Approach Considerations
Most patients with phenylketonuria (PKU) are treated in a specialty metabolic disease clinic, and such patients are probably best served by being followed in such a clinic. A psychologist should perform developmental testing at regular intervals. Whenever possible, the patient and parents should work with a nutritionist experienced in PKU, usually as part of a PKU or metabolic disease clinic.
Treatment consists of dietary restriction of phenylalanine often with tyrosine supplementation. Other essential amino acids are supplemented using various medical foods, and vitamin, mineral, and other micronutrients are followed closely. Stringent phenylalanine-restricted diets have been reported to cause deficiencies of iron, zinc, selenium, and other nutrients and essential amino acids in patients with PKU; therefore, the diet requires careful monitoring by a professional trained in PKU management and frequently requires supplementation of required nutrients.
Phenylalanine levels are followed at regular intervals, from 1 to 2 times weekly in neonates to perhaps once per month in older children and adults. Most US facilities recommend that phenylalanine levels be maintained in the range of 2 mg/dL to 6 mg/dL (120-360 µmol/L). This requires expert care and close monitoring.
The diet should not be terminated after adolescence, because strong evidence indicates that hyperphenylalaninemia can have detrimental effects in adult patients. Some adults with untreated PKU who have cognitive decline may show improvement in behavior and physical manifestations when treated with a phenylalanine-restricted diet.
Normal levels of activity should be expected in patients who are adequately treated.
Sapropterin was approved by the US Food and Drug Administration (FDA) as a treatment for PKU. It seems to be effective in a subset of patients. Although patients with classic PKU are less likely to be responders, response has been documented in this group and a trial is not unreasonable. [19] It was estimated that 10% of patients with a classic presentation of PKU and most patients with milder manifestations may respond to sapropterin. [20]
In May 2018, the FDA approved the first enzyme substitute, pegvaliase (Palynziq), to reduce phenylalanine levels in adults with PKU who have uncontrolled phenylalanine levels of more than 600 µmol/L. [6]
Dietary Measures
Because of the lack of internationally accepted guidelines, the management of PKU varies among countries; however, it is generally agreed that dietary management and/or pharmacologic treatment are essential. 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. [5]
Aspartame must also be avoided. Phenylalanine is one of the primary components of aspartame and 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).
Most newborns with PKU require 40 mg/kg/d to 60 mg/kg/d of dietary phenylalanine to maintain normal growth and development. 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 mg/d to 400 mg/d.
Providing some natural phenylalanine is essential in order to prevent deficiency of this essential amino acid. The diet requires virtual 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 of phenylalanine).
Essential amino acids, vitamins, and minerals must be supplemented by using medical foods. Most are consumed as a powder dissolved in liquid (ie, formula). 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.
As patients with PKU transition into adolescence, their caregivers have a less direct influence on their diet. It is common to see these patients "cheat" by failing to limit foods such as potatoes, pasta, and bread.
Advice on specific diet recommendations can be found at many Web sites devoted to PKU. The Web site National PKU News has extensive dietary recommendations. Links to a variety of international organizations for PKU can be found under “Related Links.” The material is available in some languages other than English, including German, Danish, Dutch, and Spanish. Food companies distributing products useful for low-protein diets are also listed.
Pharmacologic Therapy
Alternative regimens have been developed in older patients who have difficulty adhering to a strict regimen. [21]
Patients who refuse dietary treatment may benefit to some degree from consuming large neutral amino acids. These may compete with phenylalanine at the blood-brain barrier and block phenylalanine entry into the brain, and they 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 (LNAA) 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. [22] Large neutral amino acid (LNAA) use in PKU remains somewhat controversial.
Some patients with PKU experience significant lowering of plasma phenylalanine levels after administration of sapropterin, a commercially available, FDA-approved form of the tetrahydrobiopterin (BH4) cofactor. [7] One study found that, although 54% of those with plasma phenylalanine levels lower than 600 µmol/L (10 mg/dL) had a reduction in plasma phenylalanine levels of 30% or more after 10 mg/kg/day of sapropterin, only 10% of those with phenylalanine levels higher than 1200 µmol/L had such a response. [7]
In May 2018, the FDA approved the first enzyme substitute, pegvaliase (Palynziq), to reduce phenylalanine levels in adults with PKU who have uncontrolled phenylalanine levels of more than 600 µmol/L. It is administered as a pegylated SC injection of phenylalanine ammonium lyase, an enzyme capable of substituting for phenylalanine hydroxylase (PAH).
Approval of pegvaliase was based on 2 phase 3 studies, PRISM-1 and PRISM-2, which evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. Of 261 participants who received pegvaliase, 72% and 32.6% reached at least 12 months and 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood phenylalanine levels were 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. [23] In 2020, the FDA approved an increased maximum dose. [24]
Research into gene therapy for the treatment of PKU has been ongoing over the last 2 decades. The focus has been on replacement of the human mutant PAH gene in somatic cells of PKU patients. [25]
Treatment of Phenylketonuria in Pregnant Patients
Surveys have revealed that maternal phenylalanine blood concentrations higher than 1200 µmol/L are associated with maternal PKU syndrome dysmorphic facies, fetal microcephaly, learning difficulties, congenital heart defects, and intrauterine growth retardation. [26] Accordingly, maternal blood phenylalanine levels should be maintained in the range of 2-6 mg/dL (120-360 µmol/L) by means of dietary control. The diet should provide adequate energy, protein, vitamin, and mineral intake. Dietary needs of phenylalanine vary during pregnancy, so weekly measurement of phenylalanine levels is important.
Treatment at any time during pregnancy may reduce the severity of developmental delay. Women with PKU should start a phenylalanine-restricted diet before conception, and those contemplating pregnancy or who are pregnant should be treated in metabolic or PKU clinics.
Long-Term Monitoring
Phenylalanine levels are monitored typically twice a week in neonates, weekly in infants, biweekly or every 3 weeks in toddlers, and monthly thereafter, even during adult life.
Attention should be given to variability in blood phenylalanine levels and to maintenance within the recommended range. [27]
During pregnancy, weekly phenylalanine sampling is recommended.
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Phenylalanine hydroxylase converts phenylalanine to tyrosine.
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Fair skin and hair resulting from impairment of melanin synthesis.
