Science.gov

Sample records for monogenic autoinflammatory syndromes

  1. Macrophage activation syndrome in the course of monogenic autoinflammatory disorders.

    PubMed

    Rigante, Donato; Emmi, Giacomo; Fastiggi, Michele; Silvestri, Elena; Cantarini, Luca

    2015-08-01

    An overwhelming activation of cytotoxic T cells and well-differentiated macrophages leading to systemic overload of inflammatory mediators characterizes the so-called macrophage activation syndrome (MAS); this potentially life-threatening clinical entity may derive from several genetic defects involved in granule-mediated cytotoxicity but has been largely observed in patients with juvenile idiopathic arthritis, many rheumatologic diseases, infections, and malignancies. The occurrence of MAS in the natural history or as the revealing clue of monogenic autoinflammatory disorders (AIDs), rare conditions caused by disrupted innate immunity pathways with overblown release of proinflammatory cytokines, has been only reported in few isolated patients with cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome since 2001. All these patients displayed various clinical, laboratory, and histopathologic features of MAS and have often required intensive care support. Only one patient has died due to MAS. Defective cytotoxic cell function was documented in a minority of patients. Corticosteroids were the first-line treatment, but anakinra was clinically effective in three refractory cases. Even if MAS and AIDs share multiple clinical features as well as heterogeneous pathogenetic scenes and a potential response to anti-interleukin-1 targeted therapies, MAS requires a prompt specific recognition in the course of AIDs due to its profound severity and high mortality rate.

  2. Monogenic Autoinflammatory Syndromes: State of the Art on Genetic, Clinical, and Therapeutic Issues

    PubMed Central

    Costa, Luisa; Atteno, Mariangela; Compagnone, Adele; Caso, Paolo; Frediani, Bruno; Galeazzi, Mauro; Punzi, Leonardo

    2013-01-01

    Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists. PMID:24282415

  3. Monogenic autoinflammatory diseases: concept and clinical manifestations.

    PubMed

    Almeida de Jesus, Adriana; Goldbach-Mansky, Raphaela

    2013-06-01

    The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary "periodic fever syndromes", familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.

  4. Monogenic Autoinflammatory Diseases: Concept And Clinical Manifestations

    PubMed Central

    De Jesus, Adriana Almeida; Goldbach-Mansky, Raphaela

    2013-01-01

    The objectives of this review are to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary “periodic fever syndromes”, familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) 6. very rare conditions presenting with autoinflammation and immunodeficiency. PMID:23711932

  5. Old Dogs, New Tricks: Monogenic Autoinflammatory Disease Unleashed.

    PubMed

    Stoffels, Monique; Kastner, Daniel L

    2016-08-31

    Autoinflammatory diseases are inborn disorders of the innate immune system characterized by episodes of systemic inflammation that are mediated largely by myeloid cells. The field of autoinflammatory diseases has been established since 1999, following the identification of the first genes underlying periodic fever syndromes. This review focuses on developments that have transformed the field in the last two years. We discuss three newly described monogenic autoinflammatory diseases [deficiency of adenosine deaminase 2 (DADA2), a subtype of macrophage activation syndrome (MAS), and stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI)], discuss the possibilities of somatic mosaicism and digenic inheritance, and give an update on new concepts in pathways involved in familial Mediterranean fever (FMF). Finally, the new monogenic autoinflammatory disease haploinsufficiency of A20 (HA20) underscores the placement of monogenic diseases in the firmament of common autoinflammatory phenotypes. The advances in the last two years have shed light on the pathophysiology of several autoinflammatory diseases and have elucidated new pathways that play a role in innate immunity.

  6. [Autoinflammatory syndrome].

    PubMed

    Ida, Hiroaki; Eguchi, Katsumi

    2009-03-01

    The autoinflammatory syndromes include a group of inherited diseases that are characterized by 1) seemingly unprovoked episodes of systemic inflammations, 2) absence of high titer of autoantibody or auto-reactive T cell, and 3) inborn error of innate immunity. In this article, we will focus on the clinical features, the pathogenesis related the genetic defects, and the therapeutic strategies in the representative disorders including familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), hyper-IgD with periodic fever syndrome (HIDS), syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA), and Blau syndrome. Recent advances in genetics and molecular biology have proceeded our understanding of the pathogenesis of autoinflammatory syndromes.

