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

From the University of Cambridge Neurology Unit (Drs. Hupperts, Broadley, and Compston), Addenbrooke’s Hospital, Cambridge; MRC Biostatistics Unit (Dr. Mander and D. Clayton), Institute of Public Health, University Forvie Site, Cambridge; and the University of Wales College of Medicine, Department of Neurology (Dr. Robertson), Heath Park, Cardiff, UK.

Address correspondence and reprint requests to Dr. N.P. Robertson, Department of Neurology, Heath Park, Cardiff, CF14 4XN, UK.

BACKGROUND: Although the exact etiology of MS remains elusive, there is good evidence that genetic factors play an important role. These factors are likely to be polygenic, exerting both independent and interactive effects on the expression of MS. They may determine susceptibility and/or shape the clinical course.

METHODS: The authors studied clinical phenotype in 245 concordant parent–child pairs recruited from a national register of familial disease over a 10-year period. Data were examined in order to determine the effect of parental sex on expression of disease in the offspring.

RESULTS: Allowing 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 assessed independently there was no evidence that either the sex of the affected offspring or the line of inheritance influenced disability, age at onset, or disease course. However, trends were observed toward greater disability and an increased frequency of primary progressive disease in offspring of affected fathers and an earlier age at onset in offspring of affected mothers. The highest mean Expanded Disability Status Scale score was observed in male offspring of affected fathers (5.64) and this group was also more likely to have primary progressive disease (OR 1.92). Thirty-one percent of families had an additionally affected offspring with no preferential maternal or paternal transmission.

CONCLUSIONS: In offspring of concordant parent–child families with MS who are at high risk of inheriting increased numbers of susceptibility genes there is no evidence for a parent of origin effect distorting sex ratios in affected offspring, but parent of origin may influence disability and disease course as well as increasing the risk to additional offspring within the same family. The mechanism of these effects is not clear but may result from interactions between genes encoded at different loci (epistasis), which each independently influence susceptibility and phenotype.

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