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Effective Health Care Program

Adjuvant Treatment for Phenylketonuria: Future Research Needs

Systematic Review

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Archived: This report is greater than 3 years old. Findings may be used for research purposes, but should not be considered current.

This report is from AHRQ's series on Future Research Needs Projects.


Phenylketonuria (PKU) is a metabolic disorder in which an inability to properly metabolize the amino acid phenylalanine (Phe) leads to a buildup of Phe in the blood, causing neurotoxicity and resulting in intellectual disability, delayed speech, seizures and behavior abnormalities. PKU is typically diagnosed at birth following abnormal newborn screening results. With adherence to a Phe-restricted diet, poor outcomes can be mitigated. Nonetheless, management of PKU can be difficult and onerous for the patient and the family, leading to interest in identifying new ways of managing this lifelong condition.

The mainstay for treatment of PKU is a diet that restricts the intake of Phe to control the Phe concentration in the blood. In 2007 the United States Food and Drug Administration approved sapropterin dihydrochloride (Kuvan®, formerly known as Phenoptin) for the treatment of PKU under the stipulation that studies regarding the drug's efficacy and long-term safety continue. Sapropterin dihydrochloride (hereafter, BH4) is presumed to work by enhancing residual enzyme activity present in some individuals with PKU. In addition to a Phe-restricted diet and BH4, another potential treatment for PKU is large neutral amino acids (LNAAs). In theory, LNAAs decrease the brain Phe concentration by competing with Phe for shared amino acid transporters to cross the blood-brain barrier.

The Vanderbilt Evidence-based Practice Center completed an Agency for Healthcare Research and Quality (AHRQ)-funded systematic review of adjuvant treatments (BH4, LNAAs) for PKU (published February 2012). The report focused on Key Questions related to outcomes and harms of adjuvant treatment with BH4 and LNAAs in individuals with PKU, including pregnant women with PKU, and effects in subgroups (defined by demographic, clinical, genotypic, and adherence-related variables such as age, disease severity, genetic mutations, and dietary status). Key Questions also addressed evidence for optimal Phe levels for minimizing cognitive impairment.

Overall, evidence was graded as insufficient to moderate to address treatment-related questions. Dietary management remains the mainstay of treatment for PKU, and maintaining control over the lifetime is an appropriate goal. Nonetheless, there is potential to support patients in achieving their clinical goals and possibly liberalizing their diet with adjuvant therapy. BH4 has been shown in two RCTs and two open label trials to reduce Phe levels in some patients, with significantly greater reductions seen in treated versus placebo groups. Overall, harms associated with the drug were minor. To date, there are no data to directly establish the potential effects of BH4 on longer term clinically important outcomes, including cognition, executive function, and quality of life. Thus, while the strength of evidence is moderate for a large, positive effect of BH4 on reducing Phe levels over the short term in some groups of patients showing initial responsiveness, evidence for the effect of BH4 on longer term clinical outcomes is low, and based on indirect associations, including a meta-analysis of the relationship of Phe levels and IQ.

In theory, supplementation of a Phe-restricted diet with LNAAs might have a beneficial effect on cognition as LNAAs may competitively inhibit transportation of Phe through the blood-brain barrier, thereby offering protection by potentially decreasing brain Phe levels. However, there was insufficient evidence to suggest that LNAAs could be a viable treatment option for reducing Phe levels or increasing Phe tolerance.

Increasing Phe is clearly associated with decreased IQ, with a probability of IQ less than 85 exceeding the population probability (approximately 15 percent) at blood Phe over 400 μmol/L and leveling off at about 80 percent at 2000 μmol/L (moderate strength of evidence). This finding supports the typical target goal for blood Phe levels in individuals with PKU (120 to 360 μmol/L).