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NEUROLOGY 2007;68:376-383
© 2007 American Academy of Neurology

Familial effects on the clinical course of multiple sclerosis

A. E. Hensiek, MD, PhD, S. R. Seaman, PhD, L. F. Barcellos, PhD, A. Oturai, MD, PhD, M. Eraksoi, MD, E. Cocco, PhD, L. Vecsei, MD, G. Stewart, PhD, B. Dubois, MD, PhD, J. Bellman-Strobl, MD, M. Leone, MD, O. Andersen, MD, K. Bencsik, MD, D. Booth, MD, PhD, E. G. Celius, MD, PhD, H. F. Harbo, MD, PhD, S. L. Hauser, PhD, R. Heard, MD, J. Hillert, MD, PhD, K. -M. Myhr, M. G. Marrosu, PhD, J. R. Oksenberg, PhD, C. Rajda, MD, S. J. Sawcer, MD, PhD, P. S. Sørensen, PhD, F. Zipp, MD and D.A.S. Compston, MD, PhD

From the Department of Clinical Neurosciences (A.E.H., S.J.S., D.A.S.C.), University of Cambridge Clinical School, UK; MRC Biostatistics Unit (S.R.S.), Institute of Public Health, University Forvie Site, Cambridge, UK; School of Public Health (L.F.B.), University of California, Berkley; Danish Multiple Sclerosis Research Centre (A.O., P.S.S.), Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark; University of Istanbul (M.E.), Turkey; Centro Sclerosi Multipla (E.C., M.G.M.), University of Caglieri, Sardinia, Italy; University of Szeged (L.V., K.B., C.R.), Albert Szent-Gyorgyi Medical and Pharmaceutical Center, Department of Neurology; Westmead Millennium Institute (G.S., D.B., R.H.), Sydney, Australia; University of Leuven (B.D.), Belgium; Institut fuer Neuroimmunologie (J.B.-S., F.Z.), Universitaetsklinikum Charite, Berlin, Germany; Clinica Neurologica (M.L.), Ospedale Maggiore della Carità, Novara, Italy; Department of Neurology (E.G.C., H.F.H.), Ullevål University Hospital, Oslo, Norway; Department of Neurology (L.F.B., S.L.H., J.R.O.), University of California at San Francisco; Department of Neurology (J.H.), Karolinska University Hospital-Huddinge, Karolinska Institute, Sweden; The Multiple Sclerosis National Competence Centre (K.-M.M.), Department of Neurology, Haukeland University Hospital and Department of Clinical Medicine Section for Neurology, University of Bergen, Norway; and Department of Neurology (O.A.), Göteborg University Hospital, Sweden.

Address correspondence and reprint requests to Professor Alastair Compston, Department of Clinical Neuroscience, University of Cambridge Clinical School, Addenbrooke's Hospital, Box 165, Cambridge CB2 2QQ, UK; e-mail: alastair.compston{at}medschl.cam.ac.uk

Background: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease.

Method: We evaluated 1,083 families with ≥2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs.

Results: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa –0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent–child pairs and no evidence for anticipation or effects of genetic loading.

Conclusion: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.

This work follows from the individual GAMES screens that were supported by the Wellcome Trust (grant 057097). The Nordic study was supported by the EU Commission (project number BMH4-CT97-2422), B.D. is supported by the University Research Council (University of Leuven, Belgium), and F.Z. is supported by grants from the Bundesministerium für Bildung und Forschung, Germany.

Disclosure: The authors report no conflicts of interest.

Received February 20, 2006. Accepted in final form October 12, 2006.




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