Table of Contents
Washington University Experience | MYELIN (NON-IMMUNE MEDIATED) | Alexander Disease | 2I Case 1 (Comment)
Comment ---- The morphological features of the process in this case involve the entire central nervous system. The white matter of all regions, cortex in many areas, cerebellum, spinal cord, and even neural fiber layers of the eye are involved with an astrocytopathy that results not only in the deposition of numerous Rosenthal fibers along the leptomeninges and ependyma, but also an eosinophilic, granular, refractile material within the expanded cytoplasm of individual cells. While the former represents the classic histological appearance of Alexander’s disease, the latter are most consistent with the accumulation of identical material. Ultrastructural evaluation of the brain (performed previously on surgical biopsy) as well as on the eye at autopsy confirmed that the material accumulated within astrocytes cells has an appearance more similar to Rosenthal fibers than to the protein aggregates found in other astrocytopathies, e.g., hyaline astrocytopathy (Hedley-Whyte, E. T. et. al. Hyaline Protoplasmic Astrocytopathy of the Neocortex. J. Neuropathol Exp Neurol. 2009. 68:136-147) and the distribution of pathology in this case is not identical to that in hyaline astrocytopathy. The primary genetic aberration in this case (Arg239His in exon 4 of GFAP gene) as well as the morphological features are most consistent with Alexander’s disease. The involvement of the retina is a unique finding that has not been reported in the literature but is a striking feature in this individual.
Because of the striking mass-like effect within the deep structures of the brain, a neoplastic process was also considered. Although enlarged astrocytes make up the bulk of the additional material within these structures, we found no evidence of neoplastic behavior either in the form of proliferative activity or infiltrative behavior.
This is not a typical case of Alexander disease and it is possible that the other genetic features (short deletion in chromosome 17p – separate from the GFAP mutation – and a duplication in 22q) may have contributed to the striking presentation in this case, but this remains speculative as other similar combinations of genetic abnormalities have not been previously described. Alexander’s disease is a rare condition due in 95% of cases to a mutation in GFAP (Arg239His being one of the more common) that results in aberrations of astrocyte function. The changes induced by the mutation in GFAP effect its ability to polymerize partially explaining the amorphous accumulations that occur within cells which are known to also involve heat shock proteins and alpha B crystallin. The proper polymerization of GFAP is important for the regulation of its production and additional has an impact on several other signaling pathways within the cell including other stress response proteins. The clinical course varies depending on age of onset (with early onset cases having decreased survival times and more deleterious symptoms). As was seen in this case, frontal leukodystrophy is more prominent in younger patients.
