Tumor Necrosis Factor Receptor-associated Periodic Syndrome Research Articles

A novel mutation of the familial Mediterranean fever gene in a Greek family related to a non-classical, variably expressed FMF phenotype

Familial Mediterranean Fever (FMF) is a hereditary autoinXammatory disorder characterized by fever, arthritis, serosal inXammation and often secondary amyloidosis. It most commonly aVects people of Armenian, Turkish, Jewish and Arab origin and its mode of inheritance is mainly recessive connected with the MEFV gene [1, 2]. The MEFV gene, codes for the 781 amino-acid protein pyrin/marenostrin that is predominantly expressed in polymorphonuclear cells as well as in cytokine activated monocytes. It seems that pyrin acts as an anti-inXammatory molecule by inhibiting interleukin-1 (IL-1) processing and permitting macrophage apoptosis [3, 4]. At least 120 mutations or polymorphisms of the MEFV gene have been identiWed, although Wve mutations account for almost 95% of the reported cases, especially in classically aVected populations. In the current report, a novel mutation of the MEFV gene in a young woman presenting with an episode of protracted polyserositis, fever, and a signiWcant family history of recurrent fevers of unknown etiology is presented. In detail, a 20-year-old Greek female was investigated for an episode of prolonged fever and pleural, pericardial and ascitic eVusions starting approximately 4 months prior to admission. System review and physical examination were unrevealing for stigmata of autoimmune disorders including Raynaud’s phenomenon, rashes, musculoskeletal complaints, oral ulcers or renal or nervous system involvement. Her past medical history was unremarkable. However, her family medical history was signiWcant for unexplained febrile episodes during summer months of 2– 3 weeks duration of her paternal grandmother. An extensive workup for an infectious etiology, including tuberculosis, was unrevealing. Laboratory evaluation revealed elevated inXammatory markers and a positive antinuclear antibody titer (1/320, diVuse pattern), while test for antibodies against extractable nuclear antigens and double stranded antibodies was negative. A preliminary diagnosis of systemic lupus erythematosus (SLE) was presumed and an oral prednisolone regimen at a dose of 1 mg/kg was started resulting in signiWcant improvement in clinical and laboratory terms (resolution of fevers and eVusions, abatement of inXammatory markers). However, given the complete lack of other concomitant features supporting the diagnosis of SLE, the Mediterranean origin of the patient and the history of recurrent unexplained fevers of the maternal grand mother, DNA analysis including tests for both FMF and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) mutations, as well as determination of IgD levels was performed. Of interest, DNA analysis disclosed a previously unreported heterozygous mutation of the exon 2 of the MEFV gene. Testing for TRAPS mutations was unrevealing and IgD levels were within normal limits. Prednisolone was tapered and colchicine at a dose of 0.5 mg bid was instituted; no symptom recurrence was noted over 2 years of follow-up. Dimitrios Zonios and Clio P. Mavragani have equally contributed.

Tumor necrosis factor receptor-associated periodic syndrome with a C30R mutation in a Japanese family