  7. Autoinflammatory syndromes.

    PubMed

    Galeazzi, M; Gasbarrini, G; Ghirardello, A; Grandemange, S; Hoffman, H M; Manna, R; Podswiadek, M; Punzi, L; Sebastiani, G D; Touitou, I; Doria, A

    2006-01-01

    The autoinflammatory disorders are a new and expanding classification of inflammatory diseases characterized by recurrent episodes of systemic inflammation in the absence of pathogens, autoantibodies or antigen specific T cells. These disorders are caused by primary dysfunction of the innate immune system, without evidence of adaptive immune dysregulation. Innate immune abnormalities include aberrant responses to pathogen associated molecular patterns (PAMPs) like lipopolysaccharide and peptidoglycan, prominent neutrophilia in blood and tissues, and dysregulation of inflammatory cytokines (IL-1beta, TNF-alpha) or their receptors. The autoinflammatory diseases comprise both hereditary (Familial Mediterranean Fever, FMF; Mevalonate Kinase Deficiency, MKD; TNF Receptor Associated Periodic Syndrome, TRAPS; Cryopyrin Associated Periodic Syndrome, CAPS; Blau syndrome; Pyogenic sterile Arthritis, Pyoderma gangrenosum and Acne syndrome, PAPA; Chronic Recurrent Multifocal Osteomyelitis, CRMO) and multifactorial (Crohn's and Behçet's diseases) disorders. Mutations responsible for FMF, TRAPS, CAPS, PAPA are in proteins involved in modulation of inflammation and apoptosis.

  8. Monogenic IL-1 Mediated Autoinflammatory and Immunodeficiency Syndromes: Finding the Right Balance in Response to Danger Signals

    PubMed Central

    Henderson, Cailin; Goldbach-Mansky, Raphaela

    2010-01-01

    INTRODUCTION Interleukin -1 was the first cytokine identified and is a powerful inducer of fever and inflammation. The biologically active receptor for IL-1, shares signaling pathways with some pathogen recognition receptors, the toll like receptors (TLRs) which early on suggested an important role in innate immune function. DISCUSSION The discovery that some intracellular “danger receptors”, the NOD like receptors (NLRs) can assemble to form multimolecular platforms, the inflammasomes, that not only sense intracellular danger but also activate IL-1β, has provided the molecular basis for the integration of IL-1 as an early response mediator in danger recognition. The critical role of balancing IL-1 production and signaling in human disease has recently been demonstrated in rare human monogenic diseases with mutations that affect the meticulous control of IL-1 production, release and signaling by leading to decreased or increased TLR/IL-1 signaling. In diseases of decreased TLR/IL-1 signaling (IRAK-4 and MyD88 deficiencies) patients are at risk for infections with gram positive organisms; and in diseases of increased signaling, patients develop systemic autoinflammatory diseases (Cryopyrin associated periodic syndromes (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA)). CONCLUSION Monogenic defects in a number of rare diseases that affect the balance of TLR/IL-1 signaling have provided us with opportunities to study the systemic effects of IL-1 in human diseases. The molecular defects in CAPS and DIRA provided a therapeutic rationale for targeting IL-1 and the impressive clinical results from IL-1 blocking therapies have undoubtedly confirmed the pivotal role of IL-1 in human disease and spurred the exploration of modifying IL-1 signaling in a number of genetically complex common human diseases. PMID:20353899

  9. [Autoinflammatory syndromes].

    PubMed

    Lamprecht, P; Gross, W L

    2009-06-01

    In its strict sense, the term "autoinflammatory syndromes" comprises the hereditary periodic fever syndromes (HPF), which are caused by mutations of pattern-recognition receptors (PRR) and perturbations of the cytokine balance. These include the crypyrinopathies, familial Mediterranean fever, TNF-receptor associated periodic fever syndrome (TRAPS), hyper-IgD and periodic syndrome (HIDS), pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, NALP12-HPF, and the Blau syndrome. The diseases are characterized by spontaneous activation of cells of the innate immunity in the absence of ligands. Autoantibodies are usually not found. HPF clinically present with recurrent fever episodes and inflammation, especially of serosal and synovial interfaces and the skin. Intriguingly, PRR-mediated autoinflammtory mechanisms also play a role in a number of chronic inflammatory and autoimmune diseases.

  10. New monogenic autoinflammatory diseases—a clinical overview

    PubMed Central

    2015-01-01

    Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of IL-1 in driving autoinflammatory phenotypes and on therapies blocking IL-1 signaling. Recent discoveries from patients unresponsive to IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic type I interferon (IFN) production present with organ manifestations different from IL-1 mediated diseases including cerebral calcifications, myositis, and interstitial lung disease and the frequent occurrence of autoantibodies. These disorders introduce type I IFN’s as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high IL-18 production may provide a direct link between autoinflammation and macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases. PMID:25963521

  11. [Autoinflammatory syndromes].

