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Metachromatic leukodystrophy: natural course of cerebral MRI changes in relation to clinical course

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Objective

Metachromatic Leukodystrophy (MLD) is a rare disorder leading to demyelination and neurological impairment. A natural history study within the German leukodystrophy network analyzed MRI changes with respect to the clinical course.

Methods

113 MR images of 68 patients (33 late-infantile, 35 juvenile) were studied cross-sectionally and longitudinally. MRI and motor deterioration were assessed using standardized scoring systems.

Results

The temporal and spatial patterns of MR severity scores differed between the late-infantile and juvenile form. Although early (involving central white matter, corpus callosum) and late signs (involving pons, cerebellum, cerebral atrophy) were similar, high MRI scores (mean 18, SD 1.2, p < 0.001) were evident in the juvenile form already at the onset of first symptoms and even in presymptomatic patients. The progression rate of the MRI score was clearly higher and more uniform in the late-infantile (on average 8 per year, p < 0.0001) than in the juvenile patients (on average 0.4 per year, p < 0.08). In late-infantile patients, MRI changes correlated highly with motor deterioration (rho = 0.73, p < 0.001), this was less remarkable in the juvenile form (rho = 0.50, p < 0.01). Severe motor dysfunction was associated with U-fiber involvement and cerebellar changes (p < 0.05).

Conclusions

MRI showed a typical spatial pattern, which evolved gradually and uniformly during disease progression in late-infantile MLD. In juvenile MLD MRI changes were already observed at disease onset and temporal patterns were more variable. As therapeutic options for MLD are evolving, these findings are not only important for patient counseling but also for the evaluation of therapeutic interventions.

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References

  • Biffi A, Cesani M, Fumagalli F et al. (2008a) Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation. Clin Genet 74:349–357

    Article  PubMed  CAS  Google Scholar 

  • Biffi A, Lucchini G, Rovelli A, Sessa M (2008b) Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant 42(Suppl 2):S2–S6

    Article  PubMed  Google Scholar 

  • Black JW, Cumings JN (1961) Infantile metachromatic leukodystrophy. J Neurol Neurosurg Psychiatr 24:233–239

    Article  PubMed  CAS  Google Scholar 

  • Costello DJ, Eichler AF, Eichler FS (2009) Leukodystrophies: classification, diagnosis, and treatment. Neurologist 15:319–328

    Article  PubMed  Google Scholar 

  • Demaerel P, Faubert C, Wilms G, Casaer P, Piepgras U, Baert AL (1991) MR findings in leukodystrophy. Neuroradiology 33:368–371

    Article  PubMed  CAS  Google Scholar 

  • Eichler F, Grodd W, Grant E et al. (2009) Metachromatic Leukodystrophy: A Scoring System for Brain MR Observations. AJNR Am J Neuroradiol 30:1893–1897

    Article  PubMed  CAS  Google Scholar 

  • Faerber EN, Melvin J, Smergel EM (1999) MRI appearances of metachromatic leukodystrophy. Pediatr Radiol 29:669–672

    Article  PubMed  CAS  Google Scholar 

  • Gieselmann V (2008) Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options. Acta Paediatr Suppl 97:15–21

    Article  PubMed  Google Scholar 

  • Gieselmann V, Krägeloh-Mann I (2010) Metachromatic leukodystrophy–an update. Neuropediatrics 41:1–6

    Article  PubMed  CAS  Google Scholar 

  • Gieselmann V, Franken S, Klein D et al. (2003) Metachromatic leukodystrophy: consequences of sulphatide accumulation. Acta Paediatr Suppl 92:74–79

    Article  PubMed  CAS  Google Scholar 

  • Haberland C, Brunngraber E, Witting L, Daniels A (1973) Juvenile metachromatic leucodystrophy. Case report with clinical, histopathological, ultrastructural and biochemical observations. Acta Neuropathol 26:93–106

