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Isolated Peripheral Neuropathy in Atypical Metachromatic Leukodystrophy: A Recurrent Mutation

Published online by Cambridge University Press:  14 September 2018

Marion B. Coulter-Mackie ,
Derek A. Applegarth ,
Jennifer R. Toone ,
Liane Gagnier ,
André R. Anzarut  and
Glenda Hendson
Marion B. Coulter-Mackie*
Affiliation:
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada Biochemical Diseases Laboratory, British Columbia’s Children’s Hospital; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Derek A. Applegarth
Affiliation:
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada Biochemical Diseases Laboratory, British Columbia’s Children’s Hospital; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Jennifer R. Toone
Affiliation:
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
Liane Gagnier
Affiliation:
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
André R. Anzarut
Affiliation:
Adult and Pediatric Neurology, University of British Columbia, Vancouver, British Columbia, Canada
Glenda Hendson
Affiliation:
Biochemical Diseases Laboratory, British Columbia’s Children’s Hospital; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
*
MB Coulter-Mackie, BCCH, 4480 Oak St. Rm 2F22, Vancouver, British Columbia V6H 3V4 Canada.
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Abstract:

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Background:

Metachromatic leukodystrophy (MLD) is a genetic neurodegenerative disorder resulting from a deficiency of arylsulfatase A. Late onset forms are relatively rare. Central nervous system (CNS) involvement is characteristic at all ages.

Methods:

A patient in her late 40s with peripheral neuropathy was assessed by EEG, evoked potentials, CTand nerve conduction studies. Nerve and muscle biopsy samples were investigated by electron microscopy. Arylsulfatase A activity in leukocytes and excreted cerebroside sulfate were determined. The arylsulfatase A gene was investigated for mutations using polymerase chain reaction (PCR) and DNAsequencing. The identified mutation was expressed transiently in African green monkey kidney (COS) cells to determine the effect of the mutation on arylsulfatase A activity.

Results:

Central nervous system functions were normal. Nerve conduction velocities were decreased. Sural nerve biopsy showed inclusions typical of MLD. Arylsulfatase A was less than 5% of normal. A homozygous mutation thr286pro was identified in the arylsulfatase A gene and demonstrated to be deleterious through transient expression studies.

Conclusions:

Our patient has a progressive peripheral neuropathy but has apparently intact CNS function at her present age of 57 years. Biochemical, physiological and pathological findings are consistent with a diagnosis of MLD. A homozygous mutation, thr286pro, found in her arylsulfatase A gene, decreased enzyme activity to a level consistent with a late onset form of MLD.

Résumé:

Résumé:Introduction:

La leucodystrophie métachromatique (LDM) est une maladie neurodégénérative génétique résultant d’un déficit en arylsulfatase A. Les formes à début tardif sont relativement rares. L’atteinte du système nerveux central (SNC) est caractéristique quelque soit l’âge.

Méthode:

Une patiente dans la quarantaine avancée, porteuse d’une neuropathie périphérique, a été évaluée par ÉEG, potentiels évoqués, CT et étude de la conduction nerveuse. Des spécimens nerveux et musculaires ont été étudiés par microscopie électronique. L’activité de l’arylsulfatase Ades leucocytes et l’excrétion de sulfate de cérébroside ont été déterminées. On a recherché des mutations dans le gène de l’arylsulfatase A par PCR et séquençage d’ADN. La mutation identifiée a été exprimée de façon transitoire dans des cellules COS pour déterminer l’effet de la mutation sur l’activité de l’arylsulfatase A.

Résultats:

Les fonctions du SNC étaient normales. Les vitesses de conduction nerveuse étaient diminuées. La biopsie du nerf sural a montré des inclusions typiques de la LDM. Le taux d’arylsulfatase Aétait à moins de 5% du taux normal. Une mutation thr286pro à l’état homozygote a été identifiée dans le gène de l’arylsulfatase A et on a démontré son effet délétère par des études d’expression transitoire.

Conclusions:

Notre patiente était atteinte d’une neuropathie périphérique progressive avec préservation de la fonction du SNC à l’âge de 57 ans. Les évaluations biochimique, physiologique et anatomopathologique concordent avec un diagnostic de LDM. Une mutation thr286pro à l’état homozygote dans le gène de l’arylsulfatase Aa diminué l’activité enzymatique à un niveau compatible avec une forme tardive de LDM.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 29 , Issue 2 , May 2002 , pp. 159 - 163
Copyright
Copyright © Canadian Neurological Sciences Federation 2002

