Skip to main content
SpringerLink
Log in

White matter abnormalities in patients with treated hyperphenylalaninaemia: Magnetic resonance relaxometry and proton spectroscopy findings

  • Metabolic Disease
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T2 relaxometry (n=8) and/or1H spectroscopy (n=7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6-to 8-month period of strict diet control. The clinical evaluation included a detailed neurological examination. In nine out of ten patients visual evoked potentials (VEP) were obtained parallel to the MR examination. MR imaging demonstrated typical symmetrical areas of prolonged T2 relaxation time predominantly in the posterior periventricular white matter in all but one of type I and II patients. There was no consistent relationship between MRI findings and time of diagnosis/initiation of therapy, IQ or visual evoked potential changes. MRI abnormalities tended to be more severe in patients with poor dietary control and high current plasma phenylalanine levels, whereas a normal MRI was found only in patients with plasma phenylalanine levels continuously below 0.36 mmol/l. There was marked regression of MRI abnormalities already after 3 months of strict diet control. T2 relaxometry showed a bi-exponential behaviour of T2 in the affected white matter, with a slow component of about 200–450 ms, indicating an increase in free (extracellular) water.1H spectroscopy revealed no signs of severe neuronal damage. We conclude, that the observed white matter changes in treated HPA probably represent reversible structural myelin changes rather than permanent demyelination.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Cho:

choline

Cr:

total creatinine

CSF:

cerebrospinal fluid

CT:

computed tomography

HPA:

hyperphenylalaninaemia

MR1:

magnetic resonance imaging

NAA:

N-acetylaspartate

Phe:

phenylalanine

PKU:

phenylketonuria

TE:

echo time

TR:

repetition time

VEP:

visual evoked potentials

References

  1. Armsbach J-P, Gounut D, Rumbach L, Chambron J (1991) In vivo determination of multiexponential T2 relaxation in the brain of patients with multiple sclerosis. Magn Reson Imaging 9: 107–113

    Article  PubMed  Google Scholar 

  2. Avison MJ, Herschkowitz N, Novotny EJ, Petroff OAC, Rothman DL, Colombo JP, Bachmann C, Shulman RG, Prichard JW (1990) Proton NMR observation of phenylalanine and an aromatic metabolite in the rabbit brain in vivo. Pediatr Res 27: 566–570

    PubMed  Google Scholar 

  3. Barkovich AJ, Kjos BO, Jackson DE, Norman D (1988) Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T. Radiology 166: 173–180

    PubMed  Google Scholar 

  4. Barkovich AJ, Lyon G, Evrard P (1992) Formation, maturation, and disorders of white matter. AJNR 13:447–461

    PubMed  Google Scholar 

  5. Battistini S, Stefano N de, Parlanti S, Frederico A (1991) Unexpected white matter changes in an early treated PKU case and improvement after dietary treatment. Funct Neurol 6: 177–180

    PubMed  Google Scholar 

  6. Bauman ML, Kemper TL (1982) Morphologic and histoanatomic observations of the brain in untreated human phenylketonuria. Acta Neuropathol (Berl) 58: 55–63

    Article  Google Scholar 

  7. Behbehani AW, Krtsch H, Schulte FJ (1981) Cranial computerized tomography in phenylketonuria. Neuropediatrics 12: 295–302

    PubMed  Google Scholar 

  8. Bick U, Fahrendorf G, Ludolph A. Ullrich K (1989) MR imaging of the brain in patients with hyperphenylalaninemia (abstract). Abstracts of the 27th SSIEM Annual Symposium, Munich, p 23

  9. Bick U, Fahrendorf G, Ludolph AC, Vassallo P, Weglage J, Ullrich K (1991) Disturbed myelination in patients with treated hyperphenylalaninemia: evaluation with magnetic resonance imaging. Eur J Pediatr 150: 185–189

    PubMed  Google Scholar 

  10. Bird CR, Hedberg M, Drayer BP, Keller PJ, Flom RA, Hodak JA (1989) MR assessment of myelination in infants and children: usefulness of marker sites. AJNR 10: 731–740

    PubMed  Google Scholar 

  11. Blaskovics ME, Koch R, Nelson M, Philappart M (1990) MRI's and treatment in hyperphenylalaninemic patients (abstract). Abstracts of the 28th SSIEM Annual Symposium, Birmingham, p 89

