A novel TNFRSF1A mutation associated with TNF-receptor-associated periodic syndrome and its metabolic signature.

Joachim D Steiner, Andrea Annibal, Raymond Laboy, Marie Braumann, Heike Göbel, Valentin Laasch, Roman-Ulrich Müller, Martin R Späth, Adam Antebi, Torsten Kubacki

Rheumatology (Oxford, England) 2023 Oct 03

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We describe a family with a novel mutation in the TNF Receptor Superfamily Member 1A (TNFRSF1A) gene causing TNF receptor-associated periodic syndrome (TRAPS) with renal AA amyloidosis. Case series of affected family members. We further investigated the plasma metabolome of these patients in comparison with healthy controls using mass spectrometry. 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 normalization 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 and tryptophan biosynthesis, and cysteine and methionine metabolism. Interestingly, the metabolic changes observed in all three TRAPS patients seemed independent of treatment with canakinumab and subsequent remission. 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 and 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. © The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Citation

Joachim D Steiner, Andrea Annibal, Raymond Laboy, Marie Braumann, Heike Göbel, Valentin Laasch, Roman-Ulrich Müller, Martin R Späth, Adam Antebi, Torsten Kubacki. A novel TNFRSF1A mutation associated with TNF-receptor-associated periodic syndrome and its metabolic signature. Rheumatology (Oxford, England). 2023 Oct 03;62(10):3459-3468