In 1999, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) was described as an autoinfl ammatory syndrome characterized by periodic fever, rashes, abdominal pain, myalgia, periorbital edema, and arthritis, strongly associated with heterozygous mutations in the gene encoding TNF receptor type 1 (TNFRSF1A). Tumor necrosis factor-α exerts its many proinfl ammatory effects through two distinct receptors: TNFRSF1A (TNFR1, p55/ p60-TNFR) and TNFRSF1B (TNFR2, p75/p80-TNFR). TRAPS is associated with substitution of amino acids in the extracellular domain of TNFRSF1A. The TNFRSF1A gene mutations were at fi rst thought to be associated with dysregulation of shedding of TNFRSF1A, and it was recently reported that the mutations may spontaneously induce the alternative signaling, independent of binding of TNF-α. It is believed that TRAPS is a rare disease in Japanese individuals. Only three families with TRAPS have been reported before 2006: the families had the C70S mutation, T61I mutation, and C30Y mutation. We encountered a TRAPS family with substitution of the 30th amino acid of TNFRSF1A, cysteine to arginine (C30R). The nonsynonymous change resulted from a single-nucleotide mutation, T to C at +7876 bp from the transcription start site of the TNFRSF1A gene (NCBI: AY131997) (Fig. 1A), which has never been found in Japanese individuals, although this mutation was reported in an Irish-American family. In the present case, the patient family consisted of a woman and her two sons (Fig. 1B). Although the woman had experienced periodic high-grade fever of unknown origin since the birth of her elder son in 1993, her diagnosis was not determined for a long time. Fever was often accompanied by skin rash and lymphadenopathy, but she did not experience arthritis or serositis. Abnormal laboratory fi ndings with leukocytosis and high levels of C-reactive protein (CRP) were always shown during fever attack. However, neither rheumatoid factor (RF) nor antinuclear antibody (ANA) was detected. A diagnosis of adult-onset Still’s disease (AOSD) was made in 2004, although the levels of serum ferritin were always lower than 500 ng/ml. Her elder son presented with periodic high-grade fever combined with skin rash and arthralgia several times a year after he was 7 months old. No signs of chronic arthritis, myositis, abdominal pain, conjunctivitis/periorbital edema, or chest pain were observed during the infl ammatory attacks. A tentative diagnosis of systemic juvenile idiopathic arthritis (JIA) was made in 1996, and he was treated with aspirin. However, no benefi cial effect was observed, and he was then treated with prednisolone (15–20 mg/day), and his fever and rash improved immediately. When the dose of prednisolone was decreased to 5–10 mg/day, high-grade fever recurred every few months. The younger son also had periodic high-grade fever after age 3 years, in 1999, and JIA was tentatively diagnosed in 2000. His fever did not respond to nonsteroidal anti-infl ammatory drugs and various immunosuppressive therapies, including corticosteroids, γglobulin, and methotrexate. However, fever with an increase in acute-phase proteins (CRP, fi brinogen) disappeared for several months independent of treatment. We suspected that the family members’ periodic fever might be due to TRAPS or familial Mediterranean fever, in view of their clinical course and familial history. Genomic DNA was obtained after informed consent was given according to the protocol of the Tokyo Women’s Medical University Ethics Committee. DNA sequencing revealed that all three patients had a point mutation of TNFRSF1A at +7876 in only one chromosome, leading to substitution of the 30th amino acid in exon 2, as shown Fig. 1A. We also K. Takagi · Y. Kawaguchi (*) · S. Fujikawa · T. Sugiura · M. Hara Institute of Rheumatology, Tokyo Women’s Medical University, 1022 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan Tel. +81-3-5269-1725; Fax +81-3-5269-1726 e-mail: y-kawa@ior.twmu.ac.jp

Autoinflammatorische (Fieber-)Syndrome - Klinik, Genetik und Therapie

Fever is frequent during infancy and childhood. The cause is usually a common cold. In cases where the fever reoccurs at intervals for more than six months without an obvious reason, one has to consider the possibility that the child suffers from an autoinflammatory syndrome which is commonly also known as a periodic fever syndrome. This group of diseases is characterised by a multisystemic inflammation with leukocytosis, an elevation of the erythrocyte sedimentation rate, and increased C-reactive protein and amyloid A serum concentrations. Common symptoms of an attack are abdominal pain, myalgia, arthralgia, and skin rash. Fever is almost always present in children. The attack starts abruptly and can be triggered by external factors such as trauma, vaccination, stress, and menstruation. The fever persists for several days up to weeks and spontaneously resolves without therapy. It is, however, often difficult to make a definitive diagnosis based solely on the clinical presentation, because the symptoms accompanying the fever are mostly rather unspecific and typical for more than one of the autoinflammatory syndromes. It is therefore helpful to perform a genetic analysis to either confirm the suspicion or to rule out a specific diagnosis. Hereditary fever syndromes, for which gene defects are known, include familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS), hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), and the cryopyrin-associated periodic syndromes (CAPS). The most frequently observed fever syndrome in childhood is, however, the mostly transient periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome which appears not to be inherited.

THE TUMOR NECROSIS FACTOR–ASSOCIATED PERIODIC SYNDROME, THE BRAIN, AND TUMOR NECROSIS FACTOR-α ANTAGONISTS

### Case report. The tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) is an autosomally dominant inherited disorder resulting from mutations within the TNF super family 1A gene ( TNFRSF1A ), which impair cleavage of p55 TNF receptors (TNFR1), decrease soluble TNFR1 serum levels, and affect intracellular trafficking of mutant proteins.1 The associated unopposed TNFα signaling confers self-limited auto-inflammation and may promote amyloidosis. Here, we provide clinical and histologic evidence that TRAPS may affect the CNS and has to be included in the spectrum of autoimmune inflammatory CNS disorders. Our patient was diagnosed with a C55A mutation in exon 3 of the TNFRSF1A gene and had experienced recurrent attacks of fever, myalgias, arthralgias, and painful migratory rashes since childhood. At age 38 he developed brainstem and cerebellar symptoms from an extensively contrast-enhancing lesion in the left cerebellar peduncle; acute disseminated encephalomyelitis (ADEM) or lymphoma was considered.2 However, …

Falling into TRAPS – receptor misfolding in the TNF receptor 1-associated periodic fever syndrome

TNF receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disease caused by missense mutations in the TNF receptor 1 (TNFR1) gene. Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1. In the present review we discuss new findings describing aberrant trafficking and function of TNFR1 harbouring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding, and we suggest that TNFR1 might acquire novel functions in the endoplasmic reticulum, distinct from its role as a cell surface receptor. We also describe the clinical manifestations of TRAPS, current treatment regimens, and the widening array of patient mutations.