    Article  PubMed  CAS  Google Scholar 

  • Heim P, Claussen M, Hoffmann B et al. (1997) Leukodystrophy incidence in Germany. Am J Med Genet 71:475–478

    Article  PubMed  CAS  Google Scholar 

  • Jervis GA (1960) Infantile metachromatic leukodystrophy. (Greenfield's disease). J Neuropathol Exp Neurol 19:323–341

    Article  PubMed  CAS  Google Scholar 

  • Kehrer C, Blumenstock G, Gieselmann V, and Krägeloh-Mann I (2011a) The natural course of gross motor deterioration in metachromatic leukodystrophy. Dev Med Child Neurol. accepted for publication.

  • Kehrer C, Blumenstock G, Raabe C, Krägeloh-Mann I (2011b) Development and reliability of a classification system for gross motor function in children with metachromatic leucodystrophy. Dev Med Child Neurol 53:156–160

    Article  PubMed  Google Scholar 

  • Kim TS, Kim IO, Kim WS et al. (1997) MR of childhood metachromatic leukodystrophy. AJNR Am J Neuroradiol 18:733–738

    PubMed  CAS  Google Scholar 

  • Loes DJ, Hite S, Moser H et al. (1994) Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 15:1761–1766

    PubMed  CAS  Google Scholar 

  • Mahmood A, Raymond GV, Dubey P, Peters C, Moser HW (2007) Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol 6:687–692

    Article  PubMed  Google Scholar 

  • Poorthuis BJ, Wevers RA, Kleijer WJ et al. (1999) The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 105:151–156

    PubMed  CAS  Google Scholar 

  • Russel Brain W, Greenfield JG (1950) Late infantile metachromatic leuko-encephalopathy, with primary degeneration of the interfascicular oligodentroglia. Brain 73:291–317

    Article  Google Scholar 

  • Schiffmann R, van der Knaap MS (2009) Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 72:750–759

    Article  PubMed  Google Scholar 

  • Shrout PE, Fleiss JL (1979) Intraclass correlations: uses in assessing rater reliability. Psychol Bull 86:420–428

    Article  PubMed  CAS  Google Scholar 

  • van der Knaap MS, Valk J (2005) Magnetic resonance in myelin, myelination, and myelin disorders. Springer, Berlin

    Google Scholar 

  • van der Voorn JP, Pouwels PJ, Kamphorst W et al. (2005) Histopathologic correlates of radial stripes on MR images in lysosomal storage disorders. AJNR Am J Neuroradiol 26:442–446

    PubMed  Google Scholar 

  • von Figura K, Gieselmann V, and Jacken J (2001) Metachromatic leukodystrophy. In Scriver CR, Beaudet AL, Sly WS et al., eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 3695–3724

  • Zafeiriou DI, Kontopoulos EE, Michelakakis HM, Anastasiou AL, Gombakis NP (1999) Neurophysiology and MRI in late-infantile metachromatic leukodystrophy. Pediatr Neurol 21:843–846

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The work was supported by a grant from the German Federal Ministry of Education and Research (LEUKONET). In addition we thank Professor Martin Staudt, Dr Marko Wilke and Professor Thomas Naegele (University Hospital Tübingen, Germany) for participating in the inter-rater test, and Professor Volkmar Gieselmann (Department of Physiology, University of Bonn, Germany, coordinator of the Leukonet) for critical and helpful comments on the manuscript. And we do thank the children and their families for their participation.

