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We aimed to explore triggering receptor expressed on myeloid cells-1 (TREM-1) activation in familial Mediterranean fever (FMF), the most frequent monogenic auto-inflammatory disease, through the measurement of its serum soluble form, named sTREM-1. Blood samples from patients with FMF according to Livneh criteria followed in the French FMF national center and carrying two pathogenic MEFVmutations were collected. Serum level of sTREM-1 was assessed using ELISA. Demographic data, presence of FMF attack, association with histologically proven AA amyloidosis, and blood levels of C-reactive protein (CRP), serum amyloid A (SAA) protein, and creatinine were collected. TREM-1 was available in 56 patients (33.9% male, mean age 43 yr); AA amyloidosis was associated in six patients (19.6% in FMF). Mean sTREM-1 level did not differ significantly between patients having an attack or not and there was also no significant correlation between the level of sTREM-1 and CRP and SAA protein. However, the mean rate of sTREM-1 was significantly higher among FMF patients with AA amyloidosis versus without, though the concomitant SAA protein level was normal. Serum level of sTREM-1 was higher in patients with amyloidosis even though the concomitant SAA protein level was normal. sTREM-1 plasma levels could be an accurate tool to specifically identify FMF patients with amyloidosis.

Objective.To describe a new autoinflammatory syndrome with recurrent fever and monoclonal gammopathy that differs from Schnitzler syndrome.Methods.We conducted a retrospective study of patients with monoclonal gammopathy and recurrent fever of unknown origin.Results.Five patients were studied; median age at onset of symptoms was 44 years. Median frequency of fever attacks was 6 episodes per year. In the absence of treatment, the median duration of fevers was 3 days.Conclusion.This new autoinflammatory syndrome is defined by an association among monoclonal gammopathy, arthralgias, and recurrent fever.

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4(transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4mutation to 0.7%. So far, TCF4molecular abnormalities were known to cause a syndromic form of ID, Pitt–Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4(eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4mutations to nonspecific ID.

Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2Avariants are non-sense and frameshift variants causing a typical form of Wiedemann–Steiner syndrome. We studied KMT2Agene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2Aexpression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2Amissense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient’s fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.

Les lésions urticariennes chroniques peuvent être associées à des maladies auto-inflammatoires monogéniques (cryopyrinopathies) ou multifactorielles. Nous rapportons une famille pour laquelle aucune cause connue n’a été identifiée.

AbstractCongenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K+ATP). The two subunits of the K+ATP channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome.Copyright © 2006 S. Karger AG, Basel

The mechanism of NADH oxidation varies between living organisms, and is by far the most complex oxidizing system found in mitochondria. In human mitochondria, a unique, but huge structure, with more than 45 subunits, known as complex I, copes with NADH oxidation. This review compiles our present knowledge on the organization of this complex and the putative role of a small subset of its subunits. This review also describes the major progress that has been made in understanding the molecular bases of respiratory chain complex I deficiency in humans, with mutations identified in both the mitochondrial and the nuclear genes encoding complex I subunits. Finally, the puzzling questions raised by the varying clinical presentations of patients with complex I deficiency are discussed in light of our limited knowledge on complex I function in mammalian cells.

•MEFVheterozygosity is not associated with multiple sclerosis (MS)•MS is more frequent in familial Mediterranean fever (FMF) patients•MS is more likely to lack oligoclonal bands when associated with FMF•MS should be suspected upon neurological manifestations in FMF•The association between FMF and MS is plausible but remains to be confirmed

Chronic urticaria is a common skin disorder with heterogeneous causes. In the absence of physical triggers, chronic urticarial rash is called idiopathic or spontaneous. The objective of this study was to identify the molecular and cellular bases of a disease condition displayed by two unrelated patients aged over 60 years who presented for two decades with a chronic urticaria resistant to standard therapy that occurred in the context of systemic inflammation not triggered by cold. In both patients, a targeted sequencing approach using a next generation technology identified somatic mosaic mutations in NLRP3, a gene encoding a key inflammasome component. The study of several of both patients’ cell types showed that, despite the late onset of the disease, NLRP3mutations were not found to be restricted to myelomonocytic cells. Rather, the data obtained strongly suggested that the mutational event occurred very early, during embryonic development. As shown by functional studies, the identified mutations—an in-frame deletion and a recurrent NLRP3missense mutation—have a gain-of-function effect on NLRP3-inflammasome activation. Consistently, a complete remission was obtained in both patients with anti–IL-1 receptor antagonists. This study unveils that in late-onset chronic urticaria, the search for autoinflammatory markers and somatic mosaic NLRP3mutations may have important diagnostic and therapeutic consequences.