PKU and Pterin Defects

Description

Other Names

Classic PKU
Hyperphenylalaninemia
Phenylalanine hydroxylase deficiency
Phenylketonuria

Diagnosis Coding

ICD-10

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.

Description

Phenylketonuria (PKU) is a recessive disorder caused by deficiency in phenylalanine hydroxylase, the enzyme that converts the amino acid phenylalanine to tyrosine, leading to an accumulation of phenylalanine in the body. This accumulation is toxic for the development and functioning of the central nervous system and leads to intellectual disability. Phenylalanine is present in almost all foods containing proteins.

Treatment of PKU involves a restrictive diet with the reduction of phenylalanine and the addition of vitamins and minerals that are necessary for body metabolism. This requires medical formulas that contain all amino acids except phenylalanine in addition to special low-protein foods. Diet 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). Most children with PKU are identified by newborn screening.

Elevated phenylalanine levels can also be caused by defects in the synthesis or recycling of tetrahydrobiopterin, an essential cofactor of phenylalanine hydroxylase and other enzymes involved in neurotransmitter synthesis. These patients, in addition to elevated phenylalanine levels, 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 obtaining additional specialized tests. These consist of the measurement of pterin profile in urine spotted on filter paper and evaluation of the activity of an enzyme, dihydro-pteridin reductase (DHPR), in red blood 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.

Prevalence

PKU occurs in about 1:10,000 live births in the US. [Schulze: 2003] 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

Inheritance is autosomal recessive. The only gene associated with PKU is phenylalanine hydroxylase (PAH), which is located on chromosome 12. More than 600 different mutations have been identified in patients with phenylketonuria. There is a correlation among 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.

Prognosis

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. 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 might develop movement disorders and all have developmental delays. These can be improved by therapy, but it is not completely effective in the most severe forms.

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.

Practice Guidelines

There are no current published practice guidelines for the management of PKU. The last National Institutes of Health (NIH) consensus statement, Phenylketonuria: Screening and Management (NIH Consensus Development Program), was developed in 2000 and is not considered current.

For initial diagnosis based on newborn screening results, see:

American College of Medical Genetics.
Newborn screening ACT Sheet (Increased Phenylalanine) Phenylketonuria (PKU).
American College of Medical Genetics; (2011) http://www.acmg.net/StaticContent/ACT/Phenylalanine.pdf. Accessed on 11/12/2018.

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

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

Clinical Assessment

Overview

Most children with phenylketonuria (PKU) are now identified by newborn screening or in families at known risk. See the Portal's Newborn Disorders page – Phenylketonuria (PKU) or the ACT Sheet for PKU (ACMG) (PDF Document 351 KB) for additional information.

Pearls & Alerts

PKU diagnosis 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 2 weeks of age.

Increased incidence of attention problems and mood disorders

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. A positive newborn screen for PKU reflects elevated phenylalanine. False positives occur and 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.

Of Family Members

Family members do not need screening for the condition but they may want to discuss screening for carrier status with the metabolic genetics team.

For Complications

Routine screening for attention problems or academic performance is not recommended, but these issues should be monitored as reflections of inadequate maintenance of the therapeutic diet.

Presentations

Initial symptoms may include:
  • A musty or "mousy" odor of the body and urine
  • Developmental delays in sitting, crawling, and standing
  • Microcephaly
If patients remain untreated, they may develop:
  • Decreased skin and hair pigmentation (due to lack of tyrosine)
  • Eczema
  • Seizures
  • Profound mental retardation

Diagnostic Criteria

Biochemical criteria confirm the diagnosis and differentiate between the causes of high serum phenylalanine. DNA testing can be used to confirm biochemical data.

Clinical Classification

There are different forms of PKU defined by the highest levels of phenylalanine measured in blood.
  • 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.

Differential Diagnosis

Metabolic geneticists will consider several variant forms in the differential diagnosis of PKU. In addition to classic PKU, patients may have benign hyperphenylalaninemia, mild PKU, and a defect in tetrahydropbiopterin synthesis or recycling.

Comorbid Conditions

Children with treated PKU, particularly those who have not maintained low serum phenylalanine levels, may have symptoms of Attention Deficit Hyperactivity Disorder (ADHD). Children with untreated PKU will have Intellectual Disability.

History & Examination

Family History

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 doesn't screen for PKU in newborns. PKU is screened for in the United States, Europe, and others. For an interesting discussion of the history of PKU screening, see The history of newborn PKU screening (LSU Law Center).