References

1. Kolodny, EH, Fluharty, AL. Metachromatic leukodystrophy and multiple sulfatase deficiency:sulfatide lipidosis. In: Scriver, CR, Beaudet, AL, Sly, WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. v. 2. New York: McGraw-Hill, Inc., 1995: 2693-2739.Google Scholar
2. Fressinaud, C, Vallat, JM, Masson, M, et al. Adult-onset metachromatic leukodystrophy presenting as isolated peripheral neuropathy. Neurology 1992; 42: 1396-1398.Google Scholar
3. Hansen, LM, Kristensen, O, Friis, ML. Neuropathy in adult metachromatic leukodystrophy. Ugeskr Laeger 1994; 156: 2252-2253.Google Scholar
4. Felice, KJ, Gomez Lira, M, Natowicz, M, et al. Adult-onset MLD A gene mutation with isolated polyneuropathy. Neurology 2000; 55:1036-1039.CrossRefGoogle Scholar
5. Coulter-Mackie, MB, Gagnier, L, Applegarth, DA, Toone, J. A unique homozygous mutation in the arylsulfatase A gene of a patient with a late onset peripheral neuropathy. Am J Hum Genet 1996; (Suppl 4):1467.Google Scholar
6. Baum, H, Dodgson, KS, Spencer, B. The assay of arylsulfatases Aand B in human urine. Clin Chim Acta 1959; 4: 453-455.CrossRefGoogle Scholar
7. Lee-Vaupel, M, Conzelmann, E. A simple chromogenic assay for arylsulfatase A. Clin Chim Acta 1987; 164: 171-180.CrossRefGoogle Scholar
8. Rip, J, Gordon, BA. A simple spectrophotometric enzyme assay with absolute specificity for arylsulfatase A. Clin Biochem 1998; 31: 29-31.Google Scholar
9. Coulter-Mackie, MB, Gagnier, L, Beis, MJ, et al. Metachromatic leucodystrophy in three families from Nova Scotia, Canada: a recurring mutation in the arylsulphatase A gene. J Med Genet 1997; 34: 493-498.CrossRefGoogle Scholar
10. Argyrakis, A, Pilz, H, Goebel, HH, Müller, D. Ultrastructural findings of peripheral nerve in a preclinical case of adult metachromatic leukodystrophy. J Neuropathol Exp Neurol 1977; 36: 693-711.CrossRefGoogle Scholar
11. Thomas, PK, King, RHM, Kocen, RS, Brett, EM. Comparative ultrastructural observations on peripheral nerve abnormalities in the late infantile, juvenile and late onset forms of metachromatic leukodystrophy. Acta Neuropath 1977; 39: 237-245.CrossRefGoogle Scholar
12. Friede, RL. Metachromatic leukodystophy (sulfatase A deficiency) and multiple sulfatase deficiency. In: Friede, RL (ed). Developmental neuropathology. Germany: Springer-Verlag, 1989: 460-469.Google Scholar
13. Coulter-Mackie, MB, Gagnier, L. Two new polymorphisms in the arylsulfatase A gene and their haplotype associations with normal, metachromatic leukodystrophy and pseudodeficiency alleles. Am J Med Genet 1997; 73: 32-35.Google Scholar
14. Deng, WP, Nickoloff, JA. Site-directed mutagenesis of virtually any plasmid by eliminating a unique site. Ann Biochem 1992; 200:81-88.Google Scholar
15. Kreysing, J, Polten, A, Hess, B, et al. Structure of the mouse arylsulfatase A gene and cDNA. Genomics 1994; 19: 249-256.CrossRefGoogle Scholar
16. Lukatela, G, Krauss, N, Theis, K, et al. Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis. Biochemistry 1998; 37: 3654-3664.Google Scholar
17. Hyde, TM, Ziegler, JC, Weinberger DR. Psychiatric disturbances in metachromatic leukodystrophy. Arch Neurol 1992; 49: 401-406.CrossRefGoogle Scholar
18. Sadovnick, AD, Tuokko, H, Applegarth, DA, et al. The differential diagnosis of adult onset metachromatic leukodystrophy and early onset familial Alzheimer’s disease in an Alzheimer clinic population. Can J Neurol Sci 1993; 20: 312-318.CrossRefGoogle Scholar
19. Baumann, N, Masson, M, Carreau, V, et al. Adult forms of metachromatic leukodystrophy: clinical and biochemical approach. Dev Neurosci 1991; 13: 211-215.Google Scholar
20. Perusi, C, Lira, MG, Duyff, RF, et al. Mutations associated with very late onset metachromatic leukodystrophy. Clin Genet 1999;55:130.Google Scholar
21. Wulff, CH, Trojaborg, W. Adult metachromatic leukodystrophy: neurophysiologic findings. Neurology 1985; 35: 1776-1778.CrossRefGoogle Scholar
22. Hageman, ATM, Gabreëls, FJM, de Jong, JGN, et al. Clinical symptoms of adult metchromatic leukodystrophy and arylsulfatase A pseudodeficiency. Arch Neurol 1995; 52: 408-413.Google Scholar