Abstract
Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.
Highlights
Alexander disease (AxD) is a progressive and generally fatal neurogenetic disorder, with ages of onset ranging from fetal through late adulthood, resulting from heterozygous dominant mutations in the astrocyte intermediate filament protein glial fibrillary acidic protein (GFAP; Brenner et al, 2001; Messing et al, 2012b)
Studies in mouse models have led to the conclusion that, unlike most of the other intermediate filament disorders, GFAP mutations act in a gainof-function fashion, and that elevations of total GFAP levels may be a major factor in pathogenesis (Messing et al, 1998; Hagemann et al, 2006; Tanaka et al, 2007)
We here confirm the consistent elevation of GFAP levels in CSF samples in a larger cohort of patients, analyzed at the same time as control subjects
Summary
Alexander disease (AxD) is a progressive and generally fatal neurogenetic disorder, with ages of onset ranging from fetal through late adulthood, resulting from heterozygous dominant mutations in the astrocyte intermediate filament protein glial fibrillary acidic protein (GFAP; Brenner et al, 2001; Messing et al, 2012b). Studies in mouse models have led to the conclusion that, unlike most of the other intermediate filament disorders, GFAP mutations act in a gainof-function fashion, and that elevations of total GFAP levels may be a major factor in pathogenesis (Messing et al, 1998; Hagemann et al, 2006; Tanaka et al, 2007). AxD is genetically homogeneous, the clinical presentations are quite varied, with age of onset ranging from fetal through late adulthood.
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