Late-onset tumor necrosis factor receptor-associated periodic syndrome in multiple sclerosis patients carrying the TNFRSF1A R92Q mutation.
OBJECTIVE
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominantly inherited autoinflammatory disorder caused by mutations in the TNFRSF1A gene. It is characterized by episodes of autoinflammation usually associated with fever, abdominal pain, myalgia, exanthema, arthralgia/arthritis, and ocular involvement. We undertook this study to investigate the prevalence of TRAPS in patients with multiple sclerosis (MS) who reported, in addition to their neurologic symptoms, at least 2 other symptoms compatible with TRAPS.


METHODS
Twenty-five unrelated MS patients were prospectively screened for TNFRSF1A mutations. In addition, blood samples from 365 unrelated MS patients and 407 unrelated Caucasian controls were analyzed to determine the R92Q carrier frequency.


RESULTS
Six of 25 adult MS patients (24%) with symptoms suggestive of TRAPS were found to carry the identical arginine-to-glutamine substitution at amino acid position 92 (R92Q or p.Arg121Gln) encoded by exon 4 of the TNFRSF1A gene. All R92Q heterozygotes had similar symptoms, including arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue, which began before the onset of MS. In 5 of the 6 patients, we could identify family members who had TRAPS symptoms and had inherited the identical mutation. The R92Q exchange was also detected in 17 of 365 unselected MS patients (4.66%) and in 12 of 407 controls (2.95%) (P = 0.112). Three patients were heterozygous carriers of MEFV variants, in 1 patient in combination with the R92Q mutation.


CONCLUSIONS
Autoinflammatory syndromes and especially late-onset TRAPS should be considered in MS patients who report symptoms such as arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue.
Kümpfel
Tania
T
Institute of Clinical Neuroimmunology-Grosshadern, Ludwig-Maximilian-University of Munich, Marchioninistrasse 15, D-81377 Munich, Germany. tania.kuempfel@med.uni-muenchen.de
Hoffmann
Lisa-Ann
LA
Rübsamen
Heike
H
Pöllmann
Walter
W
Feneberg
Wolfgang
W
Hohlfeld
Reinhard
R
Lohse
Peter
P
D000328:Adult; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D003937:Diagnosis, Differential; D010505:Familial Mediterranean Fever / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005973:Glutamine / Q000737:chemistry / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D005973:Glutamine; D001120:Arginine