Search

Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic autoinflammatory diseases. We sought to investigate a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia. We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling, and transcriptomic analyses on samples from 2 patients. The identified candidate protein was studied after in vitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was used to unveil the associated protein network. The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of proinflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10 and IL-1 receptor antagonist [IL-1RA]) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever, and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. The affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein with a poorly known physiologic role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213. We identified a new entity characterized by chronic urticarial lesions associated with a clinically blunted hypercytokinemia. This disease, which is due to loss of function of RNF213, reveals mysterin's key role in the complex molecular network of innate immunity. [ABSTRACT FROM AUTHOR]

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease that can lead to an inflammatory A amyloidosis (AA). To study the occurrence of AA in MKD patients we performed a systemic review of the literature and described two novel patients. Amyloidosis occurred in 20 MKD patients, renal impairment being always the revealing symptom of AA. Although an accurate prevalence estimation is not possible since exact MKD prevalence is unknown, AA seems rare in MKD (about 6% if we estimate MKD prevalence at 300 patients worldwide). MVK gene study, available in 18 out of the 20 patients, confirmed two pathogenic mutations in all tested individuals. The most frequent genotype was V377I/I268T (n = 9/18). Retrospective search of clinical signs of MKD established, in all patients carrying MVK pathogenic mutations, a disease onset within the first four years of life. Nephrotic syndrome (n = 15), end-stage renal failure (n = 5) or both (n = 8) pointed out kidney amyloidosis. The youngest patient with renal amyloidosis was a European four-year-old girl previously misdiagnosed with PFAPA syndrome. Five patients died of AA amyloidosis despite the use of a biotherapy for two of them; kidney transplant was performed in nine individuals. Colchicine was not effective in any patient. Anti-interleukin-1 anakinra (n = 8), anti TNF etanercept (n = 7) and anti-interleukin 6 tocilizumab (n = 5) treatments were partially effective. Inflammatory A amyloidosis, a rare complication of MKD, can cause death or necessitate kidney transplantation. Early diagnosis and cytokine blocking biotherapy using anti-IL1, anti-TNF or anti-IL6 agents are required to prevent terminal renal failure. [ABSTRACT FROM AUTHOR]

NLRP3 -associated autoinflammatory diseases (NLRP3 -AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations. To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3 -AIDs and performed an in-depth study of 3 novel patients. The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients. We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state. The phenotypic spectrum of NLRP3 -AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations. [ABSTRACT FROM AUTHOR]

• MEFV heterozygosity 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. Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disorder; and leads to the uncontrolled production of interleukin (IL)-1β. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system; and its development seems to be partly correlated with IL-1β levels. It is hypothesized that FMF could be associated with MS. We aim to describe the features of patients displaying both diseases and to investigate the MEFV mutation rate in MS patients. Patients with definite MS were retrieved from the cohort of FMF patients in the Reference Center for Rare Auto-inflammatory Diseases and Amyloidosis (CEREMAIA). We also performed a systematic literature review of articles from PubMed that were published from 1990 to 2020. Twenty-four patients were included in the case series: five patients (1.3%) from our cohort of 364 and 19 patients from the literature. The sex ratio was 2:1. The mean age at diagnosis of FMF was 19 years old; and that for MS was 29 years old. Seven studies investigating the MEFV mutation rate in MS patients were included. Three studies found a higher mutation rate in MS patients than in the control group. FMF and MS features were comparable to those of patients with unrelated diseases; and MEFV mutation carriage was not positively correlated with MS. However; MS prevalence in FMF patients was higher than was expected in a healthy population. To a lesser extent; FMF prevalence in MS patients was higher than expected in a healthy population and the difference might not be significant. These data suggest that FMF could be associated with MS; and further studies are needed to investigate a potential causal association. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation-Ia are the most frequent type of congenital disorders of glycosylation. This condition affects the nervous system as well as other organs. The estimated incidence of congenital disorders of glycosylation-Ia is higher than the number of identified cases, therefore underdiagnosis of this heterogeneous disorder is probable. Neurologic and biologic signs are hallmarks for the identification of patients with congenital disorders of glycosylation-Ia. This report describes two children with congenital disorders of glycosylation-Ia syndrome confirmed by phosphomannomutase gene mutations with normal development and absence of biologic anomalies such as elevated transaminases and altered hemostasis. In conclusion, congenital disorders of glycosylation should be considered in cases of unexplained behavioral symptoms such as hyperactivity and concentration difficulties and mild neurologic signs. Intellectual retardation is often overestimated because of dysarthria and motor difficulties. Psychomotor reeducation might improve quality of life. [Copyright &y& Elsevier]

