eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Phenylketonuria

Georgianne L Arnold, MD, Director of Inherited Metabolic Disorders Clinic, Department of Pediatrics and Genetics, Associate Professor, University of Rochester School of Medicine and Dentistry

Updated: Feb 13, 2009

Introduction

Background

Phenylketonuria (PKU) is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid phenylalanine. Classic phenylketonuria is present when plasma phenylalanine levels exceed 20 mg/dL (1200 mmol/L) without treatment. Lesser degrees of elevation of plasma phenylalanine are considered in Hyperphenylalaninemia. Elevated phenylalanine levels negatively impact developmental function, and individuals with classic phenylketonuria almost always have mental retardation unless levels are controlled through dietary treatment. In the United States and many other countries, phenylketonuria is detected by newborn screening, and treated individuals have normal intelligence.

Pathophysiology

Most individuals with phenylketonuria have a deficiency of the enzyme phenylalanine hydroxylase. Phenylalanine hydroxylase deficiency is inherited in an autosomal recessive manner.

The mechanism by which elevated phenylalanine levels cause mental retardation is not known, although restriction of dietary phenylalanine ameliorates this effect if initiated within a few weeks of birth. This also results in normal cognitive development. A strong relationship between control of blood phenylalanine levels in childhood and intelligence quotient (IQ) is recognized. Subtle neuropsychological deficits in children with treated phenylketonuria are under investigation. Some investigators have attributed these deficits to small residual neurotransmitter abnormalities.

A small percentage of children with elevated phenylalanine levels exhibit normal phenylalanine hydroxylase but have a deficiency in synthesis or recycling of the enzyme's cofactor, tetrahydrobiopterin (see Tetrahydrobiopterin Deficiency). This condition is termed malignant phenylketonuria. The biopterin cofactor is also required for hydroxylation of tyrosine (a precursor of dopamine) and tryptophan (a precursor of serotonin). Thus, individuals with tetrahydrobiopterin cofactor deficiency have more significant neurological problems that are not fully corrected by dietary phenylalanine reduction.

Frequency

United States

Incidence of classic phenylketonuria is approximately 1 in 15,000 births.

International

Disease frequency varies by population. Turkey has the highest incidence in the world with approximately 1 in 2600 births. High incidence is also reported in the Yemenite Jewish population, as well as in regions of northern and eastern Europe, Italy, and China.

Mortality/Morbidity

Most untreated individuals with phenylketonuria have severe mental retardation. After the discovery of phenylketonuria, routine testing of institutionalized patients with mental retardation identified a 1% incidence of phenylketonuria in this group. Well-treated patients should have IQs within approximately 5-8 points of their siblings.

Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment. Treated patients with phenylketonuria often experience subtle performance and attention and behavioral changes when phenylalanine levels exceed 6 mg/dL.

Race

In the United States, phenylketonuria is most common in whites. Worldwide, phenylketonuria is most common in whites and Asians.

Sex

No sex predilection is known. Women with phenylketonuria must maintain phenylalanine levels between 2-6 mg/dL during pregnancy to avoid birth defects and mental retardation in their infants.

Age

Phenylketonuria is most commonly diagnosed in newborns by newborn screening programs. Consider phenylketonuria at any age in an individual with developmental delay or mental retardation because infants are missed by newborn screening programs on rare occasions.

Clinical

History

• Most individuals with phenylketonuria (PKU) appear normal at birth.
• If newborn screening fails, progressive developmental delay is the most common presentation.
• Other findings in untreated children in later infancy and childhood may include vomiting, mousy odor, eczema, seizures, self-mutilation, and severe behavioral disorders.
• Older individuals who cease dietary treatment in childhood may have evidence of demyelination on MRI. Occasionally, deterioration of cognitive performance or motor skills also may be present.
• Intelligence quotients (IQs) may drop by 10 points or more if the diet is stopped in mid childhood.