  12. Bottomley PA, Hardy CJ, Argersinger RE, Allen-Moore G (1987) A review of1H nuclear magnetic resonance relaxation in pathology: are T1 and T2 diagnostic? Med Phys 14: 1–37

    PubMed  Google Scholar 

  13. Brant-Zawadzki M (1988) MR imaging of the brain. Radiology 166: 1–10

    Google Scholar 

  14. Brismar J, Aqeel A, Gascon G, Ozand P (1990) Malignant hyperphenylalaninemia: CT and MR of the brain. AJNR 11: 135–138

    PubMed  Google Scholar 

  15. Brody BA, Kinney HC, Kloman AS, Gilles FH (1987) Sequence of central nervous system myelination in human infancy. I. An autopsy study of myelination. J Neuropathol Exp Neurol 46: 283–301

    PubMed  Google Scholar 

  16. Bruhn H, Frahm J, Gyngell ML, Merboldt, Hänicke W, Sauter R (1989) Cerebral mebabolism in man after acute stroke: new observations using localized proton NMR spectroscopy. Magn Res Med 9: 126–131

    Google Scholar 

  17. Burri R, Steffen C, Stieger S, Brodbeck U, Colombo JP, Herschkowitz N (1990) Reduced myelinogenesis and recovery in hyperphenylalaninemic rats. Correlation between brain phenylalanine levels, characteristic brain enzymes for myelination and brain development. Mol Chem Neuropathol 13: 57–69

    PubMed  Google Scholar 

  18. Deber CM, Reynolds SJ (1991) Central nervous system myelin: structure, function and pathology. Clin Biochem 24: 113–134

    Article  PubMed  Google Scholar 

  19. Dwivedy AK, Shah SN (1982) Effects of phenylalanine and its deaminated metabolites on Na+, K+-ATPase activity in synaptosomes from rat brain. Neurochem Res 7: 717–725

    Article  PubMed  Google Scholar 

  20. Fischer HW, Haverbeke Y van, Schmitz-Feuerhake I, Muller RN (1989) The uncommon longitudinal relaxation dispersion of human brain white matter. Magn Reson Med 9: 441–446

    PubMed  Google Scholar 

  21. Frahm J, Bruhn H, Gyngell ML, Merboldt KD, Hänicke W, Sauter R (1989) Localized high-resolution proton NMR spectroscopy using stimulated echoes: ihitial applications to human brain in vivo. Magn Reson Med 9: 79–83

    PubMed  Google Scholar 

  22. Giovanni M, Valsasina R, Villani R, Ducati A, Riva E, Landi A, Longhi R (1988) Pattern reversal visual evoked potentials in phenylketonuria. J Inherited Metab Dis 11: 416–421

    Article  PubMed  Google Scholar 

  23. Grodd W, Krägeloh-Mann I, Klose U, Sauter R (1991) Metabolic and destructive brain disorders in children: findings with localized MR spectroscopy. Radiology 181: 173–181

    PubMed  Google Scholar 

  24. Hecke P van, Marchal G, Johannik K, Demaerel P, Wilms G, Carton H, Baert AL (1991) Human brain proton localized NMR spectroscopy in multiple sclerosis. Magn Reson Med 18: 199–206

    PubMed  Google Scholar 

  25. Herschkowitz N (1988) Brain development in the fetus, neonate and infant. Biol Neonate 54: 1–19

    PubMed  Google Scholar 

  26. Hommes FA, Matsuo K (1987) On a possible mechanism of abnormal brain development in experimental hyperphenylalaninemia. Neurochem Int 11: 1–10

    Article  Google Scholar 

  27. Huether G, Kaus R, Neuhoff V (1982) Brain development in experimental hyperphenylalaninaemia: myelination. Neuropediatrics 13: 177–182

    PubMed  Google Scholar 

  28. Johannik K, Hecke P van, Francois B, Smet M, Jaeken J, Baert A (1992) Localized proton NMR spectroscopy in patients with phenylketonuria (abstract). Abstracts of the 30th SSIEM Annual Symposium, Leuven, P 12

  29. Kamman RL, Go KG, Brouwer W, Berendsen HJC (1988) Nuclear magnetic resonance relaxation in experimental brain edema: effects of water concentration, protein concentration, and temperature. Magn Reson Med 6: 265–274

