eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Phenylketonuria: Treatment & Medication
Updated: Feb 13, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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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.
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
None reported, data limited
Pregnancy
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.
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
None known
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 Phenylketonuria |
| Overview: Phenylketonuria |
| Differential Diagnoses & Workup: Phenylketonuria |
 Treatment & Medication: Phenylketonuria |
| Follow-up: Phenylketonuria |
| Multimedia: Phenylketonuria |
| References |
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References
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].
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].
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].
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].
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. Jun 2003;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. Apr 1997;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. Dec 2005;86 Suppl 1:S17-21. [Medline].
Scriver CR, Kaufman S, Eisensmith RC. The hyperphenylalaninemias. In: The Metabolic and Molecular Bases of Inherited Disease. Vol 1. 1995:1015-76.
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].
Further Reading
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