    PubMed

    Gomes, José Melo; Gomes, Sónia Melo; Conde, Marta

    2010-01-01

    Autoinflammatory syndromes (AIS) are a heterogeneous group of congenital diseases characterized by the presence of recurrent episodes of fever and local or generalized inflammation, in the absence of infectious agents, detectable auto-antibodies or antigen-specific autoreactive T-cells. These diseases have been much better understood during the past 15 years, mainly due to the marked advances of the Human Genoma Project and its implications in the identification and characterization of genetic mutations. In this paper we make a revision of the classification of AIS and focus our attention specially on the cryopyrin-associated periodic syndromes (CAPS), in particular the CINCA syndrome that shares many clinical characteristics with juvenile idiopathic arthritis.

  12. Autoinflammatory syndromes: diagnosis and management

    PubMed Central

    2010-01-01

    During the last decades the description of autoinflammatory syndromes induced great interest among the scientific community. Mainly rheumatologists, immunologists and pediatricians are involved in the discovery of etiopathogenesis of these syndromes and in the recognition of affected patients. In this paper we will discuss the most important clues of monogenic and non-genetic inflammatory syndromes to help pediatricians in the diagnosis and treatment of these diseases. PMID:20813071

  13. [Diagnosis and Clinical Examination of Autoinflammatory Syndrome].

    PubMed

    Ida, Hiroaki

    2015-05-01

    Autoinflammatory syndrome is characterized by: 1) episodes of seemingly unprovoked inflammation, 2) the absence of a high titer of autoantibodies or auto-reactive T cells, and 3) an inborn error of innate immunity. In this decade, many autoinflammatory syndromes have been reported in Japan, and so many Japanese physicians have become aware of this syndrome. Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. The main monogenic autoinflammatory syndromes are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndrome (CAPS), Blau syndrome, and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. We diagnosed these syndromes as clinical manifestations and performed genetic screening. Many serum cytokines are elevated in patients with autoinflammatory syndrome, but this is not disease-specific. The pathogeneses of many autoinflammatory syndromes are known to be related to inflammasomes, which are multiprotein complexes that serve as a platform for caspase 1 activation and interleukin-1β (IL-1β) and IL-18 muturation. Especially, NLRP3 inflammasomes may play a crucial role in the intiation and progression of FMF and CAPS. In the future, we hope to discover new clinical examinations which can provide evidence of inflammasome activation independent of genetic screening. In this issue, I introduce autoinflammatory syndromes and discuss the diagnosis and clinical examination of these syndromes.

  14. The expanding spectrum of rare monogenic autoinflammatory diseases

    PubMed Central

    2013-01-01

    Monogenic autoinflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome in which there is little or no evidence of autoimmunity. The discovery of the first causative gene in 1997 was rapidly followed by the identification of many others from the same group. The mutated proteins can be directly or indirectly involved in the regulation of inflammation. The available literature includes numerous reviews, which address the principle diseases, but we wanted to focus on the most recent rare syndromes. A comprehensive review is thus provided, including taxonomic, genetic, and epidemiological data, along with characteristics defining positive and differential diagnoses and treatment. We believe that this update will assist physicians in correctly naming their patient’s illness. This is an essential step for the effective and targeted management of an orphan disease. PMID:24131530

  15. [Autoinflammatory syndromes/fever syndromes].

    PubMed

    Schedel, J; Bach, B; Kümmerle-Deschner, J B; Kötter, I

    2011-05-01

    Hereditary periodic (fever) syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or joint symptoms. Some of these disorders present with organ involvement and serological signs of inflammation without fever. There is a strong serological inflammatory response with an elevation of serum amyloid A (SAA), resulting in an increased risk of secondary amyloidosis. There are monogenic disorders (familial mediterranean fever (FMF), hyper-IgD-syndrome (HIDS), cryopyrin-associated periodic syndromes (CAPS), "pyogenic arthritis, acne, pyoderma gangrenosum" (PAPA), and "pediatric granulomatous arthritis (PGA) where mutations in genes have been described, which in part by influencing the function of the inflammasome, in part by other means, lead to the induction of the production of IL-1β. In "early-onset of enterocolitis (IBD)", a functional IL-10 receptor is lacking. Therapeutically, above all, the IL-1 receptor antagonist anakinra is used. In case of TRAPS and PGA, TNF-antagonists (etanercept) may also be used; in FMF colchicine is first choice. As additional possible autoinflammatory syndromes, PFAPA syndrome (periodic fever with aphthous stomatitis, pharyngitis and adenitis), Schnitzler syndrome, Still's disease of adult and pediatric onset, Behçet disease, gout, chronic recurrent multifocal osteomyelitis (CRMO) and Crohn's disease also are mentioned.

