Approach
Patients with PKU should be carefully managed to avoid both the consequences of the untreated disorder and nutritional deficiencies, which can be associated with inappropriate dietary management. Such treatment is ideally conducted by a multidisciplinary team, including a metabolic specialist, a specially trained metabolic dietitian, and a social worker. Treatment should be continued for life.
Dietary treatment
The mainstay of treatment for PKU is dietary therapy involving restriction of dietary protein and phenylalanine (phe) intake, and supplementation of all other amino acids in the form of specialized formulas or other dietary products.[1] In infancy, this is achieved by providing the infant with a special phe-free formula supplemented with either breast milk or standard infant formula to supply the daily phe requirement. Phe-free formula is readily available by prescription, and is typically only prescribed by metabolic physicians.
Older children continue to drink a special phe-free product to provide their protein and calorie requirements, but obtain their limited prescribed daily phe requirement from food, including low-protein foods, fruits, and vegetables.
All meats, dairy products, rice, pasta, and commercial baked goods are restricted from the diet of patients with classical PKU. Patients with milder forms of the disorder require a less restrictive diet. The diets of patients with PKU should be carefully monitored by assessment of diet diaries, measurements of growth parameters, and laboratory studies, when indicated, to ensure that patients are receiving adequate calories, protein, and trace minerals.[1][14] Supplements such as calcium or multivitamins might be needed in some cases.
Tetrahydrobiopterin therapy
Between 20% and 50% of all patients with PKU respond to treatment with BH4 with a significant reduction in the blood phe level.[6] As a result of improved blood phe control, treatment with BH4 can lead to improvement in neurocognitive outcome. In well-controlled patients started on BH4, diet liberalization is often possible.
Some patients with mild forms of PKU may be completely controlled with BH4 therapy alone, without the need for any dietary protein or phe restriction.[6] Since late 2007, an approved form of BH4, sapropterin, has been available. BH4 serves as a cofactor in the phenylalanine hydroxylase reaction; it acts by activating the residual enzyme present in patients with PKU to increase phe conversion to tyrosine. Not all patients are responsive, because some have no residual enzyme present to activate.
In patients with a baseline blood phe near the normal range, it may be necessary to assess responsiveness by adding additional phe to the diet in stepwise increments and assessing phe tolerance. Patients should be continued on therapy until the blood phe level and the diet are stabilized. At that time, the dose could be lowered to determine whether therapeutic efficacy is preserved. Adverse effects associated with BH4 therapy have generally been mild and self-limited.[4]
Pegvaliase
Pegvaliase (injectable pegylated phenylalanine ammonia lyase) is an enzyme present in plants and bacteria but not in humans or other mammals. It converts phenylalanine (phe) to ammonia and trans-cinnamic acid, which are easily excreted. It has been developed as enzyme substitution therapy for patients with PKU to provide an alternative mechanism for phe metabolism.[15]
Pegvaliase is indicated for adolescent and adult patients and allows many treated individuals to achieve normal or near normal blood phe levels, even on an unrestricted diet. Pegvaliase is indicated to reduce blood phe levels in patients who have uncontrolled blood phe levels >10 mg/dL on existing management. It is approved for use in adults in the US and adolescents ≥16 years of age, and in adults in Europe.
Hypersensitivity reactions occur commonly, probably because antibodies to the product are produced. Because of the serious risk of anaphylaxis, the labeling includes a warning and the product is available only through a restricted Risk Evaluation and Mitigation Strategy program, which includes certification and training of prescribers, certification of pharmacies, and certification and education of patients. Consider premedication with an antihistamine and/or antipyretic for hypersensitivity reactions. Administer the first dose under medical supervision and observe the patient for 60 minutes after injection. Auto-injectable epinephrine (adrenaline) must be prescribed and be available at all times for patients taking pegvaliase.[16]
Large neutral amino acids (LNAA)
LNAA share a common transporter with phe at the level of the blood-brain barrier. It has been suggested that treatment with LNAA could reduce brain phe levels and ameliorate symptoms in patients with PKU, without altering blood phe levels.[17] A different LNAA mixture may compete with phe for absorption at the intestinal level, leading to a reduction in the blood phe level.[18]
Further data are needed to address the efficacy and safety of these products. It seems prudent to restrict their use to adolescent and adult patients whose disorder cannot be adequately controlled by dietary therapy or by tetrahydrobiopterin.
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