Affiliations: Department of Pediatrics, Vanderbilt Institute for
Global Health, Vanderbilt University Medical Center, Nashville, TN, USA | Vanderbilt Evidence-based Practice Center, Institute
for Medicine and Public Health, Vanderbilt University Medical Center,
Nashville, TN, USA | Division of Developmental Medicine, Pediatric
Residency Program and LEND, Vanderbilt University Medical Center, Nashville, TN, USA | Department of Biostatistics, Vanderbilt University
Medical Center, Nashville, TN, USA | Vanderbilt Evidence-based Practice Center, Emphasis
Program Area on Healthcare and Public Health Research and Management, Women's
Health Research, Institute for Medicine and Public Health, Vanderbilt
University Medical Center, Nashville, TN, USA
Note: [] Corresponding author: Mary Louise Lindegren, M.D., Pediatrics,
Vanderbilt Institute for Global Health, 2525 West End Avenue, Suite 750,
Vanderbilt University Medical Center, Nashville, TN 37203, USA. Tel.: +1 615
322 9374; Fax: +1 615 343 7797; E-mail: Marylou.lindegren@vanderbilt.edu
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.
