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PKU and Pterin Defects

Overview

Phenylketonuria (PKU) is a recessive disorder caused by deficiency in phenylalanine hydroxylase (PAH), the enzyme that converts the amino acid phenylalanine to tyrosine, leading to accumulation of phenylalanine in the body. This accumulation is toxic to the development and functioning of the central nervous system and leads to intellectual disability. Phenylalanine is present in almost all foods containing proteins, and treatment of PKU involves a restrictive diet with reduction of phenylalanine and addition tyrosine, which becomes essential in this condition. This requires special foods, including medical formulas that contain all amino acids except phenylalanine and special low-protein foods.

Most children with PKU are identified by newborn screening. With treatment and early introduction and maintenance of the special diet, normal IQ and development can be expected. Without treatment, symptoms in classic PKU begin by about 6 months of age.

Initial symptoms may include:
  • A musty or "mousy" odor of the body and urine
  • Developmental delays in sitting, crawling, and standing
  • Acquired microcephaly
If patients remain untreated they may develop:
  • Decreased skin and hair pigmentation (due to lack of tyrosine)
  • Eczema
  • Seizures
  • Profound intellectual disability
There are different degrees of severity of PKU defined by the highest levels of phenylalanine measured in blood at equilibrium and the tolerance to dietary phenylalanine. In benign hyperphenylalaninemia, the increase in phenylalanine levels are minimal (phenylalanine 120-360 micromolar, normal 30-90 micromolar) and require no treatment. In mild PKU, there is a mild increase in phenylalanine levels (360-1,200 micromolar, normal 30-90 micromolar) that is more easily controlled by diet or pharmacological therapy. In classic PKU, there is substantial elevation of phenylalanine levels (>1,200 micromolar, normal 30-90 micromolar) that requires strict dietary therapy and is less likely to respond to pharmacological therapy.
Some patients, particularly those with mild PKU, respond to therapy with sapropterin, a synthetic form of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase. Patients with mild phenylketonuria are more likely to respond to this therapy.

Elevated phenylalanine levels can also be caused by defects in the synthesis or recycling of tetrahydrobiopterin, an essential cofactor of phenylalanine hydroxylase and other hydroxylases involved in neurotransmitter synthesis, or deficiency of DNAJC12, a co-chaperone of phenylalanine and other hydroxylases. In addition to elevated phenylalanine levels, these patients can have neurotransmitter deficiencies, and their treatment differs from that of phenylketonuria.

As part of the initial evaluation of a child with high phenylalanine level in newborn screening, metabolic geneticists will exclude a defect in the tetrahydrobiopterin pathway by measurement of the pterin profile in urine and evaluation of the activity of an enzyme, dihydropteridin reductase (DHPR), in red blood cells spotted on filter paper. Therapy in these conditions includes the administration of a synthetic form of tetrahydrobiopterin that can normalize plasma phenylalanine level. These patients also require the administration of neurotransmitter precursors (Levodopa and 5-hydroxytryptophan). Abnormalities in DNAJC12 have also been identified in patients with autism without or with only mild hyperphenylalaninemia.

Dietary protein restriction needs to be continued for life in patients with PKU, and repeated monitoring of plasma phenylalanine and tyrosine levels are needed to make sure that they remain within the therapeutic range (phenylalanine 45-360 micromolar, Tyrosine 30-120 micromolar).

Other Names & Coding

Classic PKU
Hyperphenylalaninemia
Phenylalanine hydroxylase deficiency
Phenylketonuria
ICD-10 coding

E70.0, Classical phenylketonuria

E70.1, Other hyperphenylalaninemias

ICD-10 for Classical Phenylketonuria (icd10data.com) and ICD-10 for Other Hyperphenylalaninemias (icd10data.com) provide further coding details.

