AUTHOR INFORMATION

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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; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; 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 1 2006, VOLUME 7, Number 6

INTRODUCTION

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Background: Hyperphenylalaninemia is defined broadly as the presence of blood phenylalanine levels exceeding the limits of the upper reference range (2 mg/dL or 120 mmol/L) but trailing the levels found in patients with phenylketonuria (PKU). Phenylalanine levels exceeding 20 mg/dL (1200 mmol/L) are considered diagnostic for PKU (see Phenylketonuria). This chapter describes nonphenylketonuric hyperphenylalaninemia, which includes phenylalanine levels between 2 mg/dL and 20 mg/dL.

Phenylalanine levels of 6 mg/dL (360 mmol/L) or less in patients consuming an unrestricted diet generally indicate a benign condition. No dietary phenylalanine restrictions usually are recommended for individuals with levels in this range. In contrast, dietary restriction may be indicated for patients whose phenylalanine levels are more than 12 mg/dL (725 mmol/L); chronic phenylalanine levels in this range reportedly cause measurable intellectual impairment in children.

Dietary treatment is somewhat controversial for children with phenylalanine levels in the intermediate range of 7-11 mg/dL (425-660 mmol/L). For example, one study noted that most centers in the United States recommend restricting dietary phenylalanine when levels exceed 10 mg/dL (600 mmol/L). Many also recommend treatment for levels exceeding 8-9 mg/dL (480-545 mmol/L). The British Medical Research Council Working Party on PKU recommends dietary phenylalanine restriction when levels consistently exceed 6.6-10 mg/dL (400-600 mmol/L).

Pathophysiology: Hyperphenylalaninemia is caused by defects in the gene that encodes the enzyme phenylalanine hydroxylase, impairing the conversion of phenylalanine to tyrosine. Defects in the same gene also result in classic PKU. Broad genotype/phenotype correlations have been made (ie, mild or hyperphenylalaninemia alleles vs severe or PKU alleles), although phenylalanine tolerance may vary in unrelated individuals with identical mutations. A small percentage of individuals with elevated phenylalanine levels have normal phenylalanine hydroxylase activity but lack tetrahydrobiopterin, a crucial cofactor.

Frequency:

• In the US: Frequency is approximately 15-75 cases per 1,000,000 births.

• Internationally: The condition is less prevalent than classic PKU and shows less variation in incidence among populations.

Mortality/Morbidity:

• Most individuals with hyperphenylalaninemia have normal life expectancy.

• Several studies have identified a linear relationship between phenylalanine level and intelligence testing and performance. Intelligence quotients seem less affected by benign hyperphenylalaninemia than by PKU, even at seemingly the same levels of serum phenylalanine. This effect may be due to smaller fluctuations of serum phenylalanine concentration.

Race:

• Hyperphenylalaninemia occurs in all races.

Sex:

• Both sexes are affected equally because deficiency in phenylalanine hydroxylase activity is inherited as an autosomal-recessive trait.

• Pregnant women with phenylalanine levels exceeding 6 mg/dL risk having children with microcephaly, mental retardation, and birth defects (eg, maternal hyperphenylalaninemia).

Age:

• Hyperphenylalaninemia most commonly is diagnosed by newborn screening and must be distinguished from classic PKU by confirmatory testing at an experienced center.

• Some cases in adult women have been detected using maternal screening programs or following birth of children with birth defects.

• Elevated phenylalanine levels are associated with neuropsychological effects.

CLINICAL

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History:

• An abnormal newborn screen is the most common history. Infants are screened for elevated phenylalanine in every US state and in Puerto Rico. Several other countries also have established screening programs.



• Affected individuals missed by screening may have mild-to-moderate performance deficits, depending on the degree of phenylalanine elevation.



• At phenylalanine levels near 20 mg/dL, PKU-like symptoms may emerge, including more pronounced developmental abnormalities, eczema, and vomiting. Preliminary evidence indicates milder attention and organizational problems may arise when levels exceed 6 mg/dL.

Physical:

• Most children have few abnormal findings on physical examination.



• Some physical stigmata of PKU may be present in individuals who have phenylalanine levels near 20 mg/dL. PKU-like symptoms include eczema and fair hair and skin coloring.

Causes:

• Genetic defects in phenylalanine hydroxylase cause most cases of hyperphenylalaninemia. In a few cases, defective synthesis or recycling of the biopterin cofactor is the cause (see Tetrahydrobiopterin Deficiency).



• In some children with mild enzyme deficits, excessive protein intake may elevate phenylalanine levels to a range requiring treatment. The problem may resolve when protein intake is reduced to more ordinary levels. For example, infants with nonphenylketonuric hyperphenylalaninemia who consume excessive infant formula (60-70 oz/d or 1800-2100 mL/d) may demonstrate phenylalanine levels exceeding 10-12 mg/dL. Levels may fall when formula intake is restricted to 32-40 oz/d.

