Distribution of Disease Courses in Familial vs. Sporadic Multiple Sclerosis: Insights from a Danish Nationwide Study

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease with varying courses, including relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive MS (PPMS). Despite advances in understanding MS genetics, little is known about how disease courses differ between familial (inherited) and sporadic (non-inherited) cases. The study by Steenhof et al. (2018) in Acta Neurologica Scandinavica sheds light on these differences, examining MS courses within Danish familial cases compared to sporadic ones.

1. Study Background and Rationale
MS is generally diagnosed among young adults, often presenting as RRMS, where patients experience episodes of symptoms (relapses) followed by recovery (remissions). A significant proportion of RRMS cases transition to SPMS, where symptoms progressively worsen. Primary progressive MS, affecting a smaller percentage, involves steady symptom progression from onset. Genetic studies highlight a hereditary component to MS, especially in familial cases, but specific clinical course distributions within familial cases are under-explored​.

2. Methodology: Leveraging National Registries
The researchers conducted a nationwide analysis, utilizing data from Danish registries including the Danish MS Registry, Civil Registration System, and National Patient Registry. These comprehensive datasets enabled the identification of 7,402 MS cases, including both familial (531 cases with a first-degree relative diagnosed with MS) and sporadic cases. By tracking MS diagnoses, clinical progression, and family relations, the study could reliably categorize MS cases into RRMS, SPMS, or PPMS. The analysis required stringent inclusion criteria, ensuring only well-documented, definite MS cases diagnosed between 1994 and 2014 were considered​.

3. Key Findings: Higher Relapse-Remission Rates in Familial MS
The study found that familial MS cases were 1.64 times more likely to present with relapsing courses (RRMS or SPMS) than sporadic cases. This finding implies a genetic predisposition within familial MS cases toward relapsing-remitting courses, which may transition to secondary progression. The contrast is notable as sporadic cases showed a relatively higher incidence of PPMS, suggesting potentially different underlying pathophysiological mechanisms. Logistic regression models confirmed these associations, even after adjusting for variables like age and sex​.

4. Course Concordance Among Family Members
Further analysis focused on 133 MS families, each with at least two affected first-degree relatives, revealing a significant course concordance: 89% of families shared the same MS course type across relatives, primarily RRMS or SPMS. This consistency supports the idea that genetic factors not only contribute to MS susceptibility but may also influence the clinical course within families. Despite this course similarity, the study observed no significant correlation in age of onset among family members, indicating that while the disease course might be shared, onset timing varies widely within families​.

5. Implications for Genetic Studies and Clinical Practice
These findings add complexity to the genetic landscape of MS. The prevalence of relapsing courses in familial MS cases suggests that certain genetic factors may enhance the likelihood of RRMS and subsequent progression to SPMS. This points to a possible avenue for genetic studies to explore specific risk loci associated with MS course types. Clinically, understanding familial predispositions to specific MS courses could lead to tailored interventions and closer monitoring strategies for patients with a family history of MS​.

6. Limitations and Considerations
While this study is robust, limitations include the inability to differentiate biological from adoptive relations due to registry constraints, which could influence familial MS categorization. Additionally, excluding second- or third-degree relatives may underrepresent familial MS cases. However, the nationwide scope and registry data’s reliability provide strong support for the study's conclusions.

7. Future Directions: Toward Precision Medicine in MS
The authors advocate for further research into the genetic distinctions between familial and sporadic MS cases, particularly regarding the genetic basis of RRMS and SPMS prevalence in familial cases. With more genetic insights, it may be possible to develop predictive models for MS progression in patients with a family history, paving the way for precision medicine approaches tailored to individual genetic risk profiles.

References:
Steenhof, M., Nielsen, N. M., Stenager, E., Kyvik, K., Möller, S., & Hertz, J. M. (2019). Distribution of disease courses in familial vs sporadic multiple sclerosis. Acta Neurologica Scandinavica, 139(3), 231-237.