Prevalence

PKU caused by PAH deficiency occurs in about 1:16,500 live births in the US. [Therrell: 2014] The incidence varies greatly in other populations: Turks - 1:2,600; Irish - 1:4,500; African - 1:100,000; Japanese - 1:143,000; Finnish and Ashkenazi Jewish - 1:200,000. [Günther: 2008]

Genetics

All hyperphenylalaninemias are Inherited as autosomal recessive traits. More than 600 different pathogenic variants in the phenylalanine hydroxylase (PAH) gene located on chromosome 12 have been identified in patients with phenylketonuria. There is a correlation between the type of mutations, residual enzyme activity, and highest phenylalanine level. DNA testing can fully confirm a diagnosis of phenylketonuria and, with biochemical testing, help to exclude defects in biopterin synthesis or DNAJC12. Confirmation of the diagnosis of defects in biopterin metabolism (GTPCH, PTPS, DHPR, Carbinolamine dehydratase) or DNAJC12 requires DNA testing. For this reason, gene panels have been developed to identify pathogenic variants in all the genes listed above, and results are useful in designing an individualized care plan and formulating a prognosis.

Prognosis

Prognosis is good for individuals with PKU who remain on the diet. Relaxation of diet is associated with executive function deficits and an increased risk of attention deficit disorder and problems in school. Patients with defects in tetrahydrobiopterin synthesis or recycling or DNAJC12 deficiency might develop movement disorders and developmental delays. These can be improved by therapy, but in the most severe forms therapy is not completely effective.

Practice Guidelines

Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, et al.
Phenylketonuria Scientific Review Conference: state of the science and future research needs.
Mol Genet Metab. 2014;112(2):87-122. PubMed abstract

Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA.
Phenylalanine hydroxylase deficiency: diagnosis and management guideline.
Genet Med. 2014;16(2):188-200. PubMed abstract / Full Text

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. PubMed abstract / Full Text

Roles of the Medical Home

Children with phenylketonuria (PKU) will have periodic visits with the metabolic genetics team in co-management with the Medical Home clinician. Phenylalanine levels will be monitored periodically. A metabolic nutritionist will work with the family to devise an optimal approach to dietary management. The Medical Home clinician should support maintenance of the phenylalanine-restricted diet and supplementation of tyrosine and essential amino acids as recommended by the metabolic geneticist. For those identified after irreversible consequences, the Medical Home clinician should assist in management, particularly with developmental and educational interventions.

Clinical Assessment

Overview

Most children with phenylketonuria (PKU) are now identified by newborn screening or in families at known risk. A positive newborn screen for PKU reflects elevated phenylalanine. False positives occur; all initially positive newborn screens need to be confirmed through additional testing. The Medical Home clinician and the metabolic genetics team should work together to contact the family and arrange further testing. The infant will be treated as needed for symptoms and started as soon as possible on the special PKU diet. See the Portal's Phenylketonuria (PKU) for additional information.

Pearls & Alerts for Assessment

The diagnosis of PKU must be confirmed by quantitative plasma amino acids.

Common causes of false positive newborn screens for PKU include the administration of total parenteral nutrition, liver disease, and extreme prematurity. In these cases, elevation of several amino acids will be found, not just phenylalanine. Rapid verification, in collaboration with a metabolic specialist, is necessary to enable dietary intervention to begin before two weeks of age.

Attention problems and mood disorders

Patients with phenylketonuria have an increased incidence of attention problems and mood disorders. In general, maintenance of phenylalanine levels below 360 micromolar for life is associated with better outcomes. Unfortunately, as children become more social and are exposed to new foods, levels of phenylalanine tend to increase. Working with caregivers and school systems to provide acceptable dietary choices and ongoing education on protein and phenylalanine content of foods is very important. Perpetual surveillance for attention problems may help detect poor dietary compliance. Children with PKU who also have attention deficit disorder should respond to commonly used stimulants and other medications, assuming that phenylalanine levels are well managed.

Screening

For the Condition

All infants born in the United States and many other countries are now screened as newborns for phenylketonuria (PKU). Completion of screening should be confirmed for every newborn. Family members do not need screening for the condition but may discuss screening for carrier status with the metabolic genetics team. Routine screening for attention problems or academic performance is not recommended, but these should be monitored as reflections of inadequate maintenance of the therapeutic diet.

Of Family Members

Family members of individuals with PKU should have the normal newborn screening and have quantitative plasma amino acids measured at 24 h of life to speed up potential treatment. Thy should receive a normal diet until diagnosis is confirmed.

For Complications

Developmental surveillance and periodic screening, particularly related to speech and language development are important to detect any early signs of delay.