  16. Monogenic autoinflammatory diseases: disorders of amplified danger sensing and cytokine dysregulation.

    PubMed

    Sanchez, Gina A Montealegre; de Jesus, Adriana Almeida; Goldbach-Mansky, Raphaela

    2013-11-01

    The pathogenesis of monogenic autoinflammatory diseases converges on the presence of exaggerated immune responses that are triggered through activation of altered pattern recognition receptor (PRR) pathways and result in cytokine/chemokine amplification loops and the inflammatory clinical phenotype seen in autoinflammatory patients. The PRR response can be triggered by accumulation of metabolites, by mutations in sensors leading to their constitutive overactivation, or by mutations in mediator cytokine pathways that lead to amplification and/or inability to downregulate an inflammatory response in hematopoietic and/or nonhematopoietic cells. The study of the pathogenesis of sterile inflammation in patients with autoinflammatory syndromes continues to uncover novel inflammatory pathways.

  17. Monogenic autoinflammatory diseases: General concepts and presentation in adult patients.

    PubMed

    Hernández-Rodríguez, José; Ruiz-Ortiz, Estíbaliz; Yagüe, Jordi

    2017-09-15

    Monogenic autoinflammatory diseases (AIFD) are rare disorders characterized by an uncontrolled increase of the systemic inflammatory response, which is caused by mutations in genes involved in inflammatory pathways. Over the last few years, new genes and proteins responsible for new monogenic AIFD have been identified and a substantial improvement in their treatment has been achieved. Monogenic AIFD manifestations typically begin during childhood, but they can also occur in adults. Compared to pediatric patients, adults usually present with a less severe disease and fewer long-term complications. In addition, patients with adult-onset disease carry low-penetrance mutations more often than pathogenic variants. A late-onset of AIFD may be occasionally associated with the presence of somatic mutations. In this study, we review the most frequent monogenic AIFD, and others recently described, which may occur during adulthood. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  18. [Pathogenesis and Clinical Examination of Autoinflammatory Syndrome].

    PubMed

    Ida, Hiroaki

    2015-10-01

    Autoinflammatory syndrome is characterized by: 1) episodes of seemingly unprovoked inflammation, 2) the absence of a high titer of autoantibodies or auto-reactive T cells, and 3) an inborn error of innate immunity. In this decade, many autoinflammatory syndromes have been reported in Japan, and so many Japanese physicians have become aware of this syndrome. Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. The main monogenic autoinflammatory syndromes are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndrome (CAPS), Blau syndrome, and syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). We diagnosed these syndromes as clinical manifestations and performed genetic screening. Many serum cytokines are elevated in patients with autoinflammatory syndrome, but this is not disease-specific. The pathogeneses of many autoinflammatory syndromes are known to be related to inflammasomes, which are multiprotein complexes that serve as a platform for caspase 1 activation and interleukin-1β(IL-1β) and IL-18 maturation. Especially, NLRP3 inflammasomes may play a crucial role in the initiation and progression of FMF and CAPS. Recently, it was reported that NETs (neutrophil extracellular traps) derived from neutrophils may also play an important role in the pathogenesis of FMF. In the future, we hope to discover new clinical examinations which can provide evidence of inflammasome activation independent of genetic screening. In this issue, I introduce autoinflammatory syndromes and discuss the pathogenesis and clinical examination of these syndromes.

