Genetic Connections: Exploring Familial Multiple Sclerosis and its Global Impact
Multiple Sclerosis (MS) is a chronic, inflammatory neurological disorder of the central nervous system that leads to progressive disability, primarily affecting young adults. Familial Multiple Sclerosis (FMS), a subset of MS, refers to cases where two or more family members are diagnosed with the disease, indicating a genetic predisposition. A recent meta-analysis aimed to update the global prevalence of FMS by incorporating newer studies into the existing body of literature, offering a comprehensive picture of familial recurrence in MS across different populations and geographical regions.
Background
MS affects over 2.5 million individuals worldwide, with both genetic and environmental factors contributing to its onset. The most significant genetic risk factor identified is the HLA-DRB1*15:01 allele, which increases the risk of MS approximately 3.5 times, rising to eightfold in homozygous individuals. Environmental factors such as Epstein-Barr Virus (EBV) infection, vitamin D deficiency, and smoking also play crucial roles in the development of MS. The study of FMS provides further insights into the genetic underpinnings of MS and helps refine our understanding of its hereditary patterns.
Study Methodology
The meta-analysis followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Researchers searched multiple databases, including PubMed, Scopus, and the ISI Web of Science, for studies published up to December 2020. The inclusion criteria focused on studies that reported MS prevalence among full biological relatives, with an emphasis on both pediatric-onset MS (POMS) and adult-onset MS (AOMS) cases. Ultimately, 49 studies were selected for analysis, encompassing a total of 16,179 familial MS cases.
Key Findings
1. Prevalence of Familial MS
The pooled global prevalence of FMS was estimated to be 11.8%. This value represents a slight decrease compared to earlier estimates, but the prevalence varied widely across different regions. For example, FMS was most prevalent in Canada’s Saskatchewan region, with a rate of 32.7%, while Hungary had the lowest reported prevalence at 2.2%.
2. Age of Onset
The average age of onset for adult MS probands with familial history was calculated at 28.7 years, suggesting that individuals with a family history of MS tend to develop symptoms at a younger age than those without such history. This earlier onset may indicate a higher genetic load in FMS cases.
3. Pediatric vs. Adult-Onset MS
Interestingly, the prevalence of FMS was higher in pediatric-onset MS cases (15.5%) compared to adult-onset cases (10.8%). This finding suggests that children diagnosed with MS are more likely to have a family history of the disease, potentially due to a stronger genetic influence in early-onset forms of MS.
4. Gender and Familial MS
Contrary to expectations, there was no significant difference in FMS prevalence between males and females, with 13.7% of male MS patients having a family history of the disease compared to 15.4% of females. This finding challenges the "Carter effect," which posits that men, as the less frequently affected gender, would exhibit a higher prevalence of familial cases. The odds ratio of male to female FMS cases was 0.9, indicating no statistically significant difference.
5. Geographical Differences
A notable finding was the significant geographical variability in FMS prevalence. While certain areas like the Middle East showed higher prevalence rates, other regions, such as parts of Europe, had comparatively lower rates. These differences highlight the complex interplay between genetic and environmental factors in determining the familial occurrence of MS.
6. Latitude and MS Prevalence
One of the more unexpected findings was the inverse correlation between FMS prevalence and latitude. While MS is generally more common in regions farther from the equator, the prevalence of FMS decreased with increasing latitude. Similarly, higher overall MS prevalence was associated with a slight decrease in FMS, possibly reflecting greater public awareness and genetic counseling in regions with higher MS incidence, leading to fewer consanguineous marriages.
Implications and Future Directions
This meta-analysis highlights the importance of considering both genetic and environmental factors in understanding the familial patterns of MS. The higher prevalence of FMS in pediatric-onset cases suggests that genetic factors play a more prominent role in early-onset MS, whereas environmental triggers may be more influential in adult-onset cases. The geographical variability in FMS prevalence also underscores the need for region-specific studies to unravel the genetic and environmental determinants of MS.
Moving forward, future studies should adopt longitudinal and cohort designs to track the development of MS in family members over time. This would provide a more accurate estimate of FMS prevalence and allow for the identification of genetic variants that contribute to familial susceptibility. Additionally, greater attention should be given to the role of genetic counseling in regions with high MS prevalence, as this may reduce the incidence of FMS through informed reproductive choices.
Conclusion
In conclusion, the global prevalence of familial multiple sclerosis is influenced by several factors, including age of onset, geographical location, and environmental exposures. While FMS is more common in pediatric-onset cases and varies by region, the findings of this meta-analysis suggest that the hereditary risk of MS does not differ significantly between males and females. These insights offer valuable guidance for future genetic and epidemiological studies aimed at unraveling the complexities of MS inheritance.
References:
Ehtesham, N., Rafie, M.Z. & Mosallaei, M. The global prevalence of familial multiple sclerosis: an updated systematic review and meta-analysis. BMC Neurol 21, 246 (2021).