Presentations

Children born in the USA, Europe, Japan or Australia are rarely missed by neonatal screening. By contrast, immigrants from other countries might not be diagnosed at birth. They will have early delayed development and will usually present with nonspecific intellectual disability and, in many cases, seizures. They can have the odor of phenylacetic acid, but it is not always easy to appreciate. If left untreated, many will develop physical disabilities as well. Older patients with PKU who do not adhere to treatment are at higher risk for psychiatric symptoms.

Diagnostic Criteria

Measurement of elevated phenylalanine levels in plasma (plasma amino acids) confirms the diagnosis. Measurement of urine pterins and red blood cell DHPR activity excludes disorders of biopterin synthesis and recycling. DNA testing can be used to confirm biochemical data and to exclude DNAJC12 deficiency that cannot be differentiated by biochemical testing.

Clinical Classification

Different degrees of severity of PKU caused by phenylalanine hydroxylase deficiency are defined by the highest levels of phenylalanine measured in blood at equilibrium and tolerance to dietary phenylalanine. Some patients, particularly those with mild PKU, respond to therapy with sapropterin, a synthetic form of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase. [Blau: 2011]
  • In benign hyperphenylalaninemia, the increase in phenylalanine levels are minimal (phenylalanine 120-360 micromolar, normal 30-90 micromolar) and require no treatment.
  • In mild PKU, there is a mild increase in phenylalanine levels (360-1,200 micromolar, normal 30-90 micromolar) that is more easily controlled by diet or pharmacological therapy.
  • In classic PKU, there is substantial elevation of phenylalanine levels (>1,200 micromolar, normal 30-90 micromolar) that requires strict dietary therapy and is less likely to respond to pharmacological therapy.

Differential Diagnosis

Metabolic geneticists will differentiate hyperphenylalaninemia due to PAH deficiency from a defect in tetrahydrobiopterin synthesis or recycling or DNAJC12 deficiency.

Comorbid & Secondary Conditions

Children with treated PKU, particularly those who have not maintained low serum phenylalanine levels, may have symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). Defects in executive function are frequent in adolescents with marginal levels of phenylalanine as are psychiatric and mood disorders in adults.

History & Examination

Current & Past Medical History

Families should be questioned about how well they have managed to stay on the diet and continue the prescribed supplements. Barriers to diet compliance should be explored and overcome if possible. Some children with a very high level of phenylalanine may have an increased incidence of Gastroesophageal Reflux Disease.

Family History

PKU is a recessive disorder, and usually there is no history of this condition in the family. In rare instances, there may be relatives with PKU or unexplained intellectual disability in previous generations before newborn screening for PKU was initiated in the 1960s or if the family is from a country that does not screen for PKU in newborns or in which consanguinity is frequent. PKU is screened for in the United States, Europe, and most other nations. For an interesting discussion of the history of PKU screening, see History of Newborn PKU Screening (National Human Genome Research Institute).

Developmental & Educational Progress

Children who are not maintained on the strict diet may show symptoms of attention deficit hyperactivity disorder, mood disorders, and if non-compliance is severe, a drop in their intellectual functioning. The Medical Home clinician should follow developmental and academic progress closely.

Social & Family Functioning

Long-term adherence to the diet into adulthood is difficult for families to achieve for many reasons.

Physical Exam

General

The physical exam is normal in infants with PKU and should remain normal for children who are well-managed with diet. Their skin, hair, and eyes may be lighter than those of their unaffected siblings.

Testing

Laboratory Testing

Quantitative plasma amino acid analysis, red blood cell DHPR assay, and a urine pterin profile are performed to confirm the diagnosis of an infant with a high phenylalanine on newborn screening. Plasma amino acid testing will show a high phenylalanine without an increase in tyrosine. The red blood cell DHPR assay and urine pterin profile will identify defects in the synthesis or recycling of tetrahydropterin, which is the cofactor for phenylalanine hydroxylase. Blood levels of phenylalanine should be followed periodically. This is generally done by or in collaboration with the metabolic genetics team.

Genetic Testing

Quantitative plasma amino acid analysis, red blood cell DHPR assay, and a urine pterin profile are performed to confirm the diagnosis of an infant with a high phenylalanine on newborn screening. Plasma amino acid testing will show a high phenylalanine without an increase in tyrosine. The red blood cell DHPR assay and urine pterin profile will identify defects in the synthesis or recycling of tetrahydropterin, which is the cofactor for phenylalanine hydroxylase. PAH mutation analysis will also be ordered by the metabolic genetics team if the information is needed to define the possible response to pharmacological intervention of estimated needs for dietary phenylalanine restriction or genetic counseling. This can also exclude DNAJC12 deficiency.

