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Adjuvant Treatment for Phenylketonuria (PKU)

Systematic Review ARCHIVED Feb 22, 2012
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Structured Abstract


We systematically reviewed evidence on adjuvant treatment of phenylketonuria (PKU) and evidence for a target phenylalanine (Phe) level to minimize cognitive impairment.

Data Sources

We searched MEDLINE, PsycINFO, Embase Drugs and Pharmacology, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), the National Agricultural Library (AGRICOLA), and the reference lists of included studies. We searched the unpublished literature for additional data.

Review Methods

We included studies published in English before August 2011. We excluded studies with fewer than 10 individuals; individual case reports; and studies lacking relevance to PKU treatment or Phe levels and measures of cognition (intelligence quotient [IQ] or core domains of executive function). We meta-analyzed studies addressing Phe level and IQ, and summarized studies of treatment in tabular form.


We located 17 studies providing data regarding blood Phe levels and IQ changes, 10 studies addressing sapropterin dihydrochloride (BH4), and 3 addressing the use of large neutral amino acid formulations (LNAAs). Blood Phe level is positively correlated with the probability of having an IQ of less than 85. This predicted probability exceeds the population probability (approximately 15 percent) at 400 ?mol/L and reaches a maximum of about 80 percent at 2000 ?mol/L. Currently, findings on the association of Phe levels and measures of executive function are inconsistent, and too few studies have used the same outcome measures to combine data meaningfully. BH4 research to date includes two randomized controlled trials (RCTs) and three uncontrolled open-label trials. Phe levels were reduced by at least 30 percent in up to half of treated participants (32 to 50 percent). In the one RCT that compared the effect of placebo on likelihood of a 30-percent reduction in Phe, only 9 percent of those on placebo achieved this effect after 6 weeks, compared with 44 percent of the treated group. Three very small studies (total number of participants, 47) assessed LNAAs and reported no evidence that Phe levels were reduced to clinically meaningful levels.


The strength of the evidence is moderate for a threshold effect of a Phe level of 400 ?mol/L associated with IQ <85. Evidence on the association of Phe and measures of executive function is insufficient. The use of adjuvant therapy in PKU is novel; the strength of the evidence is currently moderate for short-term effects on reducing Phe in a subset of initially responsive individuals and low for longer term effects on cognition.

Project Timeline

Adjuvant Treatment for Phenylketonuria (PKU)

Nov 5, 2010
Feb 8, 2011
Feb 22, 2012
Systematic Review Archived
Page last reviewed December 2019
Page originally created November 2017

Internet Citation: Systematic Review: Adjuvant Treatment for Phenylketonuria (PKU). Content last reviewed December 2019. Effective Health Care Program, Agency for Healthcare Research and Quality, Rockville, MD.

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