The peroxisomal disorders are a heterogeneous
group of human diseases in which lesions of the nervous and
endocrine systems often predominate. Classical morphologic investigations
of the two prototypic peroxisomal diseases, X-linked, juvenile
adreno-leukodystrophy (ALD) and cerebro-hepato-renal (Zellweger)
syndrome (CHRS), have provided some insights into the pathogenesis
of these disorders. The major pathologic lesion in the nervous
system of ALD patients is that of an inflammatory, demyelinative
lesion of central white matter. The inflammatory component,
a morphologic marker of disease activity, has been interwoven
in ways unknown with a defect in very long chain fatty acid
catabolism to produce the pathogenetic fabric of ALD. Recently,
we have identified a number of effector molecules and cytokines
in the early stages of these lesions, particularly TNF-a. Their
primary source appears to be the hypertrophic astrocytes within
these lesions. The hypothesis that a cytokine cascade may initiate
and interact with a cell-mediated immune response has provided
a new impetus for possible treatment of the devastating CNS
demyelination in ALD patients.
The main pathologic alterations seen in Zellweger infants are
those of a central neuronal migration defect and a non-inflammatory
abnormality of central white matter. Neuronal migrations appear
to be interrupted in the first trimester and throughout the
entire neocortical migratory epoch. Preliminary ultrastructural
observations suggest that both migrating neuroblasts and radial
glia are affected. Additionally, there is a white matter abnormality
in CHRS, the pathogenesis of which is still unclear. My current
investigative interests include: 1) an elucidation of this white
matter abnormality in CHRS; 2) to further elucidate the demyelinative
lesion of ALD; and 3) to further our understanding of the spinal
cord tract degeneration seen in adrenomyeloneuropathy, a variant
of ALD. |
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Lu JF, Lawler AM, Watkins PA, Powers JM, Moser AB, Moser
HW, smith KD: A mouse Model for X-linked Adrenoleukodystrophy
Proc Natl Acad Sci 94:9366-9371, 1997.
McGuinness MC, Powers JM, Bias WB, Schmeckpeper BJ, Segal
AH, Gowda VC, Wesselingh SL, Berger J, Griffin DE, Smith KD:
Human Leukocyte Antigens and Cytokine Edpression in Cerebral
Inflammatory Demyelinative Lesions of X-linked Adrenoleukodystrophy
and Multiple Sclerosisl. J Neuroimmunol 75:174-182,
1997.
Powers, J.M. 1996. Neuropathologic overview of the neurodystrophies
and neurolipidoses. Handbook Clin. Neurol. 22(66):1-31.
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