    PubMed  Google Scholar 

  30. Knaap MS van der, Grond J van der, Rijen PC van, Faber JAJ, Valk J, Willemse K (1990) Age-dependent changes in localized proton and phosphorus MR spectroscopy of the brain. Radiology 176: 509–515

    PubMed  Google Scholar 

  31. Koch R, Azen CG, Hurst N, Gross Friedman E, Fishler K (1987) The effects of diet discontinuation in children with phenylketonuria. Eur J Pediatr 146 [Suppll]: A12-A16

    Article  PubMed  Google Scholar 

  32. Koenig SH, Brown III RD, Spiller M, Lundbom N (1990) Relaxometry of brain: why white matter appears bright on MRI. Magn Reson Med 14: 482–495

    PubMed  Google Scholar 

  33. Korinthenberg R, Ullrich K, Füllenkemper F (1988) Evoked potentials and electroencephalography in adolescents with phenylketonuria. Neuropediatrics 19: 175–178

    PubMed  Google Scholar 

  34. Leuzzi V, Fabbrizi F, Antonozzi I, Gualdi G, Biasi C di, Trasimeni G (1992) Neuroradiological (NMR) examination in PKU patients: clinical and biochemical correlation (abstract). Abstracts of the 30th SSIEM Annual Symposium, Leuven, P11

  35. Lou HC, Toft PB, Andresen J, Mikkelsen I, Olsen B, Güttler F, Wieslander S, Henriksen O (1992) An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninaemia. J Inherited Metab Dis 15: 687–695

    Article  PubMed  Google Scholar 

  36. Ludolph AC, Ullrich K, Nedjat S, Masur H, Bick U (1992) Neurological outcome in 22 treated adolescents with hyperphenylalaninemia. A clinical and electrophysiological study. Acta Neurol Scand 85: 243–248

    PubMed  Google Scholar 

  37. Matsuo K, Hommes F (1987) Regional distribution of the phenylalanine-sensitive ATP-sulphurylase in brain. J Inherited Metab Dis 10: 62–65

    Article  Google Scholar 

  38. Matthews PM, Francis G, Antel J, Arnold DL (1991) Proton magnetic resonance spectroscopy for metabolic characterization of plaques in multiple sclerosis. Neurology 41: 1251–1256

    PubMed  Google Scholar 

  39. Mirowitz S, Sartor K, Gado M, Torack R (1989) Focal signalintensity variations in the posterior internal capsule: normal MR findings and distinction from pathologic findings. Radiology 172: 535–539

    PubMed  Google Scholar 

  40. Nowell MA, Grossman RI, Hackney DB, Zimmerman RA, Goldberg HI, Bilaniuk LT (1988) MR imaging of white matter disease in children. AJR 151: 359–365

    PubMed  Google Scholar 

  41. Pearson KD, Gean-Marton AD, Levy HL, Davis KR (1990) Phenylketonuria: MR imaging of the brain with clinical correlation. Radiology 177: 437–440

    PubMed  Google Scholar 

  42. Pietz J, Schmidt E, Kutscha A, Meyding-Lamade U (1992) Sustained attention deficits and white matter changes (MRI) in phenylketonuria (PKU) (abstract). J Clin Exp Neuropsychol 14: 388

    Google Scholar 

  43. Press GA, Barshop BA, Haas RH, Nyhan WL, Glass RF, Hesselink JR (1989) Abnormalities of the brain in nonketotic hyperglycinemia: MR manifestations. AJNR 10: 315–321

    PubMed  Google Scholar 

  44. Reynolds R, Burri R, Mahal S, Herschkowitz N (1992) Disturbed myelinogenesis and recovery in hyperphenylalaninemia in rats: an immunohistochemical study. Exp Neurol 115: 347–367

    Article  PubMed  Google Scholar 

  45. Schad LR, Brix G, Zuma I, Härle W, Lorenz WJ, Semmler W (1989) Multiexponential proton spin-spin relaxation in MR imaging of human brain tumors. J Comput Ass Tomogr 13: 577–587

    Google Scholar 

  46. Schmidt H, Mahle M, Michel U, Pietz J (1987) Continuation vs discontinuation of low-phenylalanine diet in PKU adolescents. Eur J Pediatr 146 [Suppl 1]: A17-A19

