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Hyperphenylalaninemia

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

Hyperphenylalaninemia is broadly defined as the presence of blood phenylalanine levels that exceed the limits of the upper reference range (2 mg/dL or 120 mmol/L) but trail the levels found in patients with phenylketonuria (PKU). Phenylalanine levels that exceed 20 mg/dL (1200 mmol/L) are considered diagnostic for PKU (see Phenylketonuria). This article describes nonphenylketonuric hyperphenylalaninemia, which includes phenylalanine levels of 2-20 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 are usually 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 that exceed 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

United States

Frequency is approximately 15-75 cases per 1,000,000 births.

International

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 the 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 equally affected because deficiency in phenylalanine hydroxylase activity is inherited as an autosomal-recessive trait. Pregnant women with phenylalanine levels that exceed 6 mg/dL risk having children with microcephaly, mental retardation, and birth defects (eg, maternal hyperphenylalaninemia).

Age

Hyperphenylalaninemia most is commonly 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

History

  • An abnormal newborn screen is the most common history in patients with hyperphenylalaninemia. 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, phenylketonuria (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.

Differential Diagnoses

Phenylketonuria
Tetrahydrobiopterin Deficiency
Tyrosinemia

Other Problems to Be Considered

Liver disease
Tyrosinemia type II (Richner-Hanhart syndrome)

Workup

Laboratory Studies

  • Screening for hyperphenylalaninemia includes the following:
    • Newborns with abnormal screening findings should be monitored in accordance with local regulations. Different states or authorities may have various 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 phenylketonuria (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.
  • Obtain blood and urine biopterins assays through a qualified laboratory to exclude a tetrahydrobiopterin defect.

Procedures

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

Treatment

Medical Care

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

  • In one study, 54% of patients with phenylalanine levels less than 600 mmol (10 mg/dL) demonstrated a decline of 30% or more in plasma phenylalanine levels when sapropterin (commercial tetrahydrobiopterin cofactor) was administered at a dose of 10 mg/kg/d.[1 ] The percentage of patients who responded declined with increasing plasma phenylalanine levels. Response to sapropterin may improve at a dose of 20 mg/kg/d.[2 ]
  • Animal studies are underway for injectable phenylamine ammonium lyase, an enzyme substitute. This shows promise as an alternative treatment to control phenylalanine levels.[3 ]

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 is usually possible and should not be stopped unless instructed by a local health official or treatment center.
  • Aspartame restriction may be indicated.
    • 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

Pteridines

Some children respond to BH4 supplementation. Synthetic BH4 (sapropterin) is now approved 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

Further Outpatient Care

  • Phenylalanine levels determine the need for further outpatient care in patients with hyperphenylalaninemia.

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

Medicolegal 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 are also 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.

Multimedia

Phenylalanine hydroxylase converts phenylalanine ...

Media file 1: Phenylalanine hydroxylase converts phenylalanine to tyrosine.

References

  1. 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].

  2. 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].

  3. 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].

  4. Agostoni C, Verduci E, Massetto N, et al. Long term effects of long chain polyunsaturated fats in hyperphenylalaninemic children. Arch Dis Child. Jul 2003;88(7):582-3. [Medline].

  5. 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.

  6. 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].

  7. 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].

  8. 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].

  9. Medical Research Council Working Party on Phenylketonuria. Recommendations on the dietary management of phenylketonuria. Arch Dis Child. Mar 1993;68(3):426-7. [Medline].

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

Keywords

hyperphenylalaninemia, phenylketonuria, benign PKU, mild PKU, nonphenylketonuric hyperphenylalaninemia,  phenylalanine, microcephaly, mental retardation, birth defects, maternal hyperphenylalaninemia, tetrahydrobiopterin deficiency, enzyme defect

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

Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine
Margaret McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
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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