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The autoinflammatory disease familial Mediterranean fever (FMF), characterized by recurrent attacks of sterile fever, serosal, and/or synovial inflammation, is caused by variants in the Mediterranean fever gene, MEFV, coding for the pyrin inflammasome sensor. The diagnosis of FMF is mainly based on clinical symptoms and confirmed by detection of disease-associated MEFV variants. However, the diagnosis is challenging among patients carrying variants of uncertain clinical significance (VUS). In this study, we aimed to identify potential FMF discriminatory diagnostic markers in a cohort of clinically characterized FMF patients. We established a cohort of clinically and MEFV genotype-characterized FMF patients by enrolling patients from major Danish hospitals (n = 91). The secretory profile of pyrin inflammasome-activated monocytes from healthy donors (HDs) and MEFV-characterized FMF patients (n = 28) was assessed by analysing cell supernatants for a custom-designed panel of 23 cytokines, chemokines, and soluble tumour necrosis factor receptors associated with monocyte and macrophage function. MEFV genotypes in Danish FMF patients were associated with age at symptom onset (p < 0.05), FMF among relatives (p < 0.01), proportion of patients in colchicine treatment (p < 0.01), and treatment response (p < 0.05). Secretion of chemokines CCL1 and CXCL1 from pyrin-activated FMF monocytes was significantly decreased compared to HDs (p < 0.05), and could discriminate FMF patients with 'non-confirmatory' MEFV genotypes from HDs with 80.0% and 70.0% sensitivity for CCL1 and CXCL1, respectively (p < 0.05). Our data suggest that a functional diagnostic assay based on CCL1 or CXCL1 levels in pyrin-activated patient monocytes may contribute to FMF diagnosis in patients with VUS. [ABSTRACT FROM AUTHOR]

Objectives: To investigate epidemiology, demography, and genetic and clinical characteristics of patients with familial Mediterranean fever (FMF) in Denmark. Method: In this population-based, cross-sectional cohort study, we identified FMF patients from discharge diagnoses using ICD-10 codes in the Danish National Patient Register, and linked data from the Danish Civil Registration System and laboratory databases for results of MEFV gene variant screening. Results: We identified 495 FMF patients (prevalence 1:11 680) with a median age of 29 years and a female ratio of 51%. The median age at diagnosis of FMF was 13 (IQR 7-22) years, with an estimated median diagnostic delay of 3 (IQR 0.7-6.9) years. The predominant ethnicities were Turkish (41.8%), Lebanese (15.8%), Syrian (6.5%), South-West Asian (7.9%), and South-East Asian (3.0%). The MEFV genotype distribution was 18.7% homozygous, 21.2% compound heterozygous, 32.0% heterozygous, 11.0% with complex alleles or unresolved zygosity, and 17.1% with no detected variants. M694V was the most prevalent variant in the overall cohort (32.5%). Homozygous or compound heterozygous MEFV exon 10 variants were associated with younger age at diagnosis (p < 0.001) and reduced number of hospital contacts before diagnosis (p = 0.008). The Charlson Comorbidity Index was ≥ 2 in 8.1% of patients. The prevalence of amyloidosis was 1.0%. Conclusions: FMF in Denmark is rare and patients are mainly of Eastern Mediterranean ethnicity. Diagnostic delay was long but patients with exon 10 MEFV variants were diagnosed at a younger age. Prolonged diagnostic delay is probably caused by lack of FMF awareness in the Danish healthcare system. [ABSTRACT FROM AUTHOR]

Background: X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor gamma chain (gamma(c)), resulting in disruption of development of T lymphocytes and natural-killer cells. B-lymphocyte function is also intrinsically compromised. Allogeneic bone-marrow transplantation is successful if HLA-matched family donors are available, but HLA-mismatched procedures are associated with substantial morbidity and mortality. We investigated the application of somatic gene therapy by use of a gibbon-ape-leukaemia-virus pseudotyped gammaretroviral vector.Methods: Four children with SCID-X1 were enrolled. Autologous CD34-positive haemopoietic bone-marrow stem cells were transduced ex vivo and returned to the patients without preceding cytoreductive chemotherapy. The patients were monitored for integration and expression of the gamma(c) vector and for functional immunological recovery.Findings: All patients have shown substantial improvements in clinical and immunological features, and prophylactic medication could be withdrawn in two. No serious adverse events have been recorded. T cells responded normally to mitogenic and antigenic stimuli, and the T-cell-receptor (TCR) repertoire was highly diverse. Where assessable, humoral immunity, in terms of antibody production, was also restored and associated with increasing rates of somatic mutation in immunoglobulin genes.Interpretation: Gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity. [ABSTRACT FROM AUTHOR]