TY - JOUR
T1 - Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria
AU - Hood, Anna
AU - Antenor-Dorsey, Jo Ann V.
AU - Rutlin, Jerrel
AU - Hershey, Tamara
AU - Shimony, Joshua S.
AU - McKinstry, Robert C.
AU - Grange, Dorothy K.
AU - Christ, Shawn E.
AU - Steiner, Robert
AU - White, Desiree A.
N1 - Funding Information:
This research was supported by the National Institute of Child Health and Human Development ( R01HD044901 ), an Investigator Sponsored Trial grant from BioMarin Pharmaceutical Inc. , the Intellectual and Developmental Disabilities Research Center at Washington University with funding from the National Institute of Child Health and Human Development ( P30HD062171 ) and the James S. McDonnell Foundation . The authors wish to thank those who participated in our research for their contributions. We also thank Suzin Blankenship and Laurie Sprietsma for their contributions to study management, as well as the physicians, faculty, and staff of Washington University, Oregon Health & Science University, University of Missouri, New York Medical College, University of Florida, and University of Nebraska who generously contributed to the study through recruitment and phenylalanine monitoring.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - In this study, we retrospectively examined the microstructural white matter integrity of children with early- and continuously-treated PKU (. N=. 36) in relation to multiple indices of phenylalanine (Phe) control over the lifetime. White matter integrity was assessed using mean diffusivity (MD) from diffusion tensor imaging (DTI). Eight lifetime indices of Phe control were computed to reflect average Phe (mean, index of dietary control), variability in Phe (standard deviation, standard error of estimate, % spikes), change in Phe with age (slope), and prolonged exposure to Phe (mean exposure, standard deviation exposure). Of these indices, mean Phe, mean exposure, and standard deviation exposure were the most powerful predictors of widespread microstructural white matter integrity compromise. Findings from the two previously unexamined exposure indices reflected the accumulative effects of elevations and variability in Phe. Given that prolonged exposure to elevated and variable Phe was particularly detrimental to white matter integrity, Phe should be carefully monitored and controlled throughout childhood, without liberalization of Phe control as children with PKU age.
AB - In this study, we retrospectively examined the microstructural white matter integrity of children with early- and continuously-treated PKU (. N=. 36) in relation to multiple indices of phenylalanine (Phe) control over the lifetime. White matter integrity was assessed using mean diffusivity (MD) from diffusion tensor imaging (DTI). Eight lifetime indices of Phe control were computed to reflect average Phe (mean, index of dietary control), variability in Phe (standard deviation, standard error of estimate, % spikes), change in Phe with age (slope), and prolonged exposure to Phe (mean exposure, standard deviation exposure). Of these indices, mean Phe, mean exposure, and standard deviation exposure were the most powerful predictors of widespread microstructural white matter integrity compromise. Findings from the two previously unexamined exposure indices reflected the accumulative effects of elevations and variability in Phe. Given that prolonged exposure to elevated and variable Phe was particularly detrimental to white matter integrity, Phe should be carefully monitored and controlled throughout childhood, without liberalization of Phe control as children with PKU age.
KW - Brain
KW - Diffusion tensor imaging
KW - Exposure
KW - Phenylalanine
KW - Phenylketonuria
KW - White matter
UR - http://www.scopus.com/inward/record.url?scp=84920441309&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2014.11.007
DO - 10.1016/j.ymgme.2014.11.007
M3 - Article
C2 - 25481106
AN - SCOPUS:84920441309
SN - 1096-7192
VL - 114
SP - 19
EP - 24
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1
ER -