Convergent lines of evidence have indicated that MS can run in families [57]. The number of affected family members in a given proband ranges from one (the most proportion) to even seven and eight [24, 36]. Although, no Mendelian pattern has seen in the pedigree of multigenerational families. In this regard, cohort studies could be well suited on the account of a longer time period for the accumulation of new cases in the family. Concerning the degree of relatedness, the occurrence of the same condition is more prevalent in first-degree relatives, particularly siblings of the affected individuals, which underscores the combined role of shared genetic and environmental factors in MS etiology [16, 24, 25, 29, 33, 34]. While, one study reported parent-child relationship as the prevalent kinship [28]. In this context, the probability of the transmission of disease from mother to child is more than father to child [13, 8, 58]. Amongst the siblings, sister-sister, sister-brother, and brother-brother relation are, respectively, more prevalent [29, 34]. Evidently, after first-degree relatives, third-degree relatives have more chance for the development of MS [13, 18, 34].
The pooled prevalence of FMS in our study (11.8%) (Figure 2) was lower than previous meta-analysis (12.6%) [9]. Hence, we performed a meta-regression analysis based on prevalence day to examine if the prevalence of the FMS is decreased over time. Our results showed a non-significant lowering trend (Figure 9C). Hence, it seems that the worldwide frequency of FMS is steady-state over time. Nonetheless, some studies in middle-east reported the increasing [13, 24] or decreasing [16] prevalence of FMS over time, highlighting the existence of substantial difference in terms of genetic and environmental factors between different populations even in a same geographical area. Moreover, the overwhelming majority of the studies have been performed in a cross-sectional setting; while, sufficient long follow-up period is needed to evaluate the development of the disease in new members of the relatives, primarily distant relatives that would not have been found in short-term periods.
POMS is defined as the manifestation of symptoms before/under the age of 16 or 18 [59]. According to our analysis, the frequency of FMS in POMS was higher than AOMS (Figure 5). However, only 3 to 10% of sporadic cases are reported to be POMS [60]. This informs us that increased genetic load may be a pivotal feature of POMS and family history of MS could be a crucial contributing factor for POMS predisposition. It is important to remember that one reason for the difference between the results of studies on the prevalence of POMS, either in FMS or sporadic MS, is the usage of different cut-off points for POMS, extending from 15 to 18 years old. By considering follow-up time bias, it seems that the prevalence of FMS is underestimated in the pediatric group due to not emergence of this disease in relatives especially siblings at the time of the study, at least in cross-sectional studies.
The mean age of onset in adult probands with FMS was estimated to be 28.7 (Figure 4), which indicates an earlier age of onset among FMS cases in comparison to sporadic cases [61, 7]. This highlights the point that the preclinical phase of the disease would be shortened in cases with higher genetic load and consequently symptoms initiate at a lower age at onset.
Considering the concept of the “carter effect” [62], we set out to investigate the notion that in male MS patients, the prevalence of FMS is more than in females patients, as well as transmission to other members of the family, is higher when the affected individual is male. However, the prevalence of FMS in male and female cases and OR of male/female of FMS cases did not confirm this theory (Figure 6 and 7). This represents that a greater than average background of susceptibility factors in an affected male which is the less frequently affected sex does not increase the occurrence of the MS in relatives. On the contrary, a higher prevalence of FMS and positive family in males than that in females was seen in the Iranian population [63]. However, we acknowledge that low sample size for scrutinizing the effect of sex might cause underpowered interpretation.
Subgroup analysis unveiled that the distribution of FMS is different between geographical areas (Figure 8). This emphasizes the distinct underlying etiology of FMS which emanates from susceptibilities of distinct racial and ethnic groups. Also, this finding could justify the high heterogeneity between studies, at least in part. Relevantly, other meta-analysis indicated different FMS prevalence in Iran (8.9%) [63] and the Middle East North Africa region (17.8%) [64].
It is expected that with the increasing prevalence of sporadic MS, the frequency of FMS rises, as well. Quite interestingly, our meta-regression analysis revealed a weak decreasing trend of FMS in terms of increasing MS prevalence (Figure 9 A). In the same vein, mete-regression in terms of latitude disclosed that the prevalence of FMS is decreased in conjunction with an increment of latitude (Figure 9 B); although, traditionally, MS has been more prevalent in regions at higher latitudes with decreased sunlight exposure, irrespective of some exceptions [65]. Thereby, we hypothesized that with the increasing frequency of MS in a region, the public awareness and familiarity of the people, especially genetic counselors, with the disease grows, too. Therefore, the rate of marriages in which one or both sides have one or more affected members reduces. This, in turn, lowers the load of genetic and environmental risk factors in families. On the other hand, the rate of consanguineous marriage as a predictor of positive family history of MS [16], is most probably diminished in regions with a high outbreak of this disease.
In this review, we would not address the difference between the clinical course of FMS and SMS cases. However, it must allude that there is a discrepancy between the results of the studies. Most of them uncovered that FMS is not a different clinical entity and closely resembles sporadic MS [16, 28, 33, 53]. Although, it appears that disease burden and progression in first-degree relatives with the most heavily genetic load is distinct from more distant relatives [15]. In this aspect, a systematic review with pertinent keywords is justified to obtain a more concrete conclusion.
In comparison to the previous systematic review [9], the strength of our study was recruiting of a quality assessment tool for inclusion of studies, no limitation of language for searching of articles, uncovering the prevalence of FMS in different geographical areas, in POMS and AOMS cases, and men and women, unveiling the relationship between the prevalence of FMS and prevalence day, MS prevalence and latitude, determining the mean age of the disease onset in adult probands and the effect of gender. Notwithstanding, there are some issues in the included studies which mostly derived from the retrospective design. For instance, recall bias could occur when the presence of affected relatives is assessed by employing questionnaires and medical records which hinges on patients self-reporting. This might result in the under-diagnosis of distant relatives. On the other hand, the diversity in case ascertainment methodology namely population (registry or community)-based or clinical (hospital)-based may cause the sampling bias.