AUTHOR INFORMATION

Section 1 of 12

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

Georgianne L Arnold, MD, is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American Society of Human Genetics

Edited by Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Georgianne L Arnold, MD
Editor's Email:	Christian J Renner, MD

eMedicine Journal, June 5 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 12

Background: Phenylketonuria (PKU) is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid phenylalanine. Classic PKU 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 the chapter on Hyperphenylalaninemia. Elevated phenylalanine levels negatively impact developmental function, and individuals with classic PKU are almost always mentally retarded unless levels are controlled through dietary treatment. In the United States and many other countries, PKU is detected by newborn screening, and treated individuals have normal intelligence.

Pathophysiology: The majority of individuals with PKU 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, though 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 exists between control of blood phenylalanine levels in childhood and intelligence quotient (IQ). Subtle neuropsychological deficits in children with treated PKU 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 PKU. 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:

• In the US: Incidence of classic PKU is approximately 1 in 15,000 births.

• Internationally: 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 PKU have severe mental retardation. After the discovery of PKU, routine testing of institutionalized patients who are mentally retarded identified a 1% incidence of PKU 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 PKU often experience subtle performance and attention and behavioral changes when phenylalanine levels exceed 6 mg/dL.

Race:

• In the United States, PKU is most commonly present in Caucasians.

• Worldwide, PKU is most common in Caucasians and Asians.

Sex:

• No sex predilection exists.

• Women with PKU must maintain phenylalanine levels between 2-6 mg/dL during pregnancy to avoid birth defects and mental retardation in their infants.

Age:

• PKU most commonly is diagnosed in newborns by newborn screening programs.

• Consider PKU at any age in an individual who is developmentally delayed or mentally retarded because infants are missed by newborn screening programs on rare occasions.

CLINICAL

Section 3 of 12

History:

• Most individuals 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.



• IQs may drop by 10 points or more if the diet is stopped in mid childhood.

Physical:

• The most common finding of untreated phenylketonuria (PKU) is mental retardation.



• The physician also may identify the following:


• • Mousy odor
  
  
  
  • Eczema
  
  
  
  • Fair coloring as a result of tyrosine deficiency
  
  
  

Causes:

• PKU is caused by autosomal recessive inheritance due to mutations in the enzyme phenylalanine hydroxylase. The enzyme locus is on chromosome arm 12q. Over 100 known mutations exist, 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.

DIFFERENTIALS

Section 4 of 12

Hyperphenylalaninemia
Tetrahydrobiopterin Deficiency
Tyrosinemia

Other Problems to be Considered:

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

WORKUP

Section 5 of 12

Lab Studies:

• Screening


• • 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 (PKU).
  
  
  
  • 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 PKU.

Imaging Studies:

• Magnetic resonance imaging


• • 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 commonly are found. These areas appear to be related to both higher phenylalanine levels in the blood and brain and to poorer cognitive outcome.
  
  
  
• Preliminary indications suggest that brain phenylalanine levels can be measured by magnetic resonance spectroscopy (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 exists regarding 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

Section 6 of 12

Medical Care:

• Most patients 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 (PKU) who are mentally retarded adults 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 PKU, usually as part of a PKU 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.

• Aspartame also must 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 PKU 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 will cheat by consuming meat.

Activity: Normal activity is expected with adherence to treatment.

MEDICATION

Section 7 of 12

Avoid drugs containing 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).

Up to one half of children with classic PKU may respond to administration of the biopterin cofactor, with lowering of plasma phenylalanine levels by approximately one third. However, this cannot yet replace dietary restriction of phenylalanine, even if that restriction can be relaxed slightly. Biopterin is not yet FDA approved in the United States and is not yet available outside of clinical trials.

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

Drug Category: 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.

Drug Name	Large neutral amino acids (PhenylAde-PreKunil) -- Adults and older teenagers refusing diet 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. This preparation 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.
Adult Dose	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 Dose	<15 years: Not recommended
Contraindications	Pregnancy
Interactions	None reported, data limited
Pregnancy	X - Contraindicated in pregnancy
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

FOLLOW-UP

Section 8 of 12

In/Out Patient Meds:

• 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

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to provide adequate phenylalanine 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:

• Pregnancy


• • 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.
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: When a physician receives notification of an abnormal phenylketonuria screen, what is the proper course of action?

A: Immediately begin a phenylalanine-free formula.
B: Admit the child to the hospital.
C: Reassure the parents that most screening test results are falsely positive.
D: Follow the instructions from the screening laboratory.
E: Stop breastfeeding.

