE were found to be lower during the treatment period, no differences were demonstrated in assessments of behavior. However, 76% of carers' comments were scored as positive during the active phase, compared with 54% during the placebo phase (p<0.001), indicating potential benefits of quality of life for individuals with PKU and their carers. (Tier 2)
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In addition to PHE restricted diet, additional therapies to reduce plasma PHE may include sapropterin, low PHE medical food, large neutral amino acids (LNAAs), and vitamin/mineral supplementation. Any combination of therapies that facilitate improvement in PHE levels for a given individual is appropriate. Therapies may be combined and should be individualized. (Tier 2)
• Information on the effectiveness of treatment in adults diagnosed with PAH deficiency based on incidental or secondary findings were not identified.
• Two randomized controlled trials and three uncontrolled open label studies indicate that sapropterin, a synthetic form of the PAH cofactor BH4, reduces blood PHE concentrations in patients with PKU. Studies included between 29 and 90 children and adults (n=284 after accounting for duplication) who were responsive to BH4 in initial loading trials. PHE levels were reduced by at least 30% (the usual research target) in up to half of treated patients (32-50%) compared to 9% of the placebo groups. No studies have linked these results to longer term clinical or patient-reported outcomes. These studies were conducted in individuals diagnosed with PKU, it is unclear how these results would apply patients discovered from secondary findings. (Tier 1)
• LNAAs have been proposed as a therapy for PAH deficiency based on their ability to block uptake of PHE from the intestine and at the blood-brain barrier. (Tier 2) However, one systematic review of 3 small studies (total n=47) could not draw conclusions about the effectiveness of LNAA formulations in affecting short- or long-term outcomes. These studies included patients with classic PKU and were short, with treatment between 1 and 8 weeks. One RCT of 16 patients found some improvements in executive functioning with LNAAs; however, there was considerable individual variable. The two other studies reported that PHE levels remained above clinically acceptable levels throughout treatment. (Tier 1)
• 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. (Tier 2)
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Assessment of the early risk of osteopenia should be considered in affected individuals. Screening for abnormal bone mineralization may be considered, though the optimal screening for treatment for osteopenia has not been determined though one guideline recommended assessment every 5 years for all adults. However, other guidelines state that the utility of routine scans has not yet been established. A study of screening 31 adult PKU patients (mean age 25) identified osteopenia in 11 patients (38.7%) and osteoporosis in 2 patients (6.5%). (Tier 2)
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PHE is a potent teratogen with both physical and cognitive consequences for the developing fetus. Thus the management of women with PKU or HPA during childbearing years, pre-conception, during pregnancy, and post-conception should include care in consultation with practitioners from experienced PKU centers, genetic and nutritional evaluation, and counseling on the risks of adverse fetal outcomes associated with uncontrolled PHE concentrations during pregnancy. (Tier 2)
• It is strongly recommended that women with PAH deficiency use reliable methods of contraception to prevent unplanned pregnancies. (Tier 4)
• Girls and women in whom no treatment has been initiated but who have persistent blood PHE levels between 360 and 600 μmol/l should receive continued monitoring and education, as they will require treatment prior to and during pregnancy. (Tier 2)
• It is recommended that PHE levels of <360 umol/L (6 mg/dL) be achieved for at least 3 months before conception and maintained at 60-360 umol/L (or 2-6 mg/dL) during pregnancy to normalize PHE levels and optimize fetal development. After conception, maternal PHE levels should be maintained between 60 and 360 umol/L during pregnancy. Women who become pregnant without appropriate PHE control will need significant support to attain PHE levels within the recommended therapeutic range in a timely fashion. Maternal PHE requirements change significantly throughout gestation necessitating frequent testing and diet adjustments. There is a linear relationship between maternal PHE levels >360 μmol/l throughout gestation and lower IQ of the developing fetus. Further, elevated blood PHE levels in the first 8-10 weeks of gestation are associated with an increased risk of congenital heart defects and poor fetal growth, and reduction of PHE levels before conception or by 8 weeks gestation reduces the fetal sequelae. (Tier 2)
• A systematic review assessed preconception care services among women with HPA (including PKU), where services included screening to detect PHE concentrations in addition to education and counseling regarding preconception and prenatal dietary control of PHE. All four studies in the review showed that preconception dietary restrictions (resulting in reduced maternal PHE levels) were associated with improved neonatal outcomes in terms of one or more of the following: birth weight, length, head circumference, congenital malformations (particularly congenital heart defects), and neonatal deaths. In these studies preconceptional or very early prenatal dietary control was associated with better outcomes than was later prenatal dietary control alone. (Tier 1)
• Pregnancy management should include: fetal growth monitoring, detailed ultrasonographic examinations, and fetal echocardiography to detect fetal abnormalities. (Tier 2)
• Postpartum maternal PHE requirements will decrease from the increased anabolic requirements of the third trimester, and careful metabolic and nutritional monitoring should continue. (Tier 2)
