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DOI: 10.1148/radiol.2362040611
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(Radiology 2005;236:630-636.)
© RSNA, 2005

Neuroradiology

Diffusion-weighted MR Imaging in Patients with Phenylketonuria: Relationship between Serum Phenylalanine Levels and ADC Values in Cerebral White Matter1

Kinuko Kono, MD, Yoshiyuki Okano, MD, Keiko Nakayama, MD, Yutaka Hase, MD, Sosuke Minamikawa, MD, Nozomi Ozawa, MD, Hiroyuki Yokote, MD and Yuichi Inoue, MD

1 From the Departments of Radiology (K.K., K.N., S.M., N.O., H.Y., Y.I.) and Pediatrics (Y.O., Y.H.), Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, abeno-ku, Osaka 545-8585, Japan. Received April 6, 2004; revision requested June 15; revision received August 24; accepted October 4. Address correspondence to K.K.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To prospectively determine the relationship between serum phenylalanine levels and apparent diffusion coefficient (ADC) values in the cerebral white matter of patients with phenylketonuria (PKU).

MATERIALS AND METHODS: Institutional review board approval was obtained, and participants provided informed consent. Magnetic resonance (MR) imaging, which included T1- and T2-weighted, fluid-attenuated inversion-recovery (FLAIR), and diffusion-weighted examinations, was performed in 21 patients with PKU (nine male and 12 female patients; age range, 3–44 years; mean age, 19.4 years). ADC values in deep cerebral white matter were calculated for each patient. Serum phenylalanine levels were obtained in all patients within 12 days after MR imaging. Serum phenylalanine levels were measured in 16 patients 1 year before MR imaging. ADC values in cerebral white matter and serum phenylalanine levels were compared. A total of 21 control subjects (12 male and nine female patients; age range, 3–33 years; mean age, 20.6 years) underwent MR imaging. ADC values in cerebral white matter were compared with serum phenylalanine levels by using the Pearson correlation.

RESULTS: Abnormal high signal intensity in white matter on T2-weighted and FLAIR MR images was noted in patients with PKU who had serum phenylalanine levels of more than 8.5 mg/dL (514.2 µmol/L). Diffusion in posterior deep cerebral white matter tended to be restricted in patients when increased serum phenylalanine levels were measured after MR imaging (r = –0.62). There was a correlation between ADC values in posterior cerebral white matter and serum phenylalanine levels measured 1 year before MR imaging (r = –0.77). ADCs of control subjects were significantly higher than ADCs of patients with PKU (P < .005).

CONCLUSION: Posterior deep white matter in patients with PKU and a serum phenylalanine level of more than 8.5 mg/dL showed high signal intensity in white matter on T2-weighted and FLAIR MR images and revealed decreased ADC. We suggest that to avoid brain-restricted diffusion due to hyperphenylalanemia, patients with PKU should maintain serum phenylalanine levels of less than 8.5 mg/dL (514.2 µmol/L).

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Phenylketonuria (PKU) is the most common congenital disorder of amino acid metabolism (1,2) and is caused by a deficiency of phenylalanine hydroxylase. The biochemical abnormality in PKU is the inability to convert phenylalanine into tyrosine. In healthy children, less than 50% of dietary intake of phenylalanine is necessary for protein synthesis. The rest is irreversibly converted into tyrosine by the hepatic phenylalanine hydroxylase system. Dietary restriction of phenylalanine is relatively successful in the reduction or prevention of mental retardation associated with PKU. Serum phenylalanine levels are important indications for protein-restricted diet therapy. Previous articles have reported magnetic resonance (MR) spectroscopy and phenylalanine transport in the brains of patients with PKU (3–6). Pathologically specific white matter abnormalities in patients with PKU include delayed or defective myelination, diffuse white matter vacuolation (eg, status spongiosis), and gliosis (7,8). Patients with PKU and high phenylalanine levels in their blood exhibit abnormally high signal intensity in cerebral white matter on T2-weighted images (9–12).