TNF receptor-associated periodic syndrome (TRAPS) in Japan: clinical characterization, pathogenesis, diagnostic criteria, and treatment

TNF receptor-associated periodic syndrome (TRAPS) is an autosomal dominant inherited disease characterized by prolonged episodes of periodic fever and localized inflammation. The hypothetical pathogenesis of TRAPS is defective TNF receptor 1 (TNFRSF1A) shedding from cell membranes in response to a stimulus including TNFalpha. This mechanism has recently been shown to account for a minor population of TRAPS patients and other mechanisms are reported to explain the disease, such as resistance to apoptosis, TNFRSF1A internalization, or TNFRSF1A misfolding and aggregation, leading to NF-kappaB activation and apoptosis. Until now 15 TRAPS patients from 5 pedigree including 5 different mutations (C30R, C30Y, T61I, C70S, C70G) had been reported in Japan. There were many sporadic cases of TRAPS without TNFRSF1A mutation in our epidemiological study. In this issue, we described the clinical characterization, pathogenesis, diagnostic criteria, and treatment of TRAPS according to our case and literature.

TNF Receptor-associated Periodic Fever Syndrome (TRAPS) Caused by a Novel C30F Mutation Associated with the Common R92Q Low-Penetrance Mutation in TNFRSF1A

TNF Receptor-associated Periodic Fever Syndrome (TRAPS) Caused by a Novel C30F Mutation Associated with the Common R92Q Low-Penetrance Mutation in TNFRSF1A

TRAPS, un síndrome autoinflamatorio: Casos cínicos

Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disorder associated to a mutation of the Tumor Necrosis Factor Receptor 1 (TNFR1) whose clinical presentation consists on recurrent episodes of prolonged fever, abdominal pain, myalgias, migratory cutaneous erythema, conjunctivitis or periorbitary edema. The diagnosis is confirmed by genetic analysis of the TNFR1 gene. Its main complication is amyloidosis and the treatment is based on the use of corticosteroids or anti-TNF antibodies. We report a 17 year-old male and 23 year-old female with the syndrome. Both cases had heterozygous mutations of the TNFR1 gene, C30R in the first case and T50M in the second case.

Mein Kind ist immer krank – wann ist es wirklich krank? Vom periodischen Fiebersyndrom bis zum Immundefekt

Fever is one of the main symptoms leading to medical evaluation. Not only infections cause fever but also inflammatory disorders. To distinguish one from another, a thorough medical history and clinical evaluation are needed. Sometimes, only the clinical course will reveal the diagnosis. PFAPA-Syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis) is the most frequent periodic fever syndrome in Switzerland. No diagnostic test is available to support the diagnosis. Some important diseases have to be ruled out, such as Immunodeficiency, cyclic neutropenia, chronic viral infections and rheumatologic disorders. To know the diagnosis of the PFAPA-Syndrome can help avoiding antibiotic courses for febrile episodes in infants. There is a clinical overlap to hereditary periodic fever syndromes as familial Mediterranean fever (FMF), Hyper-IgD and fever syndrome (HIDS), Tumor-necrosis factor receptor associated periodic syndrome (TRAPS) and others, in which a genetic basis for the disease has already been found.

Successful treatment using tacrolimus (FK506) in a patient with TNF receptor-associated periodic syndrome (TRAPS) complicated by monocytic fasciitis

Successful treatment using tacrolimus (FK506) in a patient with TNF receptor-associated periodic syndrome (TRAPS) complicated by monocytic fasciitis

Hereditary auto-inflammatory disorders and biologics

The term auto-inflammatory disorders has been coined to describe a group of conditions characterized by spontaneously relapsing and remitting bouts of systemic inflammation without apparent involvement of antigen-specific T cells or significant production of auto-antibodies. The hereditary periodic fever syndromes are considered as the prototypic auto-inflammatory diseases, and genetic studies have yielded important new insights into innate immunity. DNA analysis has greatly enhanced the clinical characterization of these conditions, and elucidation of their molecular aetiopathogenesis has suggested that therapies may be aimed at specific targets within the immune cascade. The availability of biologic response modifiers such as inhibitors of tumour necrosis factor (TNF) and interleukin-1beta has greatly improved the outlook for some of these disorders, although effective therapies remain elusive in patients with certain conditions, including hyperimmunoglobulinaemia-D with periodic fever syndrome (HIDS) and a proportion of those with TNF-receptor associated periodic syndrome (TRAPS). Indeed, outstanding challenges and the unique potential to further elucidate molecular mechanisms in innate immunity are illustrated by the dashed early hope that TNF blockade would be a panacea for TRAPS: not only is etanercept (Enbrel) ineffective in some cases, but there are anecdotal reports of this condition being greatly exacerbated by infliximab (Remicade).

Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor–induced apoptosis: Pathogenetic and clinical implications

To explore tumor necrosis factor (TNF)-induced apoptosis in neutrophils from patients with TNF receptor-associated periodic syndrome (TRAPS) and to correlate the results with the different kinds of TNFRSF1A mutations. Two hundred sixty-five patients with clinically suspected inherited autoinflammatory syndrome were screened for mutations of the TNFRSF1A gene. Neutrophils were isolated from heparinized blood by dextran sedimentation and incubated with and without cycloheximide (CHX) and TNFalpha. Cell apoptosis was assessed by human annexin V binding, and caspase 8 activation was assessed by flow cytometry. Twenty-one patients were found to carry a variant of the TNFRSF1A gene: 13 patients had an R92Q substitution, and 8 patients presented other missense substitutions, 1 splicing mutation, and 1 in-frame interstitial deletion. Neutrophil stimulation with TNF and CHX was associated with induction of apoptosis in 12 normal controls and in 10 subjects with the R92Q mutation. Conversely, neutrophils from 8 TRAPS patients with mutations of cysteine or threonine residues or interstitial deletion did not show any induction of apoptosis after stimulation. The incidence of the R92Q mutation among patients with recurrent autoinflammatory syndromes was similar to that observed in the normal population. Resistance to TNF-mediated apoptosis is a feature in TRAPS patients who have mutations of cysteine residues or interstitial deletion, and may play a pathogenic role. The R92Q mutation does not appear to be significantly associated with TRAPS.

TNF-receptor-associated periodic syndrome (TRAPS): an autosomal dominant multisystem disorder

The TNF-receptor-associated periodic syndrome (TRAPS) is an autosomal dominant auto-inflammatory disorder, characterized by recurrent febrile attacks and localized inflammation. TRAPS is caused by mutations in the gene encoding the TNF Receptor Super Family 1A (TNFRSF1A) on chromosome 12p13. However, the incomplete penetrance and genetic heterogeneity have been reported in this syndrome. Although the ethnic diversity and clinical heterogeneity may propose the role of other genes in the pathogenesis of TRAPS, some low-penetrance TNFRSF1A variants contribute to atypical inflammatory responses in other autoimmune diseases. Furthermore, molecular studies on TRAPS and other auto-inflammatory disorders could be suggested to identify additional genes coding the molecules in the TNF signalling process.

Intra‐abdominal abscess in a patient with tumour necrosis factor receptor‐associated periodic syndrome

Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disorder characterized by periodic attacks of fever and inflammation, due to mutations in the gene coding for the TNF type I receptor (TNFRSF1A). A 16-year-old patient with the diagnosis of TRAPS was admitted to hospital because of fever and abdominal pain. Initially, the symptoms were interpreted as manifestations of another TRAPS attack, but the patient's condition worsened, despite treatment with corticosteroids and antibiotics. A repeated computer tomography revealed an intra-abdominal abscess, which necessitated urgent surgical intervention. This case stresses the importance of differential diagnostic vigilance when dealing with patients with rare genetic diseases.

Severe TNF Receptor–Associated Periodic Syndrome Due to 2 TNFRSF1A Mutations Including a New F60V Substitution

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is typically characterized by episodic fever, myalgia, skin rash, conjunctivitis, and abdominal cramps. Recently, mutations in the TNFRSF1A gene on chromosome 12p13 encoding tumor necrosis factor receptor type 1 have been linked to this autoinflammatory syndrome. We report the case of a 29-year-old white woman who experienced periodic inflammatory manifestations with fever up to 40 degrees C, leukocytosis, and elevation of C-reactive protein level (>100 mg/L) in conjunction with acute peritonitis of unknown origin since the age of 19 years. The patient had undergone 2 laparotomies with appendectomy and left hemicolectomy. Familial Mediterranean fever was excluded by sequencing of the MEFV gene. In view of the possibility of TRAPS, sequence analysis of the TNFRSF1A gene was also performed. The patient carried a novel T-->G substitution in exon 3, leading to the replacement of phenylalanine by valine at amino acid position 60 (F60V), as well as the common R92Q low-penetrance mutation, encoded by exon 4. Upon the next flare, the patient started corticosteroid therapy, resulting in complete relief and normalization of elevated C-reactive protein levels. To the best of our knowledge, we report the first case of compound heterozygosity for 2 TNFRSF1A gene mutations, including a novel one that causes a severe form of TRAPS that responds to anti-inflammatory treatment. A history of recurrent sterile peritonitis should prompt genotyping for periodic fever syndromes.

