Abstract
We tested the hypothesis that brain white matter integrity mediates the relationship between phenylalanine (Phe) control and executive abilities in children with phenylketonuria (PKU; N = 36). To do so, we examined mean diffusivity (MD) from diffusion tensor imaging (DTI) in two white matter brain regions (posterior parietal–occipital, PPO; centrum semiovale, CSO) and lifetime phenylalanine (Phe) exposure; the executive abilities examined included verbal strategic processing, nonverbal strategic processing, and working memory. Mediation modeling showed that MD in the PPO and CSO mediated the relationship between Phe exposure and nonverbal strategic processing, MD in the CSO mediated the relationship between Phe exposure and verbal strategic processing, and MD in the PPO mediated the relationship between Phe exposure and working memory. These exploratory findings demonstrate the importance of using sophisticated modeling procedures to understand the interplay among metabolic control, neural factors, and functional outcomes in individuals with PKU.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Anderson PJ, Wood SJ, Francis DE, Coleman L, Anderson V, Boneh A (2007) Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Dev Neuropsychol 32(2):645–668
Antenor-Dorsey JAV, Hershey T, Rutlin J, Shimony JS, McKinstry RC, Grange DK, White DA (2013) White matter integrity and executive abilities in individuals with phenylketonuria. Mol Genet Metab 109(2):125–131
Chiaravalloti ND, DeLuca J (2008) Cognitive impairment in multiple sclerosis. Lancet Neurol 7(12):1139–1151
Christ SE, Steiner RD, Grange DK, Abrams RA, White DA (2006) Inhibitory control in children with phenylketonuria. Dev Neuropsychol 30(3):845–864
Christ SE, Huijbregts SCJ, de Sonneville LMJ, White DA (2010) Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Mol Genet Metab 99:S22–S32
Citton V, Burlina A, Baracchini C, Gallucci M, Catalucci A, Dal Pos S, Burlina A, Manara R (2012) Apparent diffusion coefficient restriction in the white matter: going beyond acute brain territorial ischemia. Insights Imaging 3(2):155–164
Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Erlbaum, Hillsdale
Das AM, Goedecke K, Meyer U, Kanzelmeyer N, Koch S, Illsinger S et al (2013) Dietary habits and metabolic control in adolescents and young adults with phenylketonuria: self-imposed protein restriction may be harmful. In: JIMD reports-case and research reports, vol 13. Springer, Heidelberg, pp 149–158
De Groot MJ, Hoeksma M, Blau N, Reijngoud DJ, Van Spronsen FJ (2010) Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. Mol Genet Metab 99:S86–S89
DeRoche K, Welsh M (2008) Twenty-five years of research on neurocognitive outcomes in early-treated phenylketonuria: intelligence and executive function. Dev Neuropsychol 33(4):474–504
Hood A, Antenor-Dorsey JAV, Rutlin J, Hershey T, Shimony JS, McKinstry RC et al (2014) Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria. Mol Genet Metab 114(1):19–24
Hood A, Grange DK, Christ SE, Steiner R, White DA (2014b) Variability in phenylalanine control predicts IQ and executive abilities in children with phenylketonuria. Mol Genet Metab 111(4):445–451
Janos AL, Grange DK, Steiner RD, White DA (2012) Processing speed and executive abilities in children with phenylketonuria. Neuropsychology 26(6):735
Mitchell JJ, Trakadis YJ, Scriver CR (2011) Phenylalanine hydroxylase deficiency. Genet Med 13(8):697–707
Oishi K, Zilles K, Amunts K, Faria A, Jiang H, Li X et al (2008) Human brain white matter atlas: identification and assignment of common anatomical structures in superficial white matter. Neuroimage 43(3):447–457
Paine RS (1957) The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria). Pediatrics 20(2):290–302
Peng SS-F, Tseng W-YI, Chien Y-H, Hwu W-L, Liu H-M (2004) Diffusion tensor images in children with early-treated, chronic, malignant phenylketonuric: correlation with intelligence assessment. Am J Neuroradiol 25(9):1569–1574
Peng H, Peck D, White DA, Christ SE (2013) Tract-based evaluation of white matter damage in individuals with early-treated phenylketonuria. J Inherit Metab Dis 37(2):237–243
Pietz J, Kreis R, Schmidt H, Meyding-Lamade UK, Rupp A, Boesch C (1996) Phenylketonuria: findings at MR imaging and localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment. Radiology 201(2):413–420
Preacher KJ, Hayes AF (2004) SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behav Res Methods Instrum Comput 36(4):717–731