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Patients with PAH should undergo regular clinical assessments: • Nutrition visits in the clinic to assess dietary intake and nutrient analysis, nutrition-related physical findings, nutrition counseling and diet education. This should be done every 6-12 months in all adults, but more frequently during pregnancy (monthly to per trimester) and post-partum (at 6 weeks postpartum and then every 6 months). • Every clinical visit should assess anthropometrics, including weight, length or height, and BMI. • Interval nutrition visits should include diet adjustments based on blood PHE and/or counseling, and should occur monthly for all adults and more frequently during pregnancy (twice weekly to weekly) and postpartum (weekly to monthly). (Tier 2)
Due to the increased risk for neurocognitive and psychological issues in patients with PAH deficiency, regular mental health monitoring is warranted. (Tier 2)
Patients with PAH should undergo regular biochemical screenings including: PHE, tyrosine, plasma amino acids, transthyretin, albumin/total protein, complete blood count, ferritin, vitamin D 25-OH, comprehensive metabolic panel, serum vitamin B12, B6, erythrocyte folate, vitamin A, zinc, copper, selenium, and essential fatty acids. The frequency of these screenings varies and should be performed more frequently during pregnancy and postpartum. (Tier 2)
If treatment is not required before 2 years of age, monitoring on an annual or biennial basis is adequate for subsequent assessment. (Tier 2)
Family Management
Newborn sibs of an individual with PKU who have not been tested prenatally should have blood concentration of PHE measured shortly after birth (in addition to newborn screening) to allow earliest possible diagnosis and treatment. (Tier 4)
Circumstances to Avoid
Aspartame, an artificial sweetener in widespread use, contains phenylalanine. Persons with PKU should either avoid products containing aspartame or calculate intake of PHE and adapt diet components accordingly. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Mutations
The carrier frequency of PAH deficiency is approximately 1/60. (Tier 4)
However, carrier frequencies can be variable across populations: 1/26 in Turks, 1/33 in Irish, 1/50 in Northern European origin and East Asian, 1/200 in Japanese, and 1/225 in Finish and Ashkenazi Jewish populations. (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Individuals with a genotype suggestive of PKU will always have hyperphenylalaninemia on a normal diet. The impact on the clinical phenotype, that is, cognitive development is variable. (Tier 4)
Approximately 40% of young adults with PKU develop osteopenia. (Tier 3)
For maternal teratogenicity, in untreated pregnancies in which the maternal blood PHE concentration was ≥20 mg/dL (1200 micromol/L), rates of outcomes reported in offspring include intellectual disability in 91-92%, microcephaly in 73-92%, and congenital heart disease in 12-15%. (Tier 5)
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Information on relative risk was not available.
PAH deficiency is a multifactorial disorder with both environment (dietary intake of PHE) and genotype are necessary causal components of disease. Individuals with similar PAH genotypes may not have similar phenotypes. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Treatment for PAH deficiency is complex, costly, and lifelong. Adherence to recommendations diminishes with age. Many patients find the diet difficult to adhere to due to the unpalatable and bland nature of many PHE-free products as well as a variety of socioeconomic factors, such as economic and health care system issues. Trials of sapropterin did not identify any serious adverse events and side effects occurred as a similar rather in the treatment and placebo arms.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Since the initiation of newborn screening during the 1960's in North America, almost all cases of PAH deficiency are diagnosed following a positive newborn screening test. (Tier 3)
Since the appearance of universal newborn screening, symptomatic classic PKU is infrequently seen. Its predicted incidence in screened populations of fewer than one in a million live births reflects those children not detected by newborn screening. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Suboptimal plasma PHE levels / Optimal dietary and medical management to achieve goal PHE levels
Fetal teratogenicity (females only) / Pregnancy management of PHE levels
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
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2. Management of women with phenylketonuria, committee opinion number 636. Publisher: Committee on Genetics. American College of Obstetricians and Gynecologists. (2015) Website:
3. Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. (2015)
4. Phenylketonuria. Orphanet encyclopedia,
5. Lindegren ML, Krishnaswami S, Fonnesbeck C, Reimschisel T, Fisher J, Jackson K, et al.. Adjuvant treatment for phenylketonuria (pku). comparative effectiveness review no. 56. Publisher: Vanderbilt Evidence-based Practice Center under Contract No. HHSA 290-2007-10065-I.. (2012) Website:
6. DS Regier, CL Greene. Phenylalanine hydroxylase deficiency. 2000 Jan 10 [Updated 2017 Jan 05]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:
7. Committee on Genetics. Maternal phenylketonuria. Pediatrics. (2008) Website:
8. Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. (2014) 16(2):121-31.
9. Poustie VJ, Wildgoose J. Dietary interventions for phenylketonuria. Cochrane Database Syst Rev. (2010)
10. Korenbrot CC, Steinberg A, Bender C, Newberry S. Preconception care: a systematic review. Matern Child Health J. (2002) 6(2):75-88.
11. Zschocke J, Haverkamp T, Moller LB. Clinical utility gene card for: phenylketonuria. Eur J Hum Genet. (2012) 20(2).
12. Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies. N Engl J Med. (1980) 303(21):1202-8.
13. Levy HL, Ghavami M. Maternal phenylketonuria: a metabolic teratogen. Teratology. (1996) 53(3):176-84.
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