Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases.
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 alpha. 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.


CONCLUSIONS
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.
Kümpfel
T
T
Institute of Clinical Neuroimmunology-Grosshadern, Ludwig Maximilians University of Munich, Munich, Germany. tania.kuempfel@med.uni-muenchen.de
Hoffmann
L-A
LA
Pellkofer
H
H
Pöllmann
W
W
Feneberg
W
W
Hohlfeld
R
R
Lohse
P
P
D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001120:Arginine; D010505:Familial Mediterranean Fever / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D000068717:Glatiramer Acetate; D005973:Glutamine; D006681:HLA-D Antigens / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D009154:Mutation; D000069442:Natalizumab; D019683:Penetrance; D010455:Peptides / Q000627:therapeutic use; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006681:HLA-D Antigens; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D010455:Peptides; D047888:Receptors, Tumor Necrosis Factor, Type I; D005973:Glutamine; D000068717:Glatiramer Acetate; D001120:Arginine; D008942:Mitoxantrone