Hadija Trojer

Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature.

IntroductionMutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center.MethodsDNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals.ResultsNLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members.ConclusionsThe NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.

Brief Report: Association of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome With Gonosomal Mosaicism of a Novel 24-Nucleotide TNFRSF1A Deletion.

To investigate the molecular cause of persistent fevers in a patient returning from working overseas, in whom investigations for tropical diseases yielded negative results.

TNF Receptor Associated Periodic Syndrome associated with gonosomal mosaicism of a novel 24 nucleotide TNFRSF1A deletion.

To investigate the molecular cause of persistent fevers in a patient returning from working overseas, in whom investigations for tropical diseases yielded negative results.

Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism - UK Single Center Experience

Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism has been reported in some CAPS patients who were previously classified as “mutation-negative.” We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the NLRP3 gene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients’ serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired NLRP3 mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline NLRP3 mutations.

Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue—a case series and genetic exploration

Objective. This study was undertaken to characterize the phenotype and response to treatment in patients with autosomal dominant FMF caused by MEFV p.M694del mutation and to use haplotype reconstruction to investigate the possibility of common ancestry. Methods. MEFV gene was analysed in 3500 subjects with suspected FMF referred to a single UK centre between 2002 and 2014. Patients with p.M694del underwent additional screening of the SAA1 gene as well as haplotype reconstruction of the MEFV locus. Results. The p.M694del variant was identified in 21 patients, sharing an identical disease haplotype that appears to have arisen about 550 years ago. The SAA1.1 allele was found in four patients, including two with AA amyloidosis. The clinical features comprised typical FMF symptoms with median age at onset of 18 years; three patients presented with AA amyloidosis, of whom two had had symptoms of FMF in retrospect. Fifteen patients had received colchicine treatment, all with excellent responses. Conclusion. The p.M694del variant is associated with autosomal dominantly inherited FMF in Northern European Caucasians. Symptoms may develop later in life than in classical recessive FMF but are otherwise similar, as is the response to colchicine treatment. The 14% incidence of AA amyloidosis may reflect delay in diagnosis associated with extreme rarity of FMF in this population. The common haplotype suggests a single founder living in about 1460.

First case of somatic mosaicism in TRAPS caused by a novel 24 nucleotides deletion in the TNFRSF1A gene

TNF receptor associated periodic syndrome (TRAPS) is an autosomal dominant disease caused by gain-of-function mutations in the TNF superfamily receptor 1A (TNFRSF1A) gene encoding 55 kDa TNF receptor type I (TNFR1). TRAPS is characterized by episodes of fever accompanied by severe abdominal pain, arthralgia, myalgia, rash, chest pain, enlarged glands and red, swollen eyes. Duration of the attacks can range from few days to several weeks, with the onset from early childhood to adulthood.

Analysis of the TTR gene in the investigation of amyloidosis: A 25 year single UK centre experience

Transthyretin amyloidosis (ATTR) is caused by deposition of either wild‐type (ATTRwt) or variant (ATTRm) transthyretin. ATTRwt presents with restrictive cardiomyopathy, while ATTRm displays a range of organ involvement. This retrospective analysis includes all patients referred to a single UK center in the last 25 years for clinical and laboratory assessment of known or suspected amyloidosis who underwent TTR gene sequencing. A total of 4459 patients were included in this study; 37% had final diagnosis of ATTR amyloidosis; 27% light chain amyloidosis; 0.7% other types of amyloidosis; 21.3% had no amyloid and 14% had no data. TTR variants were found in 770 (17%) cases; the most prevalent were p.V142I, p.T80A, and p.V50M identified in 42, 25, and 16%, respectively. The median age at referral in each group was: 76 (range 47–93), 66 (40–81), and 45 years (21–86), respectively. Overall 42 rare or novel variants were identified. Forty‐two percent patients with ATTRm died at a median age of 73 years (33–89) with a median survival from diagnosis of 50 months. ATTRwt was the final diagnosis in 20% of patients undergoing genetic testing. Our findings of TTR variants in 17% of screened patients highlight the need for routine genetic testing in the evaluation of suspected ATTR amyloidosis.

Clinical symptoms and molecular investigations in 13 patients with Schnitzler syndrome identified at the single UK centre

Schnitzler syndrome (SchS) was first described in 1972 and to date 281 cases have been reported. SchS is an adult onset, apparently acquired disease, which clinically closely resembles CAPS including the response to IL-1 blockade. A hallmark of the disease is the IgM kappa paraprotein, identified in 85% of the patients; recently variant IgG have been reported in 7% of cases.

Deletion in MEFV resulting in the loss of p.M694 residue as the cause of autosomal dominant familial Mediterranean fever in North Western European Caucasians - a case series and genetic exploration.

Familial Mediterranean fever (FMF) is the commonest hereditary autoinflammatory disease and it has mostly been reported in populations of Mediterranean ancestry, especially Armenians, Arabs, Turks, non-Ashkenazi and Sephardic Jews. FMF has a very low prevalence amongst Western Europeans. Its hallmarks are autosomal recessive inheritance and short bursts of illness lasting up to 3 days comprising fever, serositis and arthritis, and which can largely be prevented by daily colchicine treatment. The FMF gene MEFV is located on chromosome 16p andconsists of 10 exons. Although the disease is usually inherited in an autosomal recessive fashion, deletion of methionine at position 694 has been associated with dominant inheritance.

A decade of anti-IL-1 therapy in CAPS - a spectrum of efficacy in this spectrum of diseases

Discovery of the role of the IL-1 inflammasome in CAPS has revolutionised treatment, and anti-IL-1 therapies have successfully switched off disease activity in many patients. More than 110 CAPS patients (including 24 children) in the UK have been treated with drugs targeting IL-1, over 90% of these have had complete resolution of disease.