It has been reported that patients with PKU demonstrate restricted diffusion in the cerebral white matter (13). We have noted similar decreased diffusion in white matter in patients with PKU and hyperphenylalanemia. We hypothesized that apparent diffusion coefficients (ADCs) in cerebral white matter would show lower values in patients with PKU who have a high level of serum phenylalanine. Thus, we undertook this study to prospectively determine the relationship between serum phenylalanine levels and ADC values in the cerebral white matter of patients with PKU.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patients
From January 2000 to August 2003, 23 patients with PKU who were followed up in the pediatric department were examined. Two patients younger than 1 year were excluded from our study because incomplete myelination was suggested on T1- and T2-weighted MR images. Thus, our study included 21 patients with PKU (nine male and 12 female patients; mean age, 19.4 years; age range, 3–44 years). Patients 19 and 20 were siblings. After we obtained informed consent from the patient or parents (for minors), as required by the institutional review board that approved our study, all patients underwent MR imaging, and serum phenylalanine levels were measured. Fourteen of the 21 patients were classified as having PKU at newborn mass screening. While all 21 patients had been receiving dietary treatment, the initiation of dietary treatment in seven patients was delayed, as some of them were born before the introduction of newborn mass screening. Six patients exhibited symptoms of mental retardation. There was no history of asphyxia neonatorum in 13 patients. Perinatal history was unclear in the remaining eight patients. Our patients included one set of siblings, a brother (ie, patient 20) and sister (ie, patient 19), who had the same genotype.

In all patients, serum phenylalanine levels were obtained within 12 days (range, 0–12 days; mean, 0.86 days; median, 0 days) of the MR examination. Serum phenylalanine levels had been measured 1 year prior to MR examination in 16 of the 21 patients.

Follow-up MR imaging was conducted in one patient 9 months after the first MR examination.

Control Subjects
A total of 21 control subjects (12 male and nine female subjects; mean age, 20.6 years; age range, 3–33 years) underwent MR imaging. Between the 21 patients and 21 subjects, there was no significant difference in sex and age. Subjects were included if they did not have a brain lesion affecting deep white matter. Subjects were excluded if they had a deep white matter lesion on MR images or if they had undergone medical therapy, such as medication, radiation, or surgery. Four of 21 control subjects were healthy volunteers. The remaining 17 control subjects were patients who had not undergone therapy and did not have deep white matter disease or disease that affected cerebral white matter for calculation. These subjects had the following conditions: headache (n = 3), arachnoid cyst (n = 2), meningioma (n = 2), pituitary adenoma (n = 2), Guillain-Barre syndrome (n = 2), sudden deafness (n = 1), craniopharyngioma (n = 1), chordoma (n = 1), medulloblastoma (n = 1), low-grade astrocytoma (n = 1), and small old infarction (n = 1). Eight of these patients had an extraaxial mass that did not cause mass effect in the cerebrum, and medulloblastoma was small in size, located in the right cerebellar hemisphere, and did not cause ventricular enlargement. One low-grade astrocytoma was small in size and located in the temporal lobe; it did not appear to have a mass effect on deep white matter. One small old infarction was remote from deep white matter. MR findings in six patients with headache, Guillain-Barre syndrome, and sudden deafness were determined to be normal.

MR Imaging
MR imaging was performed with a 1.5-T imager (Echo-speed Horizon LX; GE Medical Systems, Milwaukee, Wis); imaging sequences were as follows: (a) transverse T2-weighted fast spin-echo sequence (repetition time msec/echo time msec, 4000/107; number of signals acquired, two; field of view, 20 cm; matrix, 256 x 224; section thickness, 5 mm; section interval, 1.5 mm), (b) transverse fluid-attenuated inversion recovery (FLAIR) sequence (repetition time msec/echo time msec/inversion time msec, 9002/150/2200; number of signals acquired, one; field of view, 20 cm; matrix, 256 x 192; section thickness, 5 mm; section interval, 1.5 mm), (c) transverse T1-weighted spin-echo sequence (500/9; number of signals acquired, one; field of view, 20 cm; matrix, 256 x 224; section thickness, 5 mm; section interval, 1.5 mm), and (d) transverse echo-planar diffusion sequence (5000/115; number of signals acquired, two; field of view, 20 cm; matrix, 128 x 128). Isotropic diffusion images were obtained with diffusion gradients (b = 0, 600, 800 and 1000 sec/mm2). The diffusion gradients were applied in three orthogonal directions.