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see NV providers [2])

Will be involved in the diagnosis and co-management of children with PKU and variants

Newborn Screening Services (see NV providers [2])

Will assist the Medical Home clinician with the response to a high phenylalanine on a newborn screen

Nutrition, Metabolic (see NV providers [15])

Is part of the metabolic genetics team and will assist the family with initiating feeding with low phenylalanine infant formula, which is started immediately upon confirmation of the diagnosis. The nutrition team will assist families in transitioning from a low phenylalanine formula to a low-phenylalanine diet when appropriate.

Treatment & Management

Overview

Phenylalanine levels should be maintained between 40 and 360 micromolar until the teenage years. There is no consensus on the value to be targeted in adults, with the levels above being recommended by some clinics and levels up to 900 micromolar deemed adequate by others.

Pearls & Alerts for Treatment & Management

Dietary treatment

Initiate dietary treatment before 2 weeks of age and continued for life. Though maintaining the phenylalanine-restricted diet is difficult for many to achieve it is essential to avoid the sequelae and complications of high blood phenylalanine. [MacDonald: 2010]

Avoid sugar substitutes

Aspartame (e.g., NutraSweet, Equal, Sweet Mate, Canderel) is commonly found in diet drinks and medications and a rich source of phenylalanine; it must be avoided.

Pregnant women with PKU

Women with PKU who become pregnant should maintain levels of phenylalanine below 300 micromolar throughout pregnancy since phenylalanine is a powerful teratogenic agent. High levels of phenylalanine have been associated with increased risk of miscarriage, congenital heart disease, cleft lip and palate, microcephaly, and profound intellectual disability. Dietary control is recommended from least 2 months before becoming pregnant.

How should common problems be managed differently in children with PKU and Pterin Defects?

Development (Cognitive, Motor, Language, Social-Emotional)

Follow speech and development for signs of deficits in executive function.

Systems

Genetics

Infants with PKU are ideally followed by a metabolic genetics program, in collaboration with primary care, overseeing their nutrition to avoid the adverse effects of their condition. Their diet is managed with a formula that limits the amount of phenylalanine given to the infant, and supplements with additional nutrients including essential amino acids. Having PKU does not preclude breastfeeding, but diet will need to be even more closely monitored than for an infant exclusively on formula.

As the infant grows, the metabolic genetics team will help the child and family transition from low phenylalanine formula to a low phenylalanine diet. Additional supplements are added as needed to ensure that essential nutrients are included. Sapropterin, a stable form of tetrahydropterin, may be helpful for some children. [Lee: 2008] [Vernon: 2010] [Trefz: 2010]

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see NV providers [2])

Will co-manage children with PKU and periodic visits should be scheduled

Nutrition, Metabolic (see NV providers [15])

Is part of the metabolic genetics team and will provide education and support for families with children on the PKU diet

Nutrition/Growth/Bone

Dietary treatment should be initiated before 2 weeks of age and continued for life. At the time of diagnosis, phenylalanine is usually removed from the diet completely for a few days to allow for levels to drop to within the therapeutic range (45-360 micromolar or 0.75-6 mg/dL), where they should be maintained for life. Subsequently, natural proteins are introduced to provide phenylalanine for protein synthesis to allow growth. Breast milk is naturally low in protein and can be used as the source of natural protein in conjunction with a special formula devoid of phenylalanine and containing all other amino acids and needed minerals, vitamins, and other nutrients.

The child is monitored for normal growth and maintenance of adequate phenylalanine levels. The family is instructed on how to spot blood on filter paper, which is then dried and mailed to the health department for phenylalanine and tyrosine determination. This is obtained initially from a heel stick and then a fingerstick as the child gets older. Monitoring is performed weekly for the first year of life. Subsequently, the frequency decreases to every other week and then to monthly when the child enters school age and is in excellent metabolic control. The frequency is adjusted by the metabolic clinic in response to the phenylalanine levels and the severity of the patient’s PKU, with more frequent monitoring in those with poor metabolic control and persistently elevated phenylalanine levels.

