Multiple sclerosis and the TNFRSF1A R92Q mutation

Abstract

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 α. 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.