The hereditary periodic fevers are a group of Mendelian disorders characterized by seemingly unprovoked fever and localized inflammation. Recent data indicate that these illnesses represent inborn errors in the regulation of innate immunity. Pyrin, the protein mutated in familial Mediterranean fever, defines an N-terminal domain found in a large family of proteins involved in inflammation and apoptosis. Through this domain pyrin may play a role in the regulation of interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and leukocyte apoptosis. Cryopyrin/NALP3, another protein in this family, is mutated in three other hereditary febrile syndromes and participates in the inflammasome, a newly recognized macromolecular complex crucial to IL-1beta activation. Somewhat unexpectedly, mutations in the 55 kDa receptor for tumor necrosis factor also give rise to a dominantly inherited periodic fever syndrome, rather than immunodeficiency, a finding that has stimulated important investigations into both pathogenesis and treatment. Finally, the discovery of the genetic basis of the hyperimmunoglobulinemia D with periodic fever syndrome suggests an as yet incompletely understood connection between the mevalonate pathway and the regulation of cytokine production. These insights extend our understanding of the regulation of innate immunity in man, while providing the conceptual basis for the rational design of targeted therapies, both for the hereditary periodic fevers themselves and other inflammatory disorders as well. (+info)
Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome.
(2/28)
OBJECTIVE: The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was originally defined by the presence of a high serum level of immunoglobulin D associated with recurrent fever. Since the discovery of the mevalonate kinase gene (MVK) gene encoding the mevalonate kinase enzyme, most patients with a clinical diagnostic of HIDS are now found to have a mevalonate kinase deficiency based on metabolic and genetic data. We aimed to asses the value of a high IgD serum level for the diagnosis of HIDS in a cohort of patients with a phenotype of recurrent fever, and to characterize patients with a high IgD serum level without mevalonate kinase mutation. METHODS: Main clinical and biological data of 50 patients who presented with clinical signs compatible with HIDS have been prospectively registered on a standard form. Clinical data have been analysed according the IgD serum level and the presence of MVK mutation. RESULTS: The metabolic and genetic data establishing the diagnosis of HIDS correlated in all cases. In this series of 50 patients, the sensitivity of a high IgD value for the diagnosis of HIDS is 0.79. In five patients with MVK mutation, IgD levels were found to be in the normal range. Likelihood ratios indicate that IgD measurement is not relevant for the diagnostic of HIDS. Most patients with a high serum IgD level and no MVK mutation have no definite diagnosis. CONCLUSION: The clinical relevance of the IgD measurement for the diagnosis of MKD in our population appears as poor, as reflected by likelihood ratios which are both close to 1. (+info)
Autoinflammatory diseases: an update of clinical and genetic aspects.
(3/28)
Children's toxicology from bench to bed--Liver Injury (4): Mitochondrial respiratory chain disorder and liver disease in children.
(7/28)
OBJECTIVES: The present study was aimed to ascertain the contributions of mitochondrial respiratory chain (MRC) enzymes to the development of liver failure and to the liver pathophysiology of metabolic liver diseases. METHODS: We investigated liver samples obtained from 8 patients with liver failure due to unknown etiology and from 15 patients with metabolic disease: ornithine transcarbamylase deficiency, 6 cases; Wilson disease, 3 cases; metylmalonic aciduria (MMA); 3 cases, neonatal hemochromatosis, 2 cases. The estimation of MRC enzymes was carried out by the following independent methods; i) blue native polyacrylamide gel electrophoresis (BN-PAGE) in gel enzyme staining, ii) BN-PAGE western blotting, iii) in vitro MRC enzyme assay. Furthermore, we estimated the quantities of mtDNA and nDNA using qPCR. RESULT: 4 cases with liver failure showed low activities and protein levels of complex I, III and IV. We also performed qPCR and estimated the ratio mtDNA/nDNA using these samples. They all exhibited extremely low ratio. They were diagnosed as mtDNA depletion syndrome. All cases except MMA cases exhibited mildly or moderately suppressed activities of complex I-IV. However, the respective protein levels remained almost normal. MMA cases exhibited low activities and protein levels of complex I, III and IV. In particular, their low activities and protein levels of complex I were noticeable. They all exhibited normal ratios of mtDNA to nDNA. CONCLUSION: MRC defect might be an etiology of liver failure in a considerable number of patients in Japan. The present study suggested that considerable disturbance of MRC occurs in children with metabolic diseases and possibly modifies the pathophysiology. (+info)
The inherited autoinflammatory syndrome: a decade of discovery.
(8/28)
The hereditary autoinflammatory diseases arise from mutations of genes regulating the innate immune system. These rare disorders are well characterized, both clinically and in terms of their molecular pathogenesis. The recurrent attacks of febrile polyserositis of Familial Mediterranean Fever (FMF) are due to defective pyrin, a protein that down-regulates inflammation. The Hyperimmunoglobulinemia D Syndrome (HIDS), which mimics FMF, results from a genetically conferred deficiency of mevalonate kinase. TRAPS (TNF Receptor Associated Periodic Syndrome), formerly known as Familial Hibernian Fever, is caused by a defective membrane receptor for TNF. Three other hereditary disorders which overlap in their clinical expression - Familial Cold Autoinflammatory Syndrome, the Muckle Wells syndrome, and Neonatal Onset Multisystem Inflamatory Disease (NOMID) - are a consequence of gain-of-function mutations of the gene encoding cryopyrin, the scaffolding protein of the inflammasome. The PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, Acne) results from mutations of a gene that increases the binding of its product (PSPSTPIP1) to pyrin, thereby blunting the inhibitory effect of pyrin on inflammasome activation. (+info)