DIFFERENTIALS

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Phenylketonuria
Tetrahydrobiopterin Deficiency
Tyrosinemia

Other Problems to be Considered:

Liver disease
Tyrosinemia type II (Richner-Hanhart syndrome)

WORKUP

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Lab Studies:

• Screening


• • Follow up abnormal newborn screening cases in accordance with local regulations. Different states or authorities may have a variety of protocols regarding result interpretation and follow-up. Do not restrict dietary phenylalanine or interrupt breastfeeding based on screening results unless instructed by a health official or treatment center. However, immediately refer the patient to a treatment center for confirmatory testing.

  • Low-grade elevations may require repeat screening. Phenylalanine levels can rise for several weeks after birth in children with hyperphenylalaninemia or PKU. A low-grade elevation 24-72 hours following birth might signal true PKU, not merely hyperphenylalaninemia.
  
  
  
• Measure plasma phenylalanine and tyrosine levels as soon as possible after an abnormal screening result. An elevated phenylalanine level with low or normal tyrosine level is expected. Remember that patients with liver disease or tyrosinemia typically have elevated phenylalanine and tyrosine levels.



• Order blood and urine biopterins assays by a qualified laboratory to exclude a tetrahydrobiopterin defect.

Procedures:

• Diagnostic procedures, such as phenylalanine or biopterin loading tests, rarely are indicated.

TREATMENT

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Medical Care: If available, patients should be evaluated at a PKU treatment center. The extent of the hyperphenylalaninemia determines the nature and frequency of follow-up.

• Many patients with hyperphenylalaninemia show an excellent response to treatment with tetrahydrobiopterin cofactor (also known as biopterin or BH4). In many cases, the residual enzyme activity is stabilized and dietary phenylalanine restriction can be relaxed. However, not all children with hyperphenylalaninemia respond to biopterin.



• Animal studies are underway for injectable phenylamine ammonium lyase, an enzyme substitute. This shows promise as an alternative treatment to control phenylalanine levels.

Consultations:

• If dietary treatment is necessary, refer the patient to a dietitian experienced with PKU (usually a member of a PKU treatment team).



• Refer families of affected infants to a medical geneticist or genetic counselor to review the inheritance of hyperphenylalaninemia.

Diet:

• Determine the degree of dietary phenylalanine restriction for each patient based on untreated phenylalanine levels. For more detailed information on a phenylalanine-restricted diet, see
  Phenylketonuria.



• Breastfeeding usually is possible and should not be stopped unless so instructed by a local health official or treatment center.



• Aspartame restriction


• • Phenylalanine is a primary component of aspartame.

  • Aspartame may be present in many artificially sweetened substances, including medicines, vitamins, beverages, and foods. A pharmacist can help determine if a medication has a significant amount of aspartame.

  • The amount of aspartame in a children's vitamin or in a teaspoon of antibiotic may be significant for a child who can tolerate only 200 mg/d of phenylalanine, yet such a dose may be insignificant for a child who can tolerate more than 1000 mg/d.

  • Stringent phenylalanine-restricted diets have been reported to cause deficiencies of zinc, selenium, and other nutrients in patients with PKU. However, the most common deficiency is mild-to-moderate iron deficiency. Although iron is supplemented in the amino acid supplement formulas consumed by patients as part of such diets, absence of dietary heme iron and poor absorption of supplemental iron often result in deficiency.
  
  
  

Activity: Do not restrict activities.

MEDICATION

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Some children respond to biopterin supplementation. However, this is not yet approved by the Food and Drug Administration in the United States. Biopterin loading to test responsiveness is recommended where the drug is available.

Consider restricting use of drugs containing aspartame.

FOLLOW-UP

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Further Outpatient Care:

• Phenylalanine levels determine the need for further outpatient care.

Deterrence/Prevention:

• In general, patients should avoid consuming aspartame because phenylalanine is a primary component of aspartame.

Prognosis:

• Prognosis is excellent for normal development when treated as indicated.

Patient Education:

• Teach patients and parents about proper diet. Children should participate in their dietary planning as soon as they have that ability.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to provide adequate dietary phenylalanine, an essential amino acid



• Failure to recommend adequate phenylalanine restriction



• Failure to acknowledge the teratogenic effects of phenylalanine in pregnant women

Special Concerns:

• Excessively low phenylalanine levels can cause poor growth; all patients on dietary restrictions require careful follow-up.



• Although elevated maternal phenylalanine levels are associated with birth defects, excessively low levels during pregnancy also are associated with poor fetal growth and microcephaly.