The child should be given progressive control over the diet to assure that, by the teenage years, there is a good understanding of how to maintain phenylalanine levels within the therapeutic range. Unfortunately, the diet is difficult to maintain and levels of phenylalanine increase as children get older. Sapropterin, a synthetic form of tetrahydrobiopterin, can reduce phenylalanine levels in a select group of patients with PKU. It is given as a trial for about one month, measuring phenylalanine levels before and during the trial. Individuals are considered responsive if phenylalanine levels drop 30% or more. The drug seems very safe.

Specialty Collaborations & Other Services

Nutrition, Metabolic (see NV providers [15])

Is part of the metabolic genetics team and will provide ongoing education and support for families with children on the PKU diet.

Pharmacy & Medications

Some individuals with PKU respond to therapy with oral sapropterin (Kuvan) 20 mg/kg per day. Sapropterin is a synthetic form of tetrahydrobiopterin (BH4) the co-factor of PAH. Sapropterin I used in conjunction with a low protein diet and medical foods to reduce plasma Phe levels and to increase tolerance to dietary Phe.

PEGylated phenylalanine ammonia lyase (pegvalyase, Palinziq) is a new injectable medication used in PKU. This bacterial enzyme transforms circulating phenylalanine in ammonia and cinnamic acid. The latter is then excreted in urine as hyppuric acid after conjugation with glycine. Treatment with pegvaliase does not require a specific diet, but it can cause immune reactions related to the bacterial origin of the injectable drug. [Longo: 2014] [Zori: 2018] [Longo: 2018]

Learning/Education/Schools

Maintenance of a lifelong diet is challenging since almost all foods (including normal bread and pasta) contain a significant amount of protein. As children start to have a social life attending school, it becomes difficult to maintain a strict phenylalanine-restricted diet. When Phe levels rise, developmental and school problems are common. In addition to reinforcing compliance, the Medical Home clinician may need to work with the school to develop 504 plans or an individualized education program (IEPs) to ensure that the child with PKU is receiving needed developmental and educational resources. See School Types and Options.

Transitions

Because PKU is a life-long problem, individuals should be transitioned thoughtfully from pediatric to adult care. Adolescents and adults benefit from continued phenylalanine restriction, and the quality of life is improved in individuals who follow the diet. [van: 2008] Women with PKU who become pregnant need close monitoring of serum phenylalanine levels to prevent birth defects and intellectual disability in their infants. See Transition Issues.

Issues Related to PKU and Pterin Defects

Affording Formula

No Related Issues were found for this diagnosis.

Ask the Specialist

Can mothers breastfeed a baby who has just been diagnosed with phenylketonuria (PKU)?

It is often possible to breastfeed an infant with PKU, but this should be discussed in detail with the metabolic genetics team. Adjustments in the baby's diet may need to be made.

How expensive are medical foods and other special supplements children with PKU will need?

Medical foods are relatively expensive. Insurance will usually provide formula and supplements for children with PKU if they are prescribed by your doctor. However, preauthorization might be necessary. In addition, some insurance plans stop covering them as children become adults.

Resources for Clinicians

On the Web

PKU - Information for Professionals (STAR-G)
Structured list of information about the condition with links to more information; Screening, Technology, and Research in Genetics.

Phenylalanine Hydroxylase Deficiency (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Helpful Articles

PubMed search for phenylketonurias in children and adolescents, last 2 years

Blau N, van Spronsen FJ, Levy HL.
Phenylketonuria.
Lancet. 2010;376(9750):1417-27. PubMed abstract / Full Text

Viau KS, Wengreen HJ, Ernst SL, Cantor NL, Furtado LV, Longo N.
Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria.
J Inherit Metab Dis. 2011. PubMed abstract

van Spronsen FJ, Himmelreich N, Rüfenacht V, Shen N, Vliet DV, Al-Owain M, Ramzan K, Alkhalifi SM, Lunsing RJ, Heiner-Fokkema RM, Rassi A, Gemperle-Britschgi C, Hoffmann GF, Blau N, Thöny B.
Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability.
J Med Genet. 2017. PubMed abstract

Clinical Tools

Care Processes & Protocols

Confirmatory Algorithms for Phenylalanine Elevated (ACMG) (PDF Document 174 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

ACT Sheet for Increased Phenylalanine (ACMG) (PDF Document 351 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Resources for Patients & Families

Phenylketonuria (PKU) (FAQ)

Information on the Web

PKU - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of a newborn disorder; Screening, Technology and Research in Genetics.