Physical

• The most common finding of untreated phenylketonuria is mental retardation.
• The physician also may identify the following:
  • Mousy odor
  • Eczema
  • Fair coloring as a result of tyrosine deficiency

Causes

• Phenylketonuria is caused by autosomal recessive inheritance due to mutations in the enzyme phenylalanine hydroxylase. The enzyme locus is on chromosome arm 12q. More than 100 mutations are known, and mutation frequency varies among ethnic groups.
• Genotype and phenotype are broadly related (ie, reproducible mild vs severe mutations), but unrelated individuals with identical mutations have some degree of variability in phenylalanine tolerance.

Differential Diagnoses

Hyperphenylalaninemia
Tetrahydrobiopterin Deficiency
Tyrosinemia

Other Problems to Be Considered

Liver disease
Other causes of mental retardation
Tyrosinemia type II (Richner-Hanhart syndrome)

Workup

Laboratory Studies

• Screening for phenylketonuria (PKU) includes the following:
  • Follow up with abnormal newborn screening results in accordance with local regulations.
  • Low-grade elevations of phenylalanine may require repeat screening.
  • More significant elevations may require definitive testing and/or referral to a metabolic treatment facility experienced with phenylketonuria.
  • Late diagnoses are usually made during amino acid analysis of individuals who are developmentally abnormal.
• A qualified laboratory should measure plasma phenylalanine and tyrosine.
• A qualified laboratory should perform urine analysis of biopterin and neoptrins in order to rule out defects of biopterin synthesis or recycling.
• Follow nutritional adequacy on a regular basis because deficiencies of iron, vitamins, selenium, protein, essential fatty acids, and other nutrients have been reported in treated phenylketonuria.

Imaging Studies

• MRI
  • Cranial MRI studies may be indicated in older individuals who have abandoned the diet and are experiencing deficits in motor or cognitive function.
  • Areas of demyelination are common. These areas appear to be related to both higher phenylalanine levels in the blood and brain and to poorer cognitive outcome.
• Magnetic resonance spectroscopy (MRS): Preliminary indications suggest that brain phenylalanine levels can be measured by MRS and that these levels may be more predictive of outcome than blood phenylalanine levels. However, this work is done in only a few centers, and some controversy surrounds whether state-of-the-art technology makes it a useful clinical tool.

Procedures

• Older textbooks and protocols occasionally called for phenylalanine-loading studies to help determine if a child still required phenylalanine restriction after 1 or more years; however, as the treatment range for phenylalanine levels has decreased, these studies generally have been abandoned.

Treatment

Medical Care

• Most patients with phenylketonuria (PKU) are treated in a specialty metabolic clinic, usually under the auspices of a genetics or pediatric endocrinology clinic. Treatment consists of dietary restriction of phenylalanine with tyrosine supplementation. The extent of phenylalanine restriction necessary for normal outcome remains controversial.
• Phenylalanine levels are followed at regular intervals, from 1-2 times weekly in neonates to once per month in older children and adults. Most US facilities recommend that phenylalanine levels be maintained from 2-6 mg/dL (120-360 mmol/L).
• Some adults with untreated phenylketonuria who have mental retardation may show improvement in behavior and physical manifestations when treated with a phenylalanine-restricted diet.

Consultations

• A psychologist should perform developmental testing at regular intervals.
• Whenever possible, the patient and parents should work with a nutritionist experienced in phenylketonuria, usually as part of a phenylketonuria or metabolic clinic.

