European Journal of Pediatrics

, Volume 152, Issue 12, pp 1012–1020 | Cite as

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

  • U. Bick
  • K. Ullrich
  • U. Stöber
  • H. Möller
  • G. Schuierer
  • A. C. Ludolph
  • C. Oberwittler
  • J. Weglage
  • U. Wendel
Metabolic Disease
Received:
Accepted:

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.

Key words

Phenylketonuria Myelination Magnetic resonance imaging 1H spectroscopy T2 relaxometry 

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

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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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: 107–113CrossRefPubMedGoogle Scholar
  2. 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: 566–570PubMedGoogle Scholar
  3. 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: 173–180PubMedGoogle Scholar
  4. 4.
    Barkovich AJ, Lyon G, Evrard P (1992) Formation, maturation, and disorders of white matter. AJNR 13:447–461PubMedGoogle Scholar
  5. 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: 177–180PubMedGoogle Scholar
  6. 6.
    Bauman ML, Kemper TL (1982) Morphologic and histoanatomic observations of the brain in untreated human phenylketonuria. Acta Neuropathol (Berl) 58: 55–63CrossRefGoogle Scholar
  7. 7.
    Behbehani AW, Krtsch H, Schulte FJ (1981) Cranial computerized tomography in phenylketonuria. Neuropediatrics 12: 295–302PubMedGoogle Scholar
  8. 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 23Google Scholar
  9. 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: 185–189PubMedGoogle Scholar
  10. 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: 731–740PubMedGoogle Scholar
  11. 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 89Google Scholar
  12. 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: 1–37PubMedGoogle Scholar
  13. 13.
    Brant-Zawadzki M (1988) MR imaging of the brain. Radiology 166: 1–10Google Scholar
  14. 14.
    Brismar J, Aqeel A, Gascon G, Ozand P (1990) Malignant hyperphenylalaninemia: CT and MR of the brain. AJNR 11: 135–138PubMedGoogle Scholar
  15. 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: 283–301PubMedGoogle Scholar
  16. 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: 126–131Google Scholar
  17. 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: 57–69PubMedGoogle Scholar
  18. 18.
    Deber CM, Reynolds SJ (1991) Central nervous system myelin: structure, function and pathology. Clin Biochem 24: 113–134CrossRefPubMedGoogle Scholar
  19. 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: 717–725CrossRefPubMedGoogle Scholar
  20. 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: 441–446PubMedGoogle Scholar
  21. 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: 79–83PubMedGoogle Scholar
  22. 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: 416–421CrossRefPubMedGoogle Scholar
  23. 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: 173–181PubMedGoogle Scholar
  24. 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: 199–206PubMedGoogle Scholar
  25. 25.
    Herschkowitz N (1988) Brain development in the fetus, neonate and infant. Biol Neonate 54: 1–19PubMedGoogle Scholar
  26. 26.
    Hommes FA, Matsuo K (1987) On a possible mechanism of abnormal brain development in experimental hyperphenylalaninemia. Neurochem Int 11: 1–10CrossRefGoogle Scholar
  27. 27.
    Huether G, Kaus R, Neuhoff V (1982) Brain development in experimental hyperphenylalaninaemia: myelination. Neuropediatrics 13: 177–182PubMedGoogle Scholar
  28. 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 12Google Scholar
  29. 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: 265–274PubMedGoogle Scholar
  30. 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: 509–515PubMedGoogle Scholar
  31. 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-A16CrossRefPubMedGoogle Scholar
  32. 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: 482–495PubMedGoogle Scholar
  33. 33.
    Korinthenberg R, Ullrich K, Füllenkemper F (1988) Evoked potentials and electroencephalography in adolescents with phenylketonuria. Neuropediatrics 19: 175–178PubMedGoogle Scholar
