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NEUROLOGY 2006;67:859-863
© 2006 American Academy of Neurology

Late-onset metachromatic leukodystrophy

Genotype strongly influences phenotype

H. Rauschka, MD*, B. Colsch*, N. Baumann, MD, PhD, R. Wevers, PhD, M. Schmidbauer, MD, M. Krammer, J. -C. Turpin, MD, M. Lefevre, C. Olivier, PhD, S. Tardieu, BS, W. Krivit, MD, H. Moser, MD, A. Moser, V. Gieselmann, MD, B. Zalc, MD, PhD, T. Cox, MD, U. Reuner, MD, A. Tylki-Szymanska, MD, F. Aboul-Enein, MD, E. LeGuern, MD, PhD, H. Bernheimer, MD and J. Berger, PhD

From the Center for Brain Research (H.R., M.K., F.A.-E., J.B.), Medical University of Vienna, Department of Neurology (H.R., M.S.), Hospital Lainz, and Clinical Institute of Neurology (H.B.), Medical University of Vienna, Vienna General Hospital, Austria; INSERM U711 (B.C., N.B., M.L., C.O., B.Z.), Universite Pierre et Marie Curie, Faculte de Medecine, and Association pour la Recherche en Neurochimie (J.-C.T.), Hopital de la Salpetriere, Neurogenetics Laboratory and Department of Medical Genetics (S.T., E.L.G.) and INSERM Unit 679 (E.L.G.), Pitié-Salpêtrière Hôpital, Paris, France; Institute Neurology (R.W.), University Medical Centre Nijmegen, Nijmegen, the Netherlands; Department of Pediatrics (W.K.), University of Minnesota, Minneapolis; Kennedy Krieger Institute and Department of Neurology (H.M., A.M.), Johns Hopkins University, Baltimore, MD; Institut für Physiologische Chemie (V.G.), Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany; Department of Medicine (T.C.), University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Klinik und Poliklinik für Neurologie (U.R.), Universitätsklinikum Carl Gustav Carus-Technische Universität, Dresden, Germany; Zdrowia Dziecka Pomnik-Szpital (A.T.-S.), Children's Memorial Health Institute, Warszawa-Miedzylesie, Poland.

Address correspondence and reprint requests to Dr. J. Berger, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria; e-mail: johannes.berger{at}meduniwien.ac.at

Background: P426L and I179S are the two most frequent mutations in juvenile and adult metachromatic leukodystrophy (late-onset MLD), which, in contrast to infantile MLD, show marked phenotypic heterogeneity.

Objective: To search for genotype–phenotype correlations in late-onset MLD.

Methods: The authors reviewed the clinical course of 22 patients homozygous for mutation P426L vs 20 patients heterozygous for mutation I179S, in which the second arylsulfatase A (ASA) mutation had also been determined.

Results: P426L homozygotes principally presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at the onset of disease but became more apparent as the disease evolved. In contrast, compound heterozygotes for I179S presented with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits were scarce. Reduced peripheral nerve conduction velocities and less residual ASA activity were present in P426L homozygotes vs I179S heterozygotes.

Conclusion: The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype–phenotype correlation in late-onset metachromatic leukodystrophy.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 12 issue to find the title link for this article.

*These authors contributed equally to this work.

Supported by the Assistance Publique-Hôpitaux de Paris PHRC AOA 94 033, the Austrian Science Foundation (project no. P11406-MED), and the European Leukodystrophy Association (ELA).

Disclosure: The authors report no conflicts of interest.

Received December 1, 2005. Accepted in final form April 28, 2006.




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