The correct answer is D: The physician may be instructed by the screening laboratory to repeat the screen, or to make an urgent referral to a metabolic facility, depending on the nature of the abnormality and local laboratory standards. The physician should never advise the mother to stop breastfeeding or switch to a phenylalanine-free formula unless advised to do so by a metabolic treatment facility, as breast milk is lower in phenylalanine than proprietary formulas and some phenylalanine is required in the diet to meet the needs for growth and development.

CME Question 2: When are children with phenylketonuria advised to stop their diet?

A: At age 6 years
B: Never
C: When the EEG is normal
D: If the IQ is normal
E: Before pregnancy

The correct answer is B: Recent evidence notes IQ loss and performance decline when the diet is stopped. Thus, diet cessation is no longer recommended in most US clinics (although we tend to be a bit more lenient with phenylalanine levels in teens). However, some investigators do not feel that potential intellectual or performance losses are clinically significant, and they may allow patients to abandon the diet in the late teen or adult years. The diet must never be stopped in pregnancy because birth defects and mental retardation in the infant may result.

Pearl Question 1 (T/F): Gummy bears are considered appropriate for the phenylketonuria (PKU) diet because they are low in phenylalanine.

The correct answer is False: Gummy bears are restricted because they contain gelatin. Gelatin-containing snacks, such as gummy bears, marshmallows, and candy corn, may contain significant amounts of phenylalanine. Reading labels is a must on this diet. Most starchy foods also contain significant amounts of phenylalanine and must be restricted. For example, a small order of fries or a slice of regular bread contains about half the daily phenylalanine allotment.

Pearl Question 2 (T/F): Children with phenylketonuria (PKU) who are overweight should drink diet beverages that contain aspartame instead of beverages that contain sugar because these children are more prone to sugar highs.

The correct answer is False: 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, 33-50% of the usual daily intake of phenylalanine). Evidence that sugar affects behavior in children with PKU (or in children without PKU) does not exist.

Pearl Question 3 (T/F): Children with elevated phenylalanine levels can be at risk for mild dopamine deficiency in the frontal lobes.

The correct answer is True: Neuropsychological deficits in attention, organization, and processing can be mapped to the prefrontal cortex in children with treated phenylketonuria when phenylalanine levels are greater than 6 mg/dL, even when intelligence is normal. Some indirect evidence supports the idea that this highly dopamine-dependent area of the brain is most affected because elevated phenylalanine levels impair transport of tyrosine across the blood-brain barrier, thus reducing the availability of dopamine (a metabolite of tyrosine) in the brain.

Pearl Question 4 (T/F): Children with phenylketonuria (PKU) follow a protein-restricted diet.

The correct answer is False: The PKU diet is restricted in phenylalanine but not in total protein. Phenylalanine-containing foods are allowed until the daily allotment is met. The remainder of the protein intake comes from some form of medical food or formula, which contains phenylalanine-free amino acids. The medical foods may or may not contain vitamins, minerals, fat, and carbohydrate, depending on the preparation and age of the patient. Individuals with PKU who are not compliant with their medical food are at risk for nutritional deficiencies.

PICTURES

Section 11 of 12

Caption: Picture 1. Phenylalanine hydroxylase converts phenylalanine to tyrosine.
	View Full Size Image
	eMedicine Zoom View (Interactive!)
Picture Type: Graph

BIBLIOGRAPHY

Section 12 of 12

• 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].
• Bekhof J, van Spronsen FJ, Crone MR, et al: Influence of knowledge of the disease on metabolic control in phenylketonuria. Eur J Pediatr 2003 Jun; 162(6): 440-2[Medline].
• 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].
• 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].
• Fisch RO, Matalon R, Weisberg S, Michals K: Phenylketonuria: current dietary treatment practices in the United States and Canada. J Am Coll Nutr 1997 Apr; 16(2): 147-51[Medline].
• Matalon R, Michals-Matalon K, Koch R, et al: Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Mol Genet Metab 2005 Dec; 86 Suppl 1: S17-21[Medline].
• Scriver CR, Kaufman S, Eisensmith RC: The Hyperphenylalaninemias. The Metabolic and Molecular Bases of Inherited Disease 1995; 1: 1015-1076.
• Smith I, Beasley MG, Ades AE: Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 1991 Mar; 66(3): 311-6[Medline].
• 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].

eMedicine Journals > Pediatrics > Genetics And Metabolic Disease > Phenylketonuria

Please email us with any comments you have on our new chapter format.

Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Pictures | Bibliography