  34. 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, P11Google Scholar
  35. 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: 687–695CrossRefPubMedGoogle Scholar
  36. 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: 243–248PubMedGoogle Scholar
  37. 37.
    Matsuo K, Hommes F (1987) Regional distribution of the phenylalanine-sensitive ATP-sulphurylase in brain. J Inherited Metab Dis 10: 62–65CrossRefGoogle Scholar
  38. 38.
    Matthews PM, Francis G, Antel J, Arnold DL (1991) Proton magnetic resonance spectroscopy for metabolic characterization of plaques in multiple sclerosis. Neurology 41: 1251–1256PubMedGoogle Scholar
  39. 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: 535–539PubMedGoogle Scholar
  40. 40.
    Nowell MA, Grossman RI, Hackney DB, Zimmerman RA, Goldberg HI, Bilaniuk LT (1988) MR imaging of white matter disease in children. AJR 151: 359–365PubMedGoogle Scholar
  41. 41.
    Pearson KD, Gean-Marton AD, Levy HL, Davis KR (1990) Phenylketonuria: MR imaging of the brain with clinical correlation. Radiology 177: 437–440PubMedGoogle Scholar
  42. 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: 388Google Scholar
  43. 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: 315–321PubMedGoogle Scholar
  44. 44.
    Reynolds R, Burri R, Mahal S, Herschkowitz N (1992) Disturbed myelinogenesis and recovery in hyperphenylalaninemia in rats: an immunohistochemical study. Exp Neurol 115: 347–367CrossRefPubMedGoogle Scholar
  45. 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: 577–587Google Scholar
  46. 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-A19CrossRefPubMedGoogle Scholar
  47. 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 495–546Google Scholar
  48. 48.
    Shaw DWW, Weinberger E, Maravilla KR (1990) Cranial MR in phenylketonuria. J Comput Assist Tomogr 14: 458–460PubMedGoogle Scholar
  49. 49.
    Shaw DWW, Maravilla KR, Weinberger E, Garretson J, Trahms CM, Scott CR (1991) MR imaging of phenylketonuria. AJNR 12: 403–406PubMedGoogle Scholar
  50. 50.
    Smith L, Beasley MG, Ades AE (1990) Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 65: 472–478PubMedGoogle Scholar
  51. 51.
    Taylor EH, Hommes FA (1983) Effect of experimental hyperphenylalaninemia on myelin metabolism at later stages of brain development. Int J Neurosci 20: 217–228PubMedGoogle Scholar
  52. 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: 602–605CrossRefPubMedGoogle Scholar
  53. 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)CrossRefGoogle Scholar
  54. 54.
    Toma P, Oddone M, Lucigrai G, Cerone R, Romano C, Pelizza A (1991) Phenylketonuria (PKU): brai magnetic resonance (MR) findings (abstract). Neuropediatrics 22: 174Google Scholar
  55. 55.
    Valk J, Knaap MS van der (1989) Magnetic resonance of myelin, myelination and myelin disorders. Springer, Berlin Heidelberg New YorkGoogle Scholar
  56. 56.
    Villasana D, Butler IJ, Williams JC, Roongta SM (1989) Neurological deterioration in adult phenylketonuria. J Inherited Metad Dis 12: 451–457CrossRefGoogle Scholar
  57. 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: 149–153PubMedGoogle Scholar
  58. 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 10Google Scholar
  59. 59.
    Wässer S, Dietrich J, Theile H, Bergmann L (1985) Korrelation klinischer, elektroenzephalographischer und computertomographischer Befunde bei Phenylketonurie. Z Klin Med 40: 1207–1210Google Scholar
  60. 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 151:522–525Google Scholar
  61. 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: 317–324PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • U. Bick
    • 1
  • K. Ullrich
    • 2
  • U. Stöber
    • 1
  • H. Möller
    • 1
  • G. Schuierer
    • 1
  • A. C. Ludolph
    • 3
  • C. Oberwittler
    • 3
  • J. Weglage
    • 2
  • U. Wendel
    • 4
  1. 1.Department of RadiologyUniversity of MünsterGermany
  2. 2.Department of PediatricsUniversity of MünsterGermany
  3. 3.Department of NeurologyUnivesity of MünsterGermany
  4. 4.Department of PediatricsUniversity of DüsseldorfGermany

Personalised recommendations