Phenylketonuria (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Resources for PKU (Disease InfoSearch)
Compilation of information, articles, and links to support; from Genetic Alliance.

National Urea Cycle Disorders Foundation
Support and information that includes medical lectures on urea cycle disorders, nutrition and medication resources, and information about events and conferences.

Studies/Registries

PKU in Children and Adolescents (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families in Nevada (NV)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: July 2011; last update/revision: March 2019
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Authoring history
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U.
Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies.
Mol Genet Metab. 2011;104 Suppl:S2-9. PubMed abstract

Blau N, van Spronsen FJ, Levy HL.
Phenylketonuria.
Lancet. 2010;376(9750):1417-27. PubMed abstract / Full Text

Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, et al.
Phenylketonuria Scientific Review Conference: state of the science and future research needs.
Mol Genet Metab. 2014;112(2):87-122. PubMed abstract
Though its title suggests a focus on research, this also represents a consensus on best approaches to care.

Günther T, Schreiber C, Noebauer C, Eicken A, Lange R.
Treatment strategies for pediatric patients with primary cardiac and pericardial tumors: a 30-year review.
Pediatr Cardiol. 2008;29(6):1071-6. PubMed abstract

Lee P, Treacy EP, Crombez E, Wasserstein M, Waber L, Wolff J, Wendel U, Dorenbaum A, Bebchuk J, Christ-Schmidt H, Seashore M, Giovannini M, Burton BK, Morris AA.
Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria.
Am J Med Genet A. 2008;146A(22):2851-9. PubMed abstract

Longo N, Harding CO, Burton BK, Grange DK, Vockley J, Wasserstein M, Rice GM, Dorenbaum A, Neuenburg JK, Musson DG, Gu Z, Sile S.
Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.
Lancet. 2014;384(9937):37-44. PubMed abstract / Full Text

Longo N, Zori R, Wasserstein MP, Vockley J, Burton BK, Decker C, Li M, Lau K, Jiang J, Larimore K, Thomas JA.
Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study.
Orphanet J Rare Dis. 2018;13(1):108. PubMed abstract / Full Text

MacDonald A, Gokmen-Ozel H, van Rijn M, Burgard P.
The reality of dietary compliance in the management of phenylketonuria.
J Inherit Metab Dis. 2010;33(6):665-70. PubMed abstract

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. PubMed abstract / Full Text

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text

Trefz FK, Belanger-Quintana A.
Sapropterin dihydrochloride: a new drug and a new concept in the management of phenylketonuria.
Drugs Today (Barc). 2010;46(8):589-600. PubMed abstract

Vernon HJ, Koerner CB, Johnson MR, Bergner A, Hamosh A.
Introduction of sapropterin dihydrochloride as standard of care in patients with phenylketonuria.
Mol Genet Metab. 2010;100(3):229-33. PubMed abstract

Viau KS, Wengreen HJ, Ernst SL, Cantor NL, Furtado LV, Longo N.
Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria.
J Inherit Metab Dis. 2011. PubMed abstract

Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA.
Phenylalanine hydroxylase deficiency: diagnosis and management guideline.
Genet Med. 2014;16(2):188-200. PubMed abstract / Full Text

Zori R, Thomas JA, Shur N, Rizzo WB, Decker C, Rosen O, Li M, Schweighardt B, Larimore K, Longo N.
Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria.
Mol Genet Metab. 2018. PubMed abstract

van Spronsen FJ, Burgard P.
The truth of treating patients with phenylketonuria after childhood: the need for a new guideline.
J Inherit Metab Dis. 2008;31(6):673-9. PubMed abstract

van Spronsen FJ, Himmelreich N, Rüfenacht V, Shen N, Vliet DV, Al-Owain M, Ramzan K, Alkhalifi SM, Lunsing RJ, Heiner-Fokkema RM, Rassi A, Gemperle-Britschgi C, Hoffmann GF, Blau N, Thöny B.
Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability.
J Med Genet. 2017. PubMed abstract