| Alexander disease is a rare but fatal neurological disorder. It primarily strikes infants, producing motor and mental retardation, seizures, megalencephaly, and massive myelin loss in the frontal lobes. Juvenile and adult forms affect the brain stem and cerebellum instead. Development and frontal lobe myelin may be normal. Despite these differences, they were classified as Alexander disease because, like the more common infantile form, there is an abundance of Rosenthal fibers (RFs), which are protein aggregates within astrocytes. However, it has been an open question whether all three clinical types actually arise from the same disease etiology. Recently, missense mutations in glial fibrillary acidic protein (GFAP), the major component of Rosenthal fibers, were found in several cases of the infantile form. In the reprint I further explore the association of GFAP mutations with Alexander disease, particularly the later onset forms. GFAP mutations were found in almost all cases of all three clinical forms, suggesting that they indeed belong to the same disease entity. In addition to sporadic mutations, a few familial cases have been reported. In Appendix A I report on an adult female patient and her son who both had clinical signs of Alexander disease and similar diagnostic magnetic resonance imaging (MRI). Both proved to have the same GFAP mutation, further demonstrating that GFAP mutations are pathogenic. I also performed functional tests of several mutations by cell transfections to obtain evidence for their disease relatedness. These experiments also revealed that mutations in different positions in the protein may affect different steps in filament assembly. Co-transfection of mutant and wild-type (WT) expression vectors showed the mutant to be dominant, as it is in Alexander disease. These results are presented in Appendix B. In the preprint I investigated the origin of the sporadic mutations. Mutations were found to arise six times more frequently on the paternal than the maternal chromosome (p < 0.001), indicating that the mutations occurred during gametogenesis, especially during spermatogenesis. The male-to-female mutation rate ratio of 6 is consistent with results from other studies. No effect of advanced paternal age was evident. |
