Normal-appearing White Matter in Patients with Phenylketonuria: Water Content, Myelin Water Fraction, and Metabolite Concentrations 1 Sandra M. Sirrs, MD, FRCPC Cornelia Laule, PhD Burkhard Ma ¨dler, PhD Elana E. Brief, PhD Sumia A. Tahir, BSc Carole Bishop, PhD Alex L. MacKay, DPhil Purpose: To prospectively assess relative water content (RWC), myelin water fraction (MWF), and hydrogen 1 magnetic resonance (MR) spectroscopy findings in the white matter (WM) of patients with phenylketonuria (PKU). Materials and Methods: This study was approved by the institution’s investigational review board, and informed consent was obtained. T2 water relaxation data were acquired by using a 48-echo measurement in a transverse plane through the genu and splenium of the corpus callosum in 16 patients (six men, 10 women; age range, 18 – 40 years) with PKU and 16 age- and sex-matched control subjects. MR spectroscopy was performed in a voxel (94  70  15 mm) above the ventricles. WM in control subjects (defined as normal WM) was compared with normal-appearing WM (NAWM) and diffuse WM lesions in patients with PKU by using a Student t test. Results: Patients with PKU had two forms of NAWM: (a) areas that looked normal on intermediate-weighted (IW) and T2- weighted MR images and long T2 maps and (b) areas that looked normal on IW and T2-weighted MR images but were hyperintense on long T2 maps. Both forms of NAWM showed increased RWC (up to 2.5%, P  .001) and re- duced MWF (up to 56%, P  .001) relative to normal WM; these changes paralleled those seen in diffuse WM lesions. Approximately 9% of the water in diffuse WM lesions was in a reservoir with a long T2 time of 200 – 800 msec. Myoinositol concentrations were reduced by 14% (P = .003) in patients with PKU. Conclusion: In patients with PKU, NAWM and diffuse WM lesions have altered RWC and MWF relative to normal WM, and diffuse WM lesions show a redistribution of water into an extracellular reservoir with a long T2 time.  RSNA, 2007 1 From the Departments of Medicine (S.M.S.), Radiology (C.L., A.L.M.), Physics and Astronomy (B.M., S.A.T., A.L.M.), and Psychology (C.B.), University of British Co- lumbia, Vancouver, British Columbia, Canada; and Depart- ment of Physics, Simon Fraser University, Burnaby, British Columbia, Canada (E.E.B.). Received October 28, 2005; revision requested December 1; revision received January 20, 2006; accepted February 6; final version accepted March 8. Supported by a Vancouver Hospital and Health Sciences Centre Interdisciplinary Grant. Address corre- spondence to S.M.S., Level 4, Diamond Health Care Center, 2775 Laurel St, Vancouver, BC, Canada V5Z 1M9 (e-mail: sandra.sirrs@vch.ca).  RSNA, 2007 ORIGINAL RESEARCH  NEURORADIOLOGY 236 Radiology: Volume 242: Number 1—January 2007