Current And 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.

Developmental And 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 And 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 sometimes 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 for genetic counseling purposes.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Refer for diagnosis and co-management of children with PKU and variants.

Newborn Screening Programs (see Services below for relevant providers)

Assists the medical home clinician with the response to a high phenylalanine on a newborn screen.

Nutrition, Metabolic (see Services below for relevant providers)

Assists 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

Initiate dietary treatment before 2 weeks of age and continue for life

Though maintaining the phenylalanine-restricted diet is difficult for many, it is essential to avoid the sequelae and complications of high-blood phenylalanine. [MacDonald: 2010]

Avoid sugar substitutes

The sugar substitute aspartame ("NutraSweet", "Equal", "Sweetmate", “Canderal") that is commonly found in diet drinks and medications is a rich source of phenylalanine and needs to 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 mental retardation. Dietary control at least 2 months before becoming pregnant is recommended.

Systems

Genetics

Infants with PKU are put on a formula (Lofenalac) that closely controls the amount of phenylalanine given to the infant and supplements with additional nutrients, including essential amino acids. The metabolic genetics clinic will oversee the formula and monitor its use. 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]

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Periodic visits should be scheduled to co-manage children with PKU.

Nutrition, Metabolic (see Services below for relevant providers)

Provide, as a part of the metabolic genetics team, education and support for families with children on the PKU diet.

Nutrition/Growth/Bone

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.

Dietary treatment should be initiated before two 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 (40-360 micromolar or 0.75-6 mg/dL). 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 heel stick and from 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 PKUt, 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 ensure 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.

Subspecialist Collaborations & Other Resources

Nutrition, Metabolic (see Services below for relevant providers)

Provides ongoing education and support for families with children on the PKU diet.

Learning/Education/Schools

Because only about 50% of children with PKU remain on a strict phenylalanine-restricted diet, developmental and educational 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 Education & Schools.

Transitions

Individuals should be transitioned thoughtfully from pediatric to adult care. Adolescents and adults benefit from continued phenylalanine restriction and 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 complications with their infants. See Transition to Adulthood.

Questions from Clinicians

What advice should I give my patient who wants to breastfeed her 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.

How expensive are Lofenalac and the other special supplements?

Insurance will usually provide formula and supplements for children with PKU if they are prescribed.

Issues Related to PKU and Pterin Defects

No Related Issues were found for this diagnosis.

Resources

Information for Clinicians

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)
An expert-authored, peer-reviewed, disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

Resources for PKU ()
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

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

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

Clinical Tools

Algorithms/Care Processes

Newborn Screening ACT Sheets & Confirmatory Algorithms (ACMG)
ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results, membership required; American College of Medical Genetics.

ACT Sheet for PKU (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.

Patient Education & Instructions

What is Phenylketonuria? (GSLC)
A brief educational overview of single gene disorders that includes the genetics of Phenylketonuria (PKU); Genetic Science Learning Center at the University of Utah.

Information & Support for Families

Family Diagnosis Page

Information on the Web

PKU Information - 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.

PKU (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

National Urea Cycle Disorders Foundation
This non-profit organization provides support services and information for families; medical lectures on urea cycle disorders; nutrition and medication resources; and information about events and conferences.

ThinkCollege.net
Provides information, discussion board, listserve, resources, student stories, and links to colleges and programs that support youth with intellectual disabilities.

PKU Information (BioMarin)
Information with a special section for teens. Provides a clinic finder and a recipe section: BioMarin is a pharmaceutical company.

Services for Patients & Families in Rhode Island

Select services for a different state: ID, MT, NM, NV, UT

Newborn Screening Programs

We currently have no Newborn Screening Programs service providers listed; search our Services database for related services.

Nutrition, Metabolic

See all Nutrition, Metabolic services providers (2) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (4) in our database.

Pediatric Metabolic Genetics

See all Pediatric Metabolic Genetics services providers (2) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors & Reviewers

Initial Publication: September 2014; Last Update: November 2011
Current Authors and Reviewers (click on name for bio):
Author: Nicola Longo, MD, Ph.D.
Authoring history
(Limited detail is available on authoring dates before 2014.)
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

American College of Medical Genetics.
Newborn screening ACT Sheet (Increased Phenylalanine) Phenylketonuria (PKU).
American College of Medical Genetics; (2011) http://www.acmg.net/StaticContent/ACT/Phenylalanine.pdf. Accessed on 11/12/2018.

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

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

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

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract

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

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