Diet

• The mainstay of the diet consists of phenylalanine restriction and supplementation of other essential amino acids, vitamins, minerals, and energy intake, using medical foods and low-protein foods.¹
• Aspartame must also be eliminated. Phenylalanine is one of the primary components of aspartame. It is found in many artificially sweetened foods and soft drinks, as well as some vitamins and medicines. A 12-oz can of aspartame-sweetened diet drink contains approximately 105 mg of phenylalanine (ie, 25-50% of the usual daily intake).
• The age at which the diet may be discontinued is somewhat controversial. Most US facilities no longer recommend discontinuation of the diet at any age.
• Most newborns with phenylketonuria require 40-60 mg/kg/d of dietary phenylalanine to maintain normal growth. Breastfeeding is usually possible and should not be stopped unless instructed to do so by a local health official or treatment facility. As growth slows, the phenylalanine requirement falls, and most older children and adults tolerate 200-400 mg/d.
• Providing some natural phenylalanine is essential in order to prevent deficiency of this essential amino acid. The diet requires elimination of all high-protein foods, such as meat, dairy, nuts, and legumes. Starches, including bread, potatoes, corn, and beans also must be restricted (a slice of bread or small order of fries contains approximately 120-150 mg phenylalanine).
• Essential amino acids, vitamins, and minerals must be supplemented using medical foods. Currently, most are consumed as a powder dissolved in liquid (ie, formula). Newer supplements, including capsules, amino acid bars, and amino acids cooked into foods, are becoming available.
• Energy and variety are provided by low-protein foods, including fruits and nonstarchy vegetables, as well as specially ordered low-protein foods. Low-protein foods include pastas, breads, imitation cheese, baking mixes, and other foods especially designated for low-protein diets. These foods are covered by medical benefits in some states.
• Because most patients prefer a standard American diet, most teens and older children (in our clinic) cheat by failing to limit quantities of high-protein, nonmeat foods, such as potatoes (eg, fries, chips, mashed potatoes), pasta, bread, and pizza crust (minus the cheese); however, few teens who were well managed as children cheat by consuming meat.

Activity

• Normal activity is expected with adherence to treatment.

Medication

Avoid drugs and food that contain aspartame. The efficacy of very high-dose tyrosine supplementation is under investigation. Reports conflict over whether or not this may ameliorate neuropsychological deficits of the prefrontal cortex observed in children with treated phenylketonuria (PKU).

Some patients with phenylketonuria experience significant lowering of plasma phenylalanine levels after administration of sapropterin (Kuvan), a commercial form of the biopterin cofactor.²  Unfortunately, those with some residual enzyme activity are more likely to respond compared with those with no residual enzyme. One study found that, although 54% of those with plasma phenylalanine levels less than 600 mmol (10 mg/dL) had a reduction in plasma phenylalanine levels of 30% or more after 10 mg/kg/d of sapropterin, only 10% of those with phenylalanine levels of more than 1200 mmol had such a response.²

Patients who refuse dietary treatment may somewhat benefit from consuming large neutral amino acids (PreKunil or NeoPhe). These may compete with phenylalanine at the blood-brain barrier and block phenylalanine entry into the brain and may also result in a modest lowering of plasma phenylalanine levels. One study of neuropsychological response to large neutral amino acid supplementation found no advantage to consuming large neutral amino acid supplements in patients already on diet and medical food; some benefit in executive functions in some domains was reported, but attention was better on diet and medical food.³

Animal studies are in progress on an injectable form of phenylalanine ammonium lyase, an alternate enzyme capable of substituting for phenylalanine hydroxylase.⁴

Drugs acting at the blood brain barrier

Some evidence suggests that consumption of high doses of other large neutral amino acids can increase competition with phenylalanine for crossing the blood brain barrier into the brain, thus decreasing phenylalanine levels in the brain.

Large neutral amino acids (NeoPhe-PreKunil)

Adults and older teenagers refusing dietary restrictions can be prescribed a preparation of high-dose large neutral amino acids. The long-term outlook merits further study. Young women of childbearing age need to realize this drug does not protect their fetus from the teratogenic effects of phenylalanine.
PreKunil does not contain lysine, an essential amino acid, and lysine deficiency has been reported. Individuals taking PreKunil continue to require nutritional assessment because teens and adults who are "off diet" often fail to consume sufficient protein to meet essential amino acid and vitamin/mineral requirements.