Author information

Authors and Affiliations

  1. Department of Pediatric Neurology & Developmental Medicine and Experimental Pediatric Neuroimaging, University Children’s Hospital, Hoppe-Seyler-Strasse 1, 72076, Tübingen, Germany

    Samuel Groeschel

  2. Department of Pediatric Neurology & Developmental Medicine, University Children’s Hospital, Hoppe-Seyler-Strasse 1, 72076, Tübingen, Germany

    Christiane Kehrer & Ingeborg Krägeloh-Mann

  3. Center for Pediatric Clinical Studies, Biometry, University Children’s Hospital, Tübingen, Germany

    Corinna Engel

  4. Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark

    Christine í Dali

  5. Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Germany

    Annette Bley

  6. Department of Pediatrics and Pediatric Neurology, University Hospital Göttingen, Göttingen, Germany

    Robert Steinfeld

  7. Department of Psychiatry and Psychotherapy, University Hospital Aachen, Aachen, Germany

    Wolfgang Grodd

Authors
  1. Samuel Groeschel
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  2. Christiane Kehrer
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  3. Corinna Engel
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  4. Christine í Dali
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  5. Annette Bley
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  6. Robert Steinfeld
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  7. Wolfgang Grodd
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  8. Ingeborg Krägeloh-Mann
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Corresponding author

Correspondence to Samuel Groeschel.

Additional information

Communicated by Ed Wraith

Conflict of interest disclosures

The work was supported by a grant from the German Federal Ministry of Education and Research (LEUKONET).

Dr. Groeschel has received institutional research support from the German Federal Ministry of Education and Research and from Shire plc.

Dr. Kehrer has received institutional research support from the German Federal Ministry of Education and Research.

Dr. Engel reports no disclosures.

Dr. í Dali serves on a scientific advisory board for Shire plc and has received institutional research support from Shire plc and Zymenex A/S.

Dr. Bley has received institutional research support from the German Federal Ministry of Education and Research.

Dr. Steinfeld reports no disclosures.

Dr. Grodd reports no disclosures.

Dr. Krägeloh-Mann was member of the scientific board of the Scandinavian biopharmaceutical company ZYMENEX for a world-wide clinical trial I-study for enzyme replacement with the ZYMENEX’s product “Metazym” in 2007. This did not imply any involvement, nor funding in the present study.

All authors confirm independence of the sponsors; the content of the article has not been influenced by the sponsors.

Electronic supplementary materials

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Supplementary material Fig. 1

MR Severity score of patients with MLD according to chronological age. Lines connect follow-up scans of patients. Empty circles indicate MR scans of patients before the onset of first symptoms. (PPT 38 kb)

Supplementary material Fig. 2

Mean of subscores for the early, middle and late phase of the disease (scaled between 0–1). The numbers indicate specific brain areas depicted by the score. (1 parieto-occipital WM – central, 2 splenium of corpus callosum, 3 frontal WM – central, 4 parieto-occipital WM – periventricular, 5 temporal WM – central, 6 genu of corpus callosum, 7 frontal WM - periventricular, 8 temporal WM – periventricular, 9 pons, 10 parieto-occipital WM – subcortical, 11 posterior limb of internal capsule, 12 frontal WM – subcortical, 13 cerebellar atrophy, 14 cerebellar WM changes, 15 temporal WM – subcortical, 16 cerebral atrophy, 17 anterior limb of internal capsule) (PPT 58 kb)

Supplementary material Table 1

MR Severity Scoring System for MLD (Eichler et al. 2009). (DOC 25 kb)

Supplementary material, Table 2

Gross Motor Function Classification system for MLD (GMFC-MLD) (Kehrer et al. 2011b). (DOC 27 kb)

Supplementary material, Table 3

Correlation coefficients (Spearman’s rank) and their correlation p-value are given for the whole MR Severity Score and its subscores with the motor function score (GMFC-MLD) for the late-infantile and juvenile form of MLD. Highlighted correlation coefficients (in bold font) are remarkably high. (DOC 48 kb)

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Groeschel, S., Kehrer, C., Engel, C. et al. Metachromatic leukodystrophy: natural course of cerebral MRI changes in relation to clinical course. J Inherit Metab Dis 34, 1095–1102 (2011). https://doi.org/10.1007/s10545-011-9361-1

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  • DOI: https://doi.org/10.1007/s10545-011-9361-1

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