Genetics of primary progressive multiple sclerosis

Multiple sclerosis (MS) patients are classified as either having relapsing onset or progressive onset disease, also known as primary progressive MS (PPMS). Relative to relapsing onset patients, PPMS patients are older at disease onset, are equally likely to be men or women, and have more rapid accumulation of disability that does not respond well to treatments used in relapsing onset MS. Although estimates vary, 5-15% of all MS patients have a PPMS disease course. Genetic variance is a proposed determinant of MS disease course. If distinct genes associated with PPMS were identified study of these genes might lead to an understanding of the biology underlying disease progression and neural degeneration that are the hallmarks of PPMS. These genes and their biological pathways might also represent therapeutic targets. This chapter systematically reviews the PPMS genetic literature. Despite the intuitively appealing notion that differences between PPMS and relapsing onset MS are due to genetics, definite differences associated with these phenotypes at the major histocompatibility complex or elsewhere in the genome have not been found. Recent large-scale genome wide screens identified multiple genes associated with MS susceptibility outside the MHC. The genetic variants identified thus far make only weak individual contributions to MS susceptibility. If the genetic effects that contribute to the differences between PPMS and relapsing MS are similar in magnitude to those that distinguish MS from healthy controls then, given the relative scarcity of the PPMS phenotype, very large datasets will be needed to identify PPMS associated genes. International collaborative efforts could provide the means to identify such genes. Alternately, it is possible that factors other than genetics underlie the differences between these clinical phenotypes.