[Display omitted] Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility and different extra-skeletal manifestations. The severity of these manifestations makes it possible to classify OI into different subtypes based on the main clinical features. This review aims to outline and describe the current pharmacological alternatives for treating OI, grounded on clinical and preclinical reports, such as antiresorptive agents, anabolic agents, growth hormone, and anti-TGFβ antibody, among other less used agents. The different options and their pharmacokinetic and pharmacodynamic properties will be reviewed and discussed, focusing on the variability of their response and the molecular mechanisms involved to attain the main clinical goals, which include decreasing fracture incidence, improving pain, and promoting growth, mobility, and functional independence. [ABSTRACT FROM AUTHOR]

Introduction: Familial Mediterranean fever is the most frequent monogenic auto-inflammatory disorder that mostly affects Mediterranean population. Although this auto-inflammatory disease has historically been described as a recessive genetic disorder with homozygous or compound heterozygous mutations in the MEFV gene, an increasing number of cases are described with the detection of new single MEFV gene heterozygous mutations with modern molecular techniques.Case Description: We report the cases of Caucasian French descent father and daughter who exhibited joint and abdominal inflammatory attacks resembling Familial Mediterranean Fever. Genetic studies revealed in both a heterozygous mutation p.T577N in exon 8 of MEFV gene, and in which colchicine was effective for preventing the attacks.Conclusion: Single heterozygous mutation of MEFV can be responsible for typical Familial Mediterranean Fever clinical pattern and, what is more, in non-Mediterranean ethnic background patients. [ABSTRACT FROM AUTHOR]

Inflammasomes are intracellular multiprotein signaling complexes, mainly present in myeloid cells. They commonly assemble around a cytoplasmic receptor of the nucleotide-binding leucine-rich repeat containing receptor (NLR) family, although other cytoplasmic receptors like pyrin have been shown to form inflammasomes. The nucleation of the multiprotein scaffolding platform occurs upon detection of a microbial, a danger or a homeostasis pattern by the receptor that will, most commonly, associate with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) through homotypic domain interactions resulting in recruitment of procaspase-1. This will lead to the autoproteolytic activation of caspase-1, which regulates the secretion of proinflammatory IL1β and IL18 cytokines and pyroptosis, a caspase-1-mediated form of cell death. Pyroptosis occurs through cleavage of Gasdermin D, a membrane pore forming protein. Recently, non-canonical inflammasomes have been described, which directly sense intracellular pathogens through caspase-4 and -5 in humans, leading to pyroptosis. Inflammasomes are important in host defense; however, a deregulated activity is associated with a number of inflammatory, immune and metabolic disorders. Furthermore, mutations in inflammasome receptor coding genes are causal for an increasing number of rare autoinflammatory diseases. Biotherapies targeting the products of inflammasome activation as well as molecules that directly or indirectly inhibit inflammasome nucleation and activation are promising therapeutic areas. This review discusses recent advances in inflammasome biology, the molecular pathology of several inflammasomes, and current therapeutic approaches in autoinflammatory diseases and in selected common multifactorial inflammasome-mediated disorders. [ABSTRACT FROM AUTHOR]

Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures, a burst-suppression EEG pattern, and progressive disturbance of cerebral function. We present a case of EIEE associated with a de novo missense variant in ZEB2 . Heterozygous truncating mutations or deletions in ZEB2 are known to cause Mowat-Wilson syndrome (MWS), which is characterized by seizures with onset in the second year of life, distinctive dysmorphic facial features and malformations that were absent in this patient. This unique case expands the range of phenotypes associated with variants in ZEB2 and indicates that this gene should be included in the molecular investigation of EIEE cases. [ABSTRACT FROM AUTHOR]