Preacher KJ, Hayes AF (2008) Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 40(3):879–891
Rucker DD, Preacher KJ, Tormala ZL, Petty RE (2011) Mediation analysis in social psychology: current practices and new recommendations. Soc Personal Psychol Compass 5(6):359–371
Rupp A, Kreis R, Zschocke J, Slotboom J, Boesch C (2001) Variability of blood–brain ratios of phenylalanine in typical patients with phenylketonuria. J Cereb Blood Flow Metab 21(3):276–284
Scarabino T, Popolizio T, Tosetti M, Montanaro D, Giannatempo GM, Terlizzi R et al (2009) Phenylketonuria: white-matter changes assessed by 3.0-T magnetic resonance (MR) imaging, MR spectroscopy and MR diffusion. Radiol Med 114(3):461–474
Scriver CR (2007) The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat 28(9):831–845
Shimony JS, McKinstry RC, Akbudak E, Aronovitz JA, Snyder AZ, Lori NF et al (1999) Quantitative diffusion-tensor anisotropy brain MR imaging: normative human data and anatomic analysis. Radiology 212(3):770–784
Vermathen P, Robert‐Tissot L, Pietz J, Lutz T, Boesch C, Kreis R (2007) Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging. Magn Reson Med 58(6):1145–1156
Viau KS, Wengreen HJ, Ernst SL, Cantor NL, Furtado LV, Longo N (2011) Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria. J Inherit Metab Dis 34(4):963–971
Waisbren SE, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, Levy H (2007) Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab 92(1–2):63–70
Wechsler D (1999) Wechsler abbreviated scale of intelligence (WASI). The Psychological Corporation, San Antonio
Weglage J, Fromm J, van Teeffelen-Heithoff A, Möller HE, Koletzko B, Marquardt T et al (2013) Neurocognitive functioning in adults with phenylketonuria: results of a long term study. Mol Genet Metab 110:S44–S48
White DA, Connor LT, Nardos B, Shimony JS, Archer R, Snyder AZ et al (2010) Age-related decline in the microstructural integrity of white matter in children with early- and continuously-treated PKU: A DTI study of the corpus callosum. Mol Genet Metab 99:S41–S46
White DA, Antenor-Dorsey JAV, Grange DK, Hershey T, Rutlin J, Shimony JS et al (2013) White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria. Mol Genet Metab 110(3):213–217
Acknowledgments
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 and staff of Washington University and Oregon Health & Science University who generously contributed to the study through recruitment and phenylalanine monitoring.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Nicole Wolf, MD PhD
Appendices
Funding
This research was supported by the National Institute of Child Health and Human Development (R01HD044901 and U54HD087011), 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.
Compliance with Ethics Guidelines
Conflict of Interest
Anna Hood, Jerrel Rutlin, and Joshua Shimony declare that they have no conflict of interest. Desiree White and Dorothy Grange have received research grants from BioMarin Pharmaceutical Inc. and have served as consultants for BioMarin Pharmaceutical Inc.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients included in the study.
Contribution of Authors
Desiree White designed the study, wrote the protocol, trained research staff, supervised data collection, interpreted data, and co-wrote the manuscript. Anna Hood conducted literature review, analyzed, and interpreted data, and co-wrote the manuscript. Jerrel Rutlin analyzed and interpreted data and provided input on the writing of the paper. Joshua Shimony contributed to study design and provided statistical analysis, neuroimaging consultation, and input on the writing of the paper. Dorothy Grange contributed to study design, participant recruitment, and provided input on the writing of the paper. All authors contributed to and have approved the final manuscript.
Rights and permissions
Copyright information
© 2016 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Hood, A., Rutlin, J., Shimony, J.S., Grange, D.K., White, D.A. (2016). Brain White Matter Integrity Mediates the Relationship Between Phenylalanine Control and Executive Abilities in Children with Phenylketonuria. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 33. JIMD Reports, vol 33. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_579
Download citation
DOI: https://doi.org/10.1007/8904_2016_579
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-55011-3
Online ISBN: 978-3-662-55012-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)