    Article  PubMed  Google Scholar 

  47. Scriver CR, Kaufman S, Woo SLC (1989) The hyperphenylalaninemias. In: Scriver CR, Baudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease I, 6th edn. McGraw Hill, New York, pp 495–546

    Google Scholar 

  48. Shaw DWW, Weinberger E, Maravilla KR (1990) Cranial MR in phenylketonuria. J Comput Assist Tomogr 14: 458–460

    PubMed  Google Scholar 

  49. Shaw DWW, Maravilla KR, Weinberger E, Garretson J, Trahms CM, Scott CR (1991) MR imaging of phenylketonuria. AJNR 12: 403–406

    PubMed  Google Scholar 

  50. Smith L, Beasley MG, Ades AE (1990) Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 65: 472–478

    PubMed  Google Scholar 

  51. Taylor EH, Hommes FA (1983) Effect of experimental hyperphenylalaninemia on myelin metabolism at later stages of brain development. Int J Neurosci 20: 217–228

    PubMed  Google Scholar 

  52. Thompson AJ, Smith I, Brenton D, Youl BD, Rylance G, Davidson DC, Kendall B, Lees AJ (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336: 602–605

    Article  PubMed  Google Scholar 

  53. Thompson AJ, Smith I, Kendall BE, Youl BD, Brenton D (1991) Maghetic resonance imaging changes in early treated patients with phenylketonuria. Lancet 337: 1224 (Letter)

    Article  Google Scholar 

  54. Toma P, Oddone M, Lucigrai G, Cerone R, Romano C, Pelizza A (1991) Phenylketonuria (PKU): brai magnetic resonance (MR) findings (abstract). Neuropediatrics 22: 174

    Google Scholar 

  55. Valk J, Knaap MS van der (1989) Magnetic resonance of myelin, myelination and myelin disorders. Springer, Berlin Heidelberg New York

    Google Scholar 

  56. Villasana D, Butler IJ, Williams JC, Roongta SM (1989) Neurological deterioration in adult phenylketonuria. J Inherited Metad Dis 12: 451–457

    Article  Google Scholar 

  57. Waisbren SE, Schnell RR, Levy HL (1980) Diet termination in children with phenylketonuria: a review of psychological assessments used to determine outcome. J Inherited Metab Dis 3: 149–153

    PubMed  Google Scholar 

  58. Walter JH, Tyfield LA, Holton JB, Johnson C (1992) Magnetic resonance imaging, biochemical control and genetic analysis in patients with phenylketonuria (abstract). Abstracts of the 30th SSIEM Annual Symposium, Leuven, P 10

  59. Wässer S, Dietrich J, Theile H, Bergmann L (1985) Korrelation klinischer, elektroenzephalographischer und computertomographischer Befunde bei Phenylketonurie. Z Klin Med 40: 1207–1210

    Google Scholar 

  60. Weglage J, Fünders B, Wilken B, Schubert D, Schmidt E, Burgard P, Ullrich K (1992) Psychological and social findings in adolescents with phenylketonuria. Eur J Pediatrics 151:522–525

    Google Scholar 

  61. Zamaroczy D, Schluesener HJ, Jolesz FA, Sobel RA, Colucci VM, Weiner HL, Sandor T (1991) Differentiation of experimental white matter lesions using multiparametric magnetic resonance measurements. Invest Radiol 26: 317–324

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiology, University of Münster, Germany

    U. Bick, U. Stöber, H. Möller & G. Schuierer

  2. Department of Pediatrics, University of Münster, Germany

    K. Ullrich & J. Weglage

  3. Department of Neurology, Univesity of Münster, Germany

    A. C. Ludolph & C. Oberwittler

  4. Department of Pediatrics, University of Düsseldorf, Germany

    U. Wendel

Authors
  1. U. Bick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Ullrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. U. Stöber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Möller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Schuierer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. C. Ludolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Oberwittler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Weglage
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. U. Wendel
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bick, U., Ullrich, K., Stöber, U. et al. White matter abnormalities in patients with treated hyperphenylalaninaemia: Magnetic resonance relaxometry and proton spectroscopy findings. Eur J Pediatr 152, 1012–1020 (1993). https://doi.org/10.1007/BF01957228

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01957228

Key words

Search

Navigation