Systematic review of large neutral amino acids for treatment of phenylketonuria

Abstract

Individuals with phenylketonuria (PKU) have defective enzyme activity, leading to toxic accumulation of phenylalanine (Phe) in blood and tissues. Adherence to a Phe-restricted diet can mitigate poor outcomes; however, dietary restriction is difficult. Large neutral amino acids (LNAAs), which putatively decrease brain Phe concentration, have been suggested as a potential supplementary treatment in addition to a Phe-restricted diet. To systematically review evidence regarding LNAA usage in individuals with PKU, we searched 5 databases including Medline up to August 2011 and the reference lists of included articles. Two reviewers independently assessed studies against predetermined inclusion/exclusion criteria. Two reviewers independently extracted data regarding participant and intervention characteristics and outcomes; using their extracted data, they assigned overall quality and strength of evidence ratings based on predetermined criteria. Three small studies (two randomized controlled trials and one uncontrolled open label trial) of fair to poor quality investigated LNAAs. The studies included a total of 47 participants with severe PKU between 11 and 45 years of age receiving LNAAs for 1 to 8 weeks. In all three studies, blood Phe decreased after one week of treatment, but remained above clinically acceptable levels. The one trial measuring correlation between blood and brain Phe found no association. Research on adjuvant therapy in PKU to complement dietary restriction is early in its development and substantially more work is needed. The three very small studies of LNAAs to date cannot be considered as more than proof of concept.