Familial Aggregation Patterns in Multiple Sclerosis and Their Association with Disease Severity

Familial aggregation is a well-recognized feature of multiple sclerosis (MS). However, there is considerable heterogeneity in how disease susceptibility and clinical outcomes cluster within families. Although the relationship between parental lineage effects and MS risk has been previously investigated, their association with long-term disease severity remains poorly understood. In this study, we sought to explore patterns of familial aggregation according to maternal and paternal lineage in patients with familial MS and to evaluate whether these patterns are associated with long-term disease severity.

This retrospective observational study included 110 patients with familial MS from 50 families. Among patients in whom parental lineage could be determined, familial aggregation was classified as maternal or paternal based on comprehensive pedigree review. Clinical characteristics, disability status measured by the Expanded Disability Status Scale (EDSS), and time-adjusted disease severity assessed using the Multiple Sclerosis Severity Score (MSSS) were compared between lineages.

Maternal and paternal lineages differed significantly in the distribution of affected relatives by degree of relatedness (p=0.040); this difference was primarily driven by a higher proportion of first-degree affected relatives in the maternal-line group. No significant differences were observed between maternal and paternal lineages in early clinical characteristics, including age at onset, sex distribution, and initial clinical symptom distribution. Although EDSS scores were comparable between groups, MSSS values were significantly higher among patients in the maternal-line group (median 4.5 vs. 1.6, p=0.016).

The parental lineage through which familial aggregation occurs in MS may be associated with long-term disease severity. These findings suggest that lineage-based approaches may offer valuable insights into the clinical profile of familial MS, while also underscoring the need for further studies integrating genetic, epigenetic, and longitudinal data.