LAUSR

OBJECTIVE We describe a family with a novel mutation in the TNF Receptor Superfamily Member 1A gene (TNFRSF1A) causing tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with renal AA-amyloidosis. METHODS Case series of affected family members. We further investigated the plasma metabolome of these patients in comparison to healthy controls using mass spectrometry. RESULTS In all symptomatic family members, we detected the previously undescribed variant c.332A>G (p.Q111R) in the TNFRSF1A gene. Canakinumab proved an effective treatment option leading to remission in all treated patients. One patient with suspected renal amyloidosis showed near normalisation of proteinuria under treatment. Analysis of the metabolome revealed 31 metabolic compounds to be upregulated and 35 compounds to be downregulated compared with healthy controls. The most dysregulated metabolites belonged to pathways identified as arginine biosynthesis, phenylalanine, tyrosine & tryptophan biosynthesis and cysteine & methionine metabolism. Interestingly, the metabolic changes observed in all three TRAPS patients seemed independent of treatment with canakinumab and subsequent remission. CONCLUSION We present a novel mutation in the TNFRSF1A gene associated with amyloidosis. Canakinumab is an effective treatment for individuals with this new likely pathogenic variant. Alterations in the metabolome were most prominent in the pathways related to arginine biosynthesis, tryptophan metabolism and metabolism of cysteine & methionine and seemed to be unaffected by treatment with canakinumab. Further investigation is needed to determine the role of these metabolomic changes in the pathophysiology of TRAPS.