J. Inher. Metab. Dis. 20 (1997) 367– 369 © SSIEM and Kluwer Academic Publishers. Printed in the Netherlands

Short Communication

Complete reversal of moderate/severe brain MRI abnormalities in a patient with classical phenylketonuria J. H. W ALTER*, F. WHITE, J. E. W RAITH, J. P. JENKINS and B. P. M. WILSON Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital and Department of Clinical Radiology, Manchester Royal Infirmary, Manchester, UK *Correspondence: Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester M27 5ER, UK

Abnormalities on magnetic resonance imaging (MRI) of the brain are common in older patients with phenylketonuria (PKU; McKusick 261600) (Cleary et al 1994). We, and others, have previously demonstrated that these changes are partially reversible following an improvement in biochemical control (Bick et al 1993; Cleary et al 1995). We now report a patient with classical PKU in whom MRI abnormalities completely resolved following a strict low-phenylalanine (phe) diet. CASE REPORT AND METHODS B.E. is a 29-year-old woman who was diagnosed as having classical PKU at the age of 2 months. Biochemical control was only moderate in infancy and early childhood and was poor thereafter, with blood phe concentrations in excess of 1000 µmol/L. At 14 years diet was discontinued. Her IQ at 18 years was 94. At the age of 25 an MRI brain scan showed bilateral abnormal confluent high signal in the parieto-occipital and frontal lobes (Figure 1) with a severity score of 18 (as previously described (Cleary et al 1995), a score of 0 represents a normal scan; a score of >15 represents moderately severe involvement). Ten months later she restarted a low-phe diet with amino acid supplements and her blood phe concentrations fell to less than 450 µmol/L (Figure 2). Six months later repeat imaging showed a significant improvement, with a reduction in white-matter change (severity score 14). As she then wished to become pregnant she maintained strict dietary control (mean phe <300 µmol/L) for 23 months until the birth of her child. MRI, 1 month after the delivery, showed no significant white-matter abnormality (severity score 0). After a further 3 months, with a mean blood phe >900 µmol/L, white-matter changes were again present (severity score 8).

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(a) (b)

(c) (d)

Figure 1 Serial MRI brain scans: (a) severity score 18; (b) severity score 14; (c) severity score 0; (d) severity score 8. The timing of the scans is shown in Figure 2. Serial magnetic resonance imaging of the brain using a 0.5T (GE-MAX) MR system, sagittal T1-weighted spin echo and transverse intermediate and T2-weighted sequences, with a section thickness of 5mm

CONCLUSION A significant improvement in white-matter abnormalities occurs when blood phe concentrations are reduced to less than 600 µmol/L (Cleary et al 1995). This case demonstrates that these changes are not related to early biochemical control. They can be fully reversed, at least in some individuals, even when moderately severe, but it appears that the plasma phe concentrations need to be reduced and maintained below 450µmol/L.

J. Inher. Metab. Dis. 20 (1997)

Complete reversal of moderate/severe brain MRI abnormalities

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Figure 2 Biochemical control and MRI scores: plasma phe concentrations (solid curve) and MRI scores (dashed curve and solid squares) plotted against age

These findings support the hypothesis that MRI abnormalities in PKU are due to dysmyelination rather than demyelination and the time taken to show improvement may relate to myelin turnover times. REFERENCES Bick U, Ullrich K, Stober U, et al (1993) White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings. Eur J Pediatr 152: 1012–1020. Cleary MA, Walter JH, Wraith JE, et al (1994) Magnetic resonance imaging of the brain in phenylketonuria. Lancet 344: 87–90. Cleary MA, Walter JH, Wraith JE, White F, Tyler K, Jenkins JP (1995) Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 127: 251–255.

J. Inher. Metab. Dis. 20 (1997)