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Hyperphenylalaninemia: Treatment & Medication

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
Contributor Information and Disclosures

Updated: Feb 13, 2009

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.

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

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

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

More on Hyperphenylalaninemia

Overview: Hyperphenylalaninemia
Differential Diagnoses & Workup: Hyperphenylalaninemia
Treatment & Medication: Hyperphenylalaninemia
Follow-up: Hyperphenylalaninemia
Multimedia: Hyperphenylalaninemia
References
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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.

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Further Reading

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Keywords

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

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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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