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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
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
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Abstract:

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
Copyright
Copyright © Canadian Neurological Sciences Federation 2002

References

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