ADC Maps
ADC maps were constructed, and the average was calculated to produce an average ADC map with an Ultra workstation (Sun Microsystems, Santa Clara, Calif). Six to 10 regions of interest (20–30 mm2) were located carefully by a single neuroradiologist (K.K.) with 10 years of experience in the evaluation of brain MR images. These regions of interest were located in deep cerebral white matter, so as to avoid involving cerebral spinal fluid. We obtained mean ADCs in posterior and frontal deep white matter. In principle, eight regions of interest were measured. In some cases, however, only six regions of interest were measured, and in others, 10 were measured. Possible correlations were evaluated between ADCs and phenylalanine levels (K.K., Y.O., K.N.). After evaluating MR findings, ADCs, and serum phenylalanine levels, we tried to allocate patients to either a well-controlled group or a poorly controlled group. Follow-up MR imaging was performed in patient 10. ADC changes and serum phenylalanine levels were evaluated (K.K., K.N.). We compared findings in siblings with findings in other patients.

Statistical Analysis
Data were expressed as mean ± standard deviation. The difference of ADCs between frontal white matter and posterior white matter was analyzed with the Student t test. We determined the relationship between serum phenylalanine levels measured within 12 days after MR imaging and ADCs in cerebral white matter, as well as the relationship between average serum phenylalanine levels in the year prior to MR imaging and ADCs in cerebral white matter with the Pearson correlation coefficient. The difference of ADCs between the well-controlled group and the poorly controlled group was assessed with the Student t test. P values of less than .05 were considered to indicate a statistically significant difference.

A statistical software package (StatView, version 5.0; SAS Institute, Cary, NC) was used to perform all statistical analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
MR Findings and Phenylalanine Levels
Thirteen patients exhibited hyperintensity in the posterior cerebral white matter on T2-weighted and FLAIR MR images (Table). Twelve of these patients had high signal intensity on diffusion-weighted MR images obtained in the corresponding area. Seven of 13 patients with high-signal-intensity posterior white matter had high signal intensity in the frontal white matter on T2-weighted and FLAIR MR images (Fig 1 ). The remaining six patients did not have abnormal signal intensity in frontal deep white matter. The range of ADCs in posterior deep white matter in these 21 patients was (0.47–0.91) x 10–3 mm2/sec (mean, [0.68 ± 0.14]x 10–3 mm2/sec). The range of ADCs in frontal deep white matter in 21 patients was (0.45–0.94) x 10–3 mm2/sec (mean, [0.76 ± 0.14]x 10–3 mm2/sec). ADCs in posterior deep white matter were significantly (P < .001) lower than ADCs in frontal deep white matter. Serum phenylalanine levels measured within 12 days of the MR examination ranged from 1.12 to 26.18 mg/dL (67.7–1583.9 µmol/L) (mean, 13.09 mg/dL ± 7.36 [791.9 ± 445.3 µmol/L]). ADCs in posterior white matter tended to be lower in patients with increased serum phenylalanine levels (r = –0.63, P < .005) (Fig 2). Average serum phenylalanine levels measured in the year before the MR examination ranged from 3.73 to 24.26 mg/dL (225.7–1467.7 µmol/L) (mean, 13.56 mg/dL ± 6.45 [820.4 µmol/L ± 390.2]). There was a significant association between ADCs in the posterior white matter and averaged serum phenylalanine levels throughout the year before MR imaging (r = –0.77, P < .001) (Fig 3). There was a weak relationship between ADCs in frontal deep white matter and the serum phenylalanine levels (r = –0.47, P < .05), and there was a weak relationship between ADCs in frontal deep white matter and serum phenylalanine levels throughout the past year (r = –0.51, P < .05).


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  		Patient Data

 


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  		Figure 1a. Patient 7. Posterior and frontal deep white matter shows high signal intensity (arrows) on (a) FLAIR (9002/149/2200) and (b) diffusion-weighted (5000/102) MR images. (c) Regions of interest were located on ADC maps.

