Patterns of disease in concordant parent-child pairs with multiple sclerosis

Background: Although the exact etiology of MS remains elusive, there is goo d evidence that genetic factors play an important role. These factors are l ikely to be polygenic, exerting both independent and interactive effects on the expression of MS. They may determine susceptibility and/or shape the c linical course. Methods: The authors studied clinical phenotype in 245 conc ordant parent-child pairs recruited from a national register of familial di sease over a 10-year period. Data were examined in order to determine the e ffect of parental sex on expression of disease in the offspring. Results: A llowing for the observed sex ratio of 2.6 F:1 M in this group of patients, sex pairings of parents and offspring were close to those expected. When as sessed independently there was no evidence that either the sex of the affec ted offspring or the line of inheritance influenced disability, age at onse t, or disease course. However, trends were observed toward greater disabili ty and an increased frequency of primary progressive disease in offspring o f affected fathers and an earlier age at onset in offspring of affected mot hers. The highest mean Expanded Disability Status Scale score was observed in male offspring of affected fathers (5.64) and this group was also more l ikely to have primary progressive disease (OR 1.92), Thirty-one percent of families had an additionally affected offspring with no preferential matern al or paternal transmission. Conclusions: In offspring of concordant parent -child families with MS who are at high risk of inheriting increased number s of susceptibility genes there is no evidence for a parent of origin effec t distorting sex ratios in affected offspring, but parent of origin may inf luence disability and disease course as well as increasing the risk to addi tional offspring within the same family. The mechanism of these effects is not clear but may result from interactions between genes encoded at differe nt loci (epistasis), which each independently influence susceptibility and phenotype.