TNF and TNF Receptors in TRAPS

Tumor necrosis factor receptor associated periodic syndrome (TRAPS) is a hereditary auto-inflammatory periodic fever syndrome associated with autosomal dominant ectodomain mutations in the 55kDa tumor necrosis factor receptor (TNFRSF1A). Over forty mutations in TNFRSF1A are associated with TRAPS. Plasma levels of soluble TNFRSF1A (sTNFRSF1A) are abnormally low in TRAPS patients, as is shedding of TNFRSF1A by some patients leucocytes. It was hypothesised that a deficit in neutralisation of TNF by sTNFRSF1A in TRAPS might result in an increased sensitivity to the inflammatory effects of TNF. However, not all TRAPS-related TNFRSF1A mutations result in defective receptor shedding by leucocytes. We found that dermal fibroblasts, but not leucocytes, from TRAPS patients with C33Y mutation demonstrated reduced shedding of TNFRSF1A, and that shedding of both wild-type and mutant truncated TNFRSF1A from transfected cell lines was similar. It is unlikely that a defect in TNFRSF1A shedding fully explains the clinical features of TRAPS. We investigated the behaviour of TRAPS-related TNFRSF1A mutants compared with wildtype in transfected cell lines: the mutant forms of TNFRSF1A retained signalling functions, but showed abnormalities of intra-cellular trafficking and TNF binding suggestive of protein misfolding. The severity of the abnormalities were observed with different mutants correlated with the degree of penetrance and clinical severity. We hypothesise that aggregation and ligand-independent signalling of mutant TNFRSF1A may occur. The increased understanding of the genetic basis and pathophysiology of TRAPS has facilitated therapeutic advances in the clinical management of this condition, particularly the use of the TNF-neutralising agent etanercept. Keywords: second cysteine-rich domains (CRDs), mutations, TNFRSF1A gene, TNF receptorassociated death domain (TRADD), amyloidosis, recessive autoinflammatory disorder

Hereditary Periodic Fever Syndrome Sans Fever or Distinct Periodicity Presenting With Psychosis

The genetic basis for several hereditary periodic fever syndromes has been identified and consequently, the phenotypic spectrum of these disorders has broadened. We describe a young woman with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), proven by mutational analysis, who presented with psychosis but without fever, symptom periodicity, or similar family medical history. This patient represents the first case of TRAPS-associated psychosis. This case illustrates the importance of mutation analysis for this group of disorders in individuals presenting with unexplained inflammatory symptoms and recurrent psychoses.

Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A

To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.

Hereditary periodic fever and reactive amyloidosis

Hereditary periodic fever syndromes (HPF) are a group of diseases characterised by recurrences of fever and inflammation separated by symptom-free intervals. Familial Mediterranean fever (FMF) is the most frequent entity within this group of disorders which further consists of hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS). In recent years the causative genes have been identified. Reactive amyloidosis is a severe complication of HPFs. This is caused by deposition of fibrils that consist of the proteolytically cleaved acutephase protein serum amyloid A (SAA). Several factors have been identified that modulate the risk for developing amyloidosis, including SAA concentrations, polymorphisms in the SAA gene and ethnic origin. Furthermore, the risk of developing amyloidosis varies widely between the different HPFs. Colchicine is the cornerstone in the management of FMF, as it reduces the severity and frequency of attacks and is also effective in preventing amyloidosis. In the other HPFs, the introduction of anticytokine-based therapies is a promising new option in treating these inflammatory conditions and they potentially can prevent amyloidosis.

Mutation of the extracellular domain of tumour necrosis factor receptor 1 causes reduced NF-κB activation due to decreased surface expression

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) results from point mutations in the extracellular domain of TNF receptor 1 (TNFRSF1A), but the effects of the mutations are controversial. This study shows that reduced NF-κB signalling is a feature of four TRAPS mutations. Reduced signalling correlates with reduced surface expression, measured by flow cytometry and microscopy. This suggests that correct formation of the extracellular domain of TNFRSF1A is important for localisation and receptor function. Importantly, our data provides a mechanism for the reduced TNFRSF1 signalling observed in a patient cell line.