 


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  		Figure 1b. Patient 7. Posterior and frontal deep white matter shows high signal intensity (arrows) on (a) FLAIR (9002/149/2200) and (b) diffusion-weighted (5000/102) MR images. (c) Regions of interest were located on ADC maps.

 


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  		Figure 1c. Patient 7. Posterior and frontal deep white matter shows high signal intensity (arrows) on (a) FLAIR (9002/149/2200) and (b) diffusion-weighted (5000/102) MR images. (c) Regions of interest were located on ADC maps.

 


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  		Figure 2. Graph shows linear regression of ADCs in relation to recent serum phenylalanine levels in patients with PKU. There is a statistically significant correlation.

 


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  		Figure 3. Graph shows linear regression of ADCs in relation to serum phenylalanine levels over the preceding year in 16 patients with PKU. There is strong correlation.

 
Well- and Poorly Controlled Patients
Patients were allocated to either the "well-controlled" group or the "poorly controlled" group on the basis of MR findings. In other words, all patients (except for one) who did not have high signal intensity on diffusion-weighted MR images were allocated to the well-controlled group. Patients with high signal intensity on diffusion-weighted MR images were allocated to the poorly controlled group. ADCs in posterior deep white matter for the two groups were compared. The well-controlled group included seven patients whose serum phenylalanine levels had remained below 8.5 mg/dL (514.3 µmol/L; range, 1.12–8.47 mg/dL [67.8 µmol/L]; mean, 4.78 mg/dL ± 2.82 [289.2 µmol/L ± 170.6]) within 12 days after the MR examination. The poorly controlled group included 14 patients with serum phenylalanine levels greater than 8.5 mg/dL (514.3 µmol/L; range, 8.63–26.18 mg/dL [522.1–1583.9 µmol/L]; mean, 17.25 mg/dL ± 4.88 [1043.6 µmol/L ± 295.2]) over the same period. Posterior white matter ADCs of patients in the poorly controlled group (mean, [0.61 ± 0.1]x 10–3 mm2/sec) were significantly lower than those of patients in the well-controlled group (mean, [0.82 ± 0.07]x 10–3 mm2/sec; P < .001) (Fig 4).



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  		Figure 4. Graph shows ADCs for poorly controlled and well-controlled serum phenylalanine levels in 16 patients with PKU. There is a significant difference between the groups.

 
Follow-up Examination
A follow-up MR examination was performed in patient 10. His serum phenylalanine level was 8.63 mg/dL (522.1 µmol/L) at the first MR examination. At the time of the second MR examination (ie, 9 months later), his serum phenylalanine level was 4.48 mg/dL (271.0 µmol/L). His ADC rose from 0.62 x 10–3 mm2/sec at the first MR examination to 0.72 x 10–3 mm2/sec at the second MR examination. High signal intensity in the deep cerebral white matter, however, did not disappear on T2- or diffusion-weighted MR images.

Sibling Comparison
In patient 19, the area of high signal intensity on T2-weighted MR images revealed mild high signal intensity on diffusion-weighted images (Fig 5) without restricted diffusion. Patient 20 (ie, the brother of patient 19) did not have decreased ADC in the cerebral white matter. His cerebral white matter did not show high signal intensity on T2-weighted or FLAIR MR images.



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  		Figure 5a. Patient 19. Posterior deep white matter shows (a) high signal intensity (arrows) on a FLAIR (9002/149/2200) MR image and (b) mild high signal intensity (arrows) on a diffusion-weighted (5000/102) MR image. (c) Regions of interest were located on ADC maps.

 


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  		Figure 5b. Patient 19. Posterior deep white matter shows (a) high signal intensity (arrows) on a FLAIR (9002/149/2200) MR image and (b) mild high signal intensity (arrows) on a diffusion-weighted (5000/102) MR image. (c) Regions of interest were located on ADC maps.

 


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  		Figure 5c. Patient 19. Posterior deep white matter shows (a) high signal intensity (arrows) on a FLAIR (9002/149/2200) MR image and (b) mild high signal intensity (arrows) on a diffusion-weighted (5000/102) MR image. (c) Regions of interest were located on ADC maps.