  19. The protean ocular involvement in monogenic autoinflammatory diseases: state of the art.

    PubMed

    Bascherini, Vittoria; Granato, Carmela; Lopalco, Giuseppe; Emmi, Giacomo; Vannozzi, Lorenzo; Bacherini, Daniela; Franceschini, Rossella; Iannone, Florenzo; Salerni, Annabella; Molinaro, Francesco; Messina, Mario; Frediani, Bruno; Selmi, Carlo; Rigante, Donato; Cantarini, Luca

    2015-07-01

    Ocular involvement is frequent in the monogenic autoinflammatory disorders and generally occurs as spontaneously recurring inflammatory events at different ocular sites caused by the aberrant release of proinflammatory cytokines, mainly IL-1β. Over the past decade, we witnessed a significant growth of eye abnormalities associated with idiopathic granulomatous disorders, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and cryopyrin-associated periodic syndrome. The pathogenetic mechanisms of these disorders have shown the evidence of disrupted cytokine signaling, but the explanation for the heterogeneous ocular involvement remains to be elucidated. We herein review the monogenic autoinflammatory disorders affecting the eye, describing their main clinical features with specific regard to the ocular involvement, which can lead to decreased visual acuity and even blindness, if the primary disorder is undetected or left untreated.

  20. Therapy of autoinflammatory syndromes

    PubMed Central

    Hoffman, Hal M.

    2015-01-01

    The therapy of autoinflammatory syndromes is an excellent example of the power of translational research. Recent advances in our understanding of the molecular and immunologic basis of this newly identified classification of disease have allowed for the application of novel, effective, targeted treatments with life-changing effects on patients. Although colchicine and TNF-α inhibitors are important therapies for specific autoinflammatory syndromes, the novel IL-1–targeted drugs are particularly effective for many of these diseases. Recently, the pharmaceutical industry has adopted a strategy of confirming the efficacy of new targeted drugs in often-ignored patients with orphan diseases, and US Food and Drug Administration policies have allowed for accelerated approval of these drugs, creating a win-win situation for patients and industry. This article reviews the general approach to the therapy of autoinflammatory diseases, focusing on current approved therapies and novel approaches that might be used in the future. PMID:20004774

  1. Genetics Home Reference: familial cold autoinflammatory syndrome

    MedlinePlus

    ... Home Health Conditions familial cold autoinflammatory syndrome familial cold autoinflammatory syndrome Printable PDF Open All Close All ... to view the expand/collapse boxes. Description Familial cold autoinflammatory syndrome is a condition that causes episodes ...

  2. Systemic and organ involvement in monogenic autoinflammatory disorders: a global review filtered through internists' lens.

    PubMed

    Cattalini, Marco; Soliani, Martina; Lopalco, Giuseppe; Rigante, Donato; Cantarini, Luca

    2016-09-01

    Monogenic autoinflammatory disorders (AIDs) are rare diseases driven by cytokine-mediated extraordinary sterile inflammation that results from the activation of innate immune pathways. The clinical hallmark of these diseases is the recurrence of stereotyped episodes of systemic- and organ-specific inflammation; the most common systems involved being the skin, musculoskeletal system, gastrointestinal tract, and central nervous system. The autoinflammatory disorders may have a profound impact on the quality of life of the affected patients, and a delayed diagnosis may lead to severe complications, the most dreadful of which is AA-Amyloidosis. This review gives an overview on the four main AIDs, namely familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrinopathies, and mevalonate kinase deficiency, focusing on their clinical phenotype in adults and differential diagnosis, suggesting a diagnostic algorithm, and reviewing the available treatments.

  3. [Auto-inflammatory syndromes].

    PubMed

    Grateau, Gilles

    2005-02-28

    Auto-inflammatory syndromes are a group of hereditary diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever, which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases, as underlied by a specific inflammatory pathway. This new group of diseases has already opened new avenues in our understanding of the inflammatory response.

  4. IL-1 blockade in autoinflammatory syndromes.

    PubMed

    Jesus, Adriana A; Goldbach-Mansky, Raphaela

    2014-01-01

    Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)-regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.

  5. Monogenic human obesity syndromes.

    PubMed

    Farooqi, I S; O'Rahilly, S

    2004-01-01

    Over the past decade, we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes and the novel physiological pathways revealed by those genetic discoveries. We and others recently have identified several single-gene defects causing severe human obesity. Many of these defects have occurred in molecules identical or similar to those identified as a cause of obesity in rodents. This chapter will consider the human monogenic obesity syndromes that have been characterized to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

  6. Monogenic human obesity syndromes.

    PubMed

    Farooqi, I S

    2006-01-01

    Over the past decade we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes, and the novel physiological pathways revealed by those genetic discoveries. Others and we have also recently identified several single gene defects causing severe human obesity. Many of these defects have been in molecules identical or similar to those identified as a cause of obesity in rodents. I will review the human monogenic obesity syndromes that have been characterised to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

  7. Biological treatments: new weapons in the management of monogenic autoinflammatory disorders