• A few patients with mild-to-moderate elevations of phenylalanine later present with levels requiring dietary treatment. For this reason, follow-up over time is recommended.

TEST QUESTIONS

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CME Question 1: A physician is informed of a newborn with a phenylalanine level of 5 mg/dL from the newborn screen. Which of the following possibilities is the proper course of action?

A: Reassure the parents that this level does not require treatment.
B: Repeat the newborn screen.
C: Begin a phenylalanine-free formula.
D: Stop breastfeeding.
E: Follow the instructions of the screening laboratory.

The correct answer is E: Phenylalanine levels can rise for several weeks after birth in children with hyperphenylalaninemia or PKU. A level of 5 mg/dL at 24-72 hours of life might signal true PKU, not merely hyperphenylalaninemia. Different states and authorities have a variety of protocols regarding interpretation and follow-up of newborn screening results. In most states, a 5 mg/dL level prompts referral for immediate evaluation by a metabolic treatment center, not merely a repeat of the screen. Physicians should not restrict dietary phenylalanine or interrupt breastfeeding based on an initial screening result unless so instructed by a health official or PKU treatment center.

CME Question 2: Aspartame may be present in which of the following items?

A: Antibiotics
B: Vitamins
C: Beverages
D: All of the above
E: None of the above

The correct answer is D: Aspartame may be present in many artificially sweetened substances, including medicines, vitamins, beverages, and foods. A pharmacist can determine if a medication contains a significant amount of aspartame. The degree of aspartame restriction recommended depends on phenylalanine levels. The amount of aspartame in a children`s vitamin or in a teaspoon of antibiotic may be significant for a child who can tolerate only 200 mg/d of phenylalanine, yet such a dose may be insignificant for a child who can tolerate more than 1000 mg/d.

Pearl Question 1 (T/F): Children with hyperphenylalaninemia should avoid foods containing aspartame.

The correct answer is True: A primary ingredient of aspartame, an artificial sweetener, is phenylalanine. Eating aspartame-sweetened foods can increase levels of phenylalanine.

Pearl Question 2 (T/F): Iron is the trace metal most likely to be deficient in a stringent phenylalanine-restricted diet.

The correct answer is True: While deficiencies of zinc, selenium, and other nutrients have been described in phenylketonuria (PKU), the most common deficiency is mild-to-moderate iron deficiency. Although iron is supplemented in the medical foods (formulas) consumed by patients as part of this diet, absence of dietary heme iron and poor absorption of supplemental iron often result in deficiency.

Pearl Question 3 (T/F): Patients with biopterin cofactor deficiencies have relatively poor outcome, even when dietary phenylalanine is restricted.

The correct answer is True: The biopterin cofactor also is involved in the hydroxylation of tyrosine (a precursor of dopamine) and tryptophan (a precursor of serotonin). Thus, patients have additional neurological deficits unresponsive to dietary treatment alone.

Pearl Question 4 (T/F): The goal of a phenylalanine-restricted diet is to lower phenylalanine levels into the normal range (<2 mg/dL).

The correct answer is False: The phenylalanine restriction required to lower levels into the normal range would result in insufficiency of this essential amino acid, leading to negative nitrogen balance, growth deficiency, and potentially impaired brain growth. The goal `treatment range` for phenylalanine levels in children with phenylalanine hydroxylase deficiency is 2-6 mg/dL.

PICTURES

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Caption: Picture 1. Phenylalanine hydroxylase converts phenylalanine to tyrosine.
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BIBLIOGRAPHY

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• Agostoni C, Verduci E, Massetto N, et al: Long term effects of long chain polyunsaturated fats in hyperphenylalaninemic children. Arch Dis Child 2003 Jul; 88(7): 582-3[Medline].
• Berlin CM, Levy HL, Hanley WB: Delayed increase in blood phenylalanine concentration in phenylketonuric children initially classified as mild hyperphenylalaninemia. Screening 1995; 4: 35-39.
• Diamond A, Prevor MB, Callender G: Prefrontal cortex cognitive deficits in children treated early and continuously for PKU. Monogr Soc Res Child Dev 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].
• Gassio R, Artuch R, Vilaseca MA, et al: Cognitive functions in classic phenylketonuria and mild hyperphenylalaninemia: experience in a pediatric population. Dev Med Child Neurol 2005; 47: 443-8[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].
• Medical Research Council Working Party on Phenylketonuria: Recommendations on the dietary management of phenylketonuria. Arch Dis Child 1993 Mar; 68(3): 426-7[Medline].
• Scriver CR, Kaufman S, Eijsensmith RC: The Hyperphenylalaninemias. The Metabolic and Molecular Bases of Inherited Disease 1995; 1: 1015-1076.

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