 
Control Subjects
The range of ADC in control subjects was (0.77–0.9) x 10–3 mm2/sec (mean, [0.84 ± 0.04]x 10–3 mm2/sec) in posterior cerebral white matter and (0.74–0.89) x 10–3 mm2/sec (mean, [0.83 ± 0.05]x 10–3 mm2/sec) in frontal white matter. ADCs of control subjects were significantly higher than ADCs of patients with PKU (P < .005). There was no significant difference between ADCs of patients in the well-controlled group and ADCs of healthy volunteers.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Demonstration that diffusion in patients with PKU is restricted in the lesion area is not new, but this finding has been described in one case report of findings in three patients with PKU (13). The main strength of our study is the inclusion of a larger number of patients and measurement of serum phenylalanine levels. The most interesting finding in our study is that patients with PKU who have serum phenylalanine levels below 8.5 mg/dL (514.3 µmol/L) showed no abnormal high signal intensity in white matter on T2-weighted and FLAIR MR images and no abnormality in ADCs. Discontinuation of the phenylalanine-restricted diet has variable detrimental effects (14). For children and adults with PKU, recommendations regarding dietary management have been reported (15). To avoid restricted cerebral diffusion, we believe that patients with PKU should maintain serum phenylalanine levels of less than 8.5 mg/dL (514.3 µmol/L).

In our study, patients with PKU who had poorly controlled serum phenylalanine levels had significantly decreased ADCs in cerebral deep white matter. Diffusion-weighted MR imaging has been used to assess various diseases. Several diseases of the brain have been reported in patients with decreased ADCs: acute cerebral infarction (16,17), Creutzfeldt-Jakob disease (18,19), abscess (20–22), and metastasis (22). In Creutzfeldt-Jakob disease, authors have postulated that restricted diffusion could be related to the presence of vacuoles seen histologically in spongiform encephalopathy (19). High viscosity of proteinaceous fluid with a high concentration of inflammatory cells in brain abscess has been reported to cause restricted diffusion (21,22). With cerebral metastases, it has been reported that increased protein concentration in the form of highly viscous mucin may cause restricted diffusion (22). Phillips et al (13) reported that three patients with PKU demonstrated diffusion reduction within their white matter. The authors postulated that the restricted diffusion seen in that study may reflect the presence of status spongiosis within the white matter. In mitochondrial encephalopathies with stroke like episodes, decreased ADCs have been reported (23) and attributed to cytotoxic edema.

In acute cerebral infarction and hypoxia-ischemia, intracellular edema with reduction of the Na+K+-ATPase activity causing decreased ADCs has been described in rat models (24). It has been demonstrated in the rat brain that the Na+K+-ATPase activity is inhibited in synaptosomes by phenylalanine (25), which may interfere with cellular water and electrolyte homeostasis. In erythrocyte membranes of patients with PKU, reduction of the Na+K+-ATPase activity was observed (26). A disturbance in Na+K+-ATPase function during hypoxia or ischemia is thought to trigger cell swelling and movement of water from the extracellular space into the intracellular space (21). This would result in intracellular edema, which may reduce ADCs in cerebral white matter. Cytotoxic edema associated with cerebral infarction may disappear within a few days (27,28). If chronic intracellular edema without enough mass effect is maintained for a long time, restricted diffusion in the brain might persist for several years. Restricted diffusion in PKU may reflect chronic intracellular edema due to disturbance of Na+K+-ATPase activity due to hyperphenylalanemia. We suggest that chronically elevated serum phenylalanine levels may result in prolonged reduction of ADCs in the brain.

In our study, ADCs of posterior deep white matter in patients with PKU correlated with serum phenylalanine levels, and patients with PKU and decreased ADC showed abnormally high signal intensity in cerebral white matter on T2-weighted MR images. It has been reported that abnormal signal in the brain in patients with PKU may reflect current biochemical control rather than substantial neurologic damage (12). Our results suggest that abnormal signal in the brain in patients with PKU seems to reflect poor current biochemical control. In our study, ADCs in posterior white matter tended to be lower in patients with higher serum phenylalanine levels measured after MR imaging, which suggests that the serum phenylalanine level affects posterior deep white matter signal intensity. In the patients with PKU who were included in our study, abnormal high signal intensity on T2-weighted and FLAIR MR images associated with decreased ADCs was seen in posterior deep white matter. In more severe cases, lesions extended to frontal white matter. Our result is in accordance with the report of Pearsen et al (29). We believe that deep posterior white matter is more vulnerable to increased serum phenylalanine levels than is frontal white matter, although the pathologic mechanism is unclear at the present time.