Dosing

Adult

Dose (number of tablets) is individualized by body weight (kg) X 0.4
For example, an individual who weighs 50 kg would receive 20 tab daily (ie, 50 kg X 0.4 = 20 tab)
Divide daily dose into 3-4 doses administered with meals or snacks

Pediatric

<15 years: Not recommended

Interactions

None reported, data limited

Contraindications

Pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Does not lower plasma phenylalanine levels and does not protect the fetus from elevated phenylalanine levels; does not allow unlimited consumption of high-protein foods; protein consumption not to exceed 1 g/kg/24 h

Pteridines

Some children respond to BH4 supplementation. Synthetic BH4 (sapropterin) is now approved as an orphan drug by the US Food and Drug Administration. Also consider restricting use of drugs and food that contain aspartame.

Sapropterin (Kuvan)

Synthetic form of tetrahydrobiopterin (BH4), the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates phenylalanine through an oxidative reaction to form tyrosine. PAH activity is absent or deficient in patients with PKU. Treatment with BH4 can activate residual PAH enzyme, improve normal oxidative metabolism of phenylalanine, and decrease phenylalanine levels in some patients. Indicated to reduce blood phenylalanine levels in patients with hyperphenylalaninemia caused by BH4-responsive PKU. Used in conjunction with a phenylalanine-restricted diet.

Dosing

Adult

10 mg/kg PO qd initially; dosage ranges from 5-20 mg/kg/d; dissolve tab in 4-8 oz of water or apple juice and drink contents within 15 min of dissolving (tab may not dissolve completely, but swallowing small pieces floating on top of water or juice is normal and safe); administer with food to increase absorption

Pediatric

<4 years: Not established
>4 years: Administer as in adults

Interactions

Use caution with coadministration of drugs known to affect folate metabolism (eg, methotrexate, sulfamethoxazole) and their derivatives because these drugs can decrease BH4 levels by inhibiting the enzyme dihydropteridine reductase (DHPR); coadministration with drugs that affect nitric oxide–mediated vasorelaxation (eg, PDE-5 inhibitors such as sildenafil, vardenafil, and tadalafil) may increase risk of hypotension; a 10-year postmarketing safety surveillance program for a non-PKU indication using another formulation of sapropterin resulted in 3 patients with underlying neurologic disorders experiencing convulsions, exacerbation of convulsions, overstimulation, or irritability during coadministration with levodopa

Contraindications

None known

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Regularly monitor blood phenylalanine levels to avoid hyperphenylalaninemia and resulting neurologic impairment and mental retardation; use does not eliminate need for ongoing dietary management (ie, phenylalanine-restricted diet); common adverse effects include headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, diarrhea, abdominal pain, vomiting, nausea, upper respiratory tract infection, and pharyngolaryngeal pain

Follow-up

Inpatient & Outpatient Medications

• Patients with phenylketonuria should avoid aspartame (an artificial sweetener). Aspartame is widely used in medicines, vitamins, beverages, and other substances.

Complications

• Subtle attention and performance deficits in organization and planning persist in treated patients. These deficits are related to phenylalanine levels and may interfere with academic achievement.
• A few patients experience psychological problems, including poor self-esteem. Agoraphobia and more severe problems have been described, especially in women who have discontinued the diet. Because phenylalanine competes with tryptophan (the precursor of serotonin) for entry into the brain, psychological symptoms may have a biological basis and improved dietary control is recommended.

Prognosis

• Prognosis for normal intelligence is excellent with dietary treatment. However, school functioning can be mildly impaired in some children, particularly when dietary control is poor.

Patient Education

• Teach parents how to administer the diet at home and involve all caregivers as well.
• Children should begin involvement in their dietary planning as soon as they are developmentally ready.

