HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kümpfel, T. Articles by Lohse, P. Search for Related Content PubMed PubMed Citation Articles by Kümpfel, T. Articles by Lohse, P. Related Collections Autoimmune diseases Multiple sclerosis All Genetics

Multiple sclerosis and the TNFRSF1A R92Q mutation

Clinical characteristics of 21 cases

From the Institute of Clinical Neuroimmunology–Grosshadern (T.K., L.-A.H., H.P., R.H.) and Department of Clinical Chemistry–Grosshadern (P.L.), Ludwig Maximilians University of Munich; and Marianne Strauss-Klinik Kempfenhausen–Berg (W.P., W.F.), Germany.

Address correspondence and reprint requests to Dr. Tania Kümpfel, Institute of Clinical Neuroimmunology–Grosshadern, University of Munich, Marchioninistr. 15, D-81377 Munich, Germany tania.kuempfel{at}med.uni-muenchen.de

Objective: Tumor necrosis factor receptor 1–associated periodic syndrome (TRAPS) is an autosomal dominantly inherited autoinflammatory disorder resulting from mutations in the TNFRSF1A gene, which encodes the p55 receptor for tumor necrosis factor . We recently identified the R92Q mutation encoded by exon 4 in six patients with multiple sclerosis (MS) who reported at least two symptoms suggestive of TRAPS. The current study presents the characteristics of a larger cohort of MS patients carrying this mutation.

Methods: Clinical and laboratory parameters, including human leukocyte antigen (HLA)-DR15 status, were evaluated, and genetic testing was performed. Whenever possible, family members were also invited for interview and mutation analysis.

Results: Twenty TNFRSF1A R92Q carriers had MS according to the McDonald criteria, and 1 had clinically isolated syndrome. The majority of patients had typical onset and features of MS. Nine patients carried an HLA-DR15 haplotype. All individuals showed TRAPS-compatible symptoms, which consisted mainly of myalgias, arthralgias, headache, severe fatigue, and skin rashes; were milder than usually described; and appeared mainly in adulthood. Most patients experienced severe side effects during immunomodulatory therapy for MS. Seventeen family members carried the identical mutation, and 15 of them reported symptoms suggestive of TRAPS.

Conclusion: In most cases with multiple sclerosis (MS) and coexisting tumor necrosis factor receptor 1–associated periodic syndrome (TRAPS), features of MS were quite typical, whereas TRAPS presented mostly without the fever episodes observed in childhood. The penetrance of the R92Q mutation in affected family members was higher than reported. We recommend careful observation of MS patients with coexisting TRAPS with regard to unexpected side effects of immunomodulatory therapies.

GLOSSARY: ANA = antinuclear antibody; CIS = clinically isolated syndrome; COP = Copaxone; CRP = C-reactive protein; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; FLS = flu-like symptoms; FMF = familial Mediterranean fever; GC = glucocorticoid; GI = gastrointestinal; HLA = human leukocyte antigen; IFN = interferon beta; MIM = Mendelian Inheritance in Man; MS = multiple sclerosis; MSSS = Multiple Sclerosis Severity Score; NK = not known; NSAID = nonsteroidal anti-inflammatory drug; OCB = oligoclonal band; PI = progression index; RA = rheumatoid arthritis; SAA = serum amyloid A; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor; TRAPS = tumor necrosis factor receptor 1–associated periodic syndrome; WBC = white blood cell.

Supported in part by Bayer Vital GmbH (Bayer Schering Pharma) and the "Verein Therapieforschung für Multiple Sklerose Kranke."

Disclosure: R.H. is supported by the Deutsche Forschungsgemeinschaft (SFB 571, A1) and has received personal compensations from Bayer Schering Pharma, Teva, Merck-Serono, Biogen-Idec, and Novartis. T.K. has received personal compensations from Bayer Schering Pharma, Teva, Merck-Serono, and Biogen-Idec. The other authors report no disclosures.

Received May 26, 2008. Accepted in final form August 25, 2008.

This article has been cited by other articles:

				E. Lainka, U. Neudorf, P. Lohse, C. Timmann, S. Stojanov, K. Huss, R. von Kries, and T. Niehues Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics Rheumatology, August 1, 2009; 48(8): 987 - 991. [Abstract] [Full Text] [PDF]