Follow-up MR imaging was performed in one patient after an interval of 9 months. His serum phenylalanine level had improved with a phenylalanine-restricted diet. ADC in his brain increased and neared a normal value, although his hyperintense white matter on T2-weighted and FLAIR MR images persisted and did not decrease signal intensity difference on visual inspection when compared with the previous MR images. This single case of an increase in ADC with improvement of serum phenylalanine levels suggests that ADC may be reversible. This finding, however, needs to be explored in a large series of patients. Some authors (11,30–32) described reversible MR imaging abnormalities in the cerebrum that responded to implementation of a strict diet within a few weeks or months. Reversed white matter change with decreased ADC has been reported in maple syrup urine disease (33). The authors have described that the pathogenesis of reversible diffusion restriction could not be fully clarified. It is unclear whether high signal intensity in the brain on T2-weighted and FLAIR MR images with decreased ADC in patients with PKU may indicate reversible changes.

In siblings (ie, patients 19 and 20) with serum phenylalanine levels greater than 8.5 mg/dL (514.3 µmol/L), ADC in white matter did not decrease. The findings in patient 19 are not in accordance with findings in other patients' lesions. As described earlier, Malamud (7) has stated that there is more demyelination in older patients with PKU, whereas status spongiosis is a main feature in younger patients. It is believed that intramyelinic or cytotoxic edema reduces diffusion. Impaired or delayed myelination would be expected to induce increased diffusion (34). Demyelinating lesion manifested at a more advanced age (7). The white matter high signal intensity without decreased ADC observed in patient 19 may reflect demyelination. The serum phenylalanine level in patient 20 was elevated; ADCs in cerebral white matter were not restricted, and the white matter did not show high signal intensity on T2-weighted and FLAIR MR images. Substantial individual differences in phenylalanine transport have been reported (35). The reason why ADC was not restricted in both patients, in spite of hyperphenylalanemia, might be related to phenylalanine transport characteristics.

Although increased signal intensity in cerebral white matter on T2-weighted MR images can be caused by several factors, including aging and ischemic change, measurement of ADCs may be useful in the differentiation of the characteristic abnormal white matter changes due to elevated serum phenylalanine levels from other disease.

One potential limitation in our study was the use of a combination of patients and healthy volunteers as the control subjects. The patients who did not have PKU were deemed justifiable because they did not have deep white matter disease.

In conclusion, poorly controlled serum phenylalanine levels cause a decrease of ADC in the deep cerebral white matter of patients with PKU. Deep white matter in patients with PKU and serum phenylalanine levels greater than 8.5 mg/dL (514.3 µmol/L) showed high signal intensity on T2-weighted and FLAIR MR images and revealed decreased ADCs, which suggested that patients with PKU should maintain serum phenylalanine levels of less than 8.5 mg/dL (514.3 µmol/L) to avoid restricted diffusion.


   FOOTNOTES
 

Abbreviations: ADC = apparent diffusion coefficient • FLAIR = fluid-attenuated inversion recovery • PKU = phenylketonuria

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, K.K.; study concepts, K.K., Y.O.; study design, K.K.; literature research, K.K., Y.O.; clinical and experimental studies, K.K., Y.O., Y.H.; data acquisition, K.K., N.O.; data analysis/interpretation, K.K., Y.O.; statistical analysis, K.K., K.N.; manuscript preparation, K.K., S.M.; manuscript definition of intellectual content, K.K., H.Y.; manuscript editing, K.K., Y.I.; manuscript revision/review, K.K., Y.O., Y.I.; manuscript final version approval, K.K., Y.I.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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S. M. Sirrs, C. Laule, B. Madler, E. E. Brief, S. A. Tahir, C. Bishop, and A. L. MacKay
Normal-appearing White Matter in Patients with Phenylketonuria: Water Content, Myelin Water Fraction, and Metabolite Concentrations
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