Familial vs sporadic multiple sclerosis in the Israeli population: Differences in ethnicity distribution and disease progression, with anticipation in successive generations

Abstract

BackgroundMultiple Sclerosis (MS) may cluster in families, an entity known as familial MS (FMS), possibly due to aggregation of genetic and environmental factors. Though previous studies have characterized FMS in different populations, no study to the best of our knowledge has yet characterized FMS in the unique Israeli population, which is comprised of relatively endogamous ethnicities. Our goal in this study was to compare demographic and clinical characteristics between FMS and sporadic MS (SMS), and to search for intra-familial patterns. MethodsIn a retrospective study of 101 FMS patients and 508 SMS patients, ethnicity and sex distribution was assessed. Clinical aspects were compared between 172 paired FMS and SMS patients, matched for sex, age and ethnicity, and between generations of the FMS cohort. ResultsFemales comprised 75.3 % of FMS and 67.5 % of SMS patients (p = 0.1). Ethnic distribution was significantly different between FMS and SMS (p = 0.014), with the former comprising a higher proportion of Christian-Arabs (15.4% vs. 5.1 %, p = 0.004) and lower proportion of Jews (60% vs. 74.2 %, p = 0.016). Age at disease onset or diagnosis, frequency of positive Oligoclonal bands and comorbidity of other autoimmune/inflammatory disease or chronic diseases was comparable between FMS and SMS, yet motor symptoms at onset were more prevalent in FMS (34% vs. 20 %, p = 0.02). Annualized relapse rates throughout 10 years from onset were comparable. Among FMS, mean Expanded-Disability-Status-Scale (EDSS) and slope of deterioration in EDSS over 20 years from diagnosis were higher (p = 0.0004 and p = 0.023, respectively), time to EDSS ≥ 3 was shorter (7.1 vs. 12.1 years, HR 1.6, p = 0.036) and MS-Severity-Score (MSSS) was higher (3.84 vs. 2.95, p = 0.04), compared to SMS. Following adjustment for smoking, which tended to be higher among FMS patients (P = 0.06), mean EDSS and slope of deterioration in EDSS over 20 years remained significantly higher (p = 0.0006 and p = 0.025, respectively) in FMS, time to EDSS ≥ 3 tended to be higher (HR 1.5, p = 0.06), while MSSS was comparable. An inter-generational analysis of the total FMS cohort, as well as an intra-familial analysis, both adjusted for year of diagnosis, revealed significantly earlier age of onset (p < 0.0001 and p < 0.0001) and diagnosis (p = 0.001 and p < 0.0001) in the younger compared to the older generations, respectively. ConclusionIn this Israeli cohort, the proportions of specific ethnicities differ between FMS and SMS, indicating that FMS has a population-specific prevalence pattern, and that further investigation for susceptibility genes is warranted. Disease progression is faster in FMS patients and anticipation is observed in families with multiple cases of MS. Closer surveillance and application of a pro-active induction or early highly-effective therapeutic strategy for FMS patients should be considered, to reduce high disease activity and fast disability progression.