The pathogenesis of globoid cell leucodystrophy in peripheral nerve of the mouse mutant twitcher

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Abstract

The twitcher mouse is affected by a disease with pathological features resembling those of human globoid cell leucodystrophy (Krabbe's disease): it also has an identical enzyme deficiency. The progress of the disease has been studied in peripheral nerves. Myelin sheaths develop normally until about the 15th day when the rate of myelination declines.

Demyelination, first affecting paranodal regions is seen from the 10th–11th day before clinical signs appear. Krabbe-type inclusions are seen in macrophages and Schwann cells a few days later. Demyelination becomes extensive with increasing age, affecting fibres of all sizes, and axons rapidly remyelinate. Axons are not involved but quantitative studies show that they remain smaller than normal. Changes in twitcher nerves are compared to those in the neuropathy in human Krabbe's disease.

References (30)

  • B. Hagberg et al.

    Infantile globoid cell leucodystrophy (Krabbe's disease) — A clinical and genetic study of 32 Swedish cases, 1953–1967

    Neuropädiatrie

    (1969)
  • E.T. Hedley-Whyte

    Myelination of rat sciatic nerve — Comparison of undernutrition and cholesterol biosynthesis inhibition

    J. Neuropath. exp. Neurol.

    (1973)
  • G.R. Hogan et al.

    The peripheral neuropathy of Krabbe's (globoid) leukodystrophy

    Neurology (Minneap.)

    (1969)
  • J.M. Jacobs

    Experimental diphtheritic neuropathy in the rat

    Brit. J. exp. Path.

    (1967)
  • E.M.G. Joosten et al.

    Infantile globoid cell leucodystrophy (Krabbe's disease) — Some remarks on clinical, biochemical and sural nerve biopsy findings

    Neuropädiatrie

    (1974)
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    This research was supported by the Brain Research Trust and a WHO fellowship (F.T.A.).

    Present address: Division de Patologia, Unidad de Investigacion Biomedica del Centro Medico Nacional, Apdo. Postal 73-032, Mexico 7, D.F.

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