Miscellaneous

Medicolegal Pitfalls

• Failure to provide adequate phenylalanine to patients with phenylketonuria (PKU), resulting in deficiency of this essential amino acid (eg, beginning a phenylalanine-free formula in a neonate without adding a source of phenylalanine)
• Failure to consider diagnosis in a child who is developmentally abnormal even if screening was normal
• Failure to perform testing for biopterin defects
• Failure to provide adequate energy intake, essential amino acids, vitamins, and minerals
• Failure to monitor for common nutritional deficiencies
• Failure to recognize that screening may have been performed too soon (ie, before 12-24 h of life, depending on local standards), leading to in a false-negative result

Special Concerns

• Birth defects, microcephaly, and mental retardation are common in infants of mothers with phenylketonuria if the mother's phenylalanine levels are not controlled during pregnancy.
• Women must maintain phenylalanine levels from 2-6 mg/dL during pregnancy.

Multimedia

Media file 1: Phenylalanine hydroxylase converts phenylalanine to tyrosine.

References

1. Yannicelli S, Ryan A. Improvements in behaviour and physical manifestations in previously untreated adults with phenylketonuria using a phenylalanine-restricted diet: a national survey. J Inherit Metab Dis. 1995;18(2):131-4. [Medline].

2. Burton BK, Grange DK, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis. Oct 2007;30(5):700-7. [Medline].

3. Schindeler S, Ghosh-Jerath S, Thompson S, et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab. May 2007;91(1):48-54. [Medline].

4. Sarkissian CN, Gamez A, Wang L, et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc Natl Acad Sci U S A. Dec 30 2008;105(52):20894-9. [Medline].

5. Anderson PJ, Wood SF, Francis DE, et al. Neuropsychological function in children with early-treated phenylketonuria: impact of white matter abnormalities. Dev Med Child Neurol. 2004;46:230-8. [Medline].

6. Bekhof J, van Spronsen FJ, Crone MR, et al. Influence of knowledge of the disease on metabolic control in phenylketonuria. Eur J Pediatr. Jun 2003;162(6):440-2. [Medline].

7. Brumm VL, Azen C, Moats RA, et al. Neuropsyhchological outcome of subjects participating in the PKU adult collaborative study: a preliminary review. J Inherit Metab Dis. 2004;27:549-66. [Medline].

8. Diamond A, Prevor MB, Callender G, Druin DP. Prefrontal cortex cognitive deficits in children treated early and continuously for PKU. Monogr Soc Res Child Dev. 1997;62(4):i-v, 1-208. [Medline].

9. Fisch RO, Matalon R, Weisberg S, Michals K. Phenylketonuria: current dietary treatment practices in the United States and Canada. J Am Coll Nutr. Apr 1997;16(2):147-51. [Medline].

10. Matalon R, Michals-Matalon K, Koch R, et al. Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Mol Genet Metab. Dec 2005;86 Suppl 1:S17-21. [Medline].

11. Scriver CR, Kaufman S, Eisensmith RC. The hyperphenylalaninemias. In: The Metabolic and Molecular Bases of Inherited Disease. Vol 1. 1995:1015-76.

12. Smith I, Beasley MG, Ades AE. Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child. Mar 1991;66(3):311-6. [Medline].

Keywords

phenylketonuria, PKU, Folling disease, Folling's disease, hyperphenylalaninemia, phenylalanine hydroxylase deficiency, mental retardation, tetrahydrobiopterin deficiency, malignant phenylketonuria, agoraphobia, developmental delay, mousy odor, seizures, self-mutilation, behavioral disorder

Contributor Information and Disclosures

Author

Georgianne L Arnold, MD, Director of Inherited Metabolic Disorders Clinic, Department of Pediatrics and Genetics, Associate Professor, University of Rochester School of Medicine and Dentistry
Georgianne L Arnold, MD is a member of the following medical societies: American College of Medical Genetics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for the Study of Inborn Errors of Metabolism
Disclosure: Biomarin Grant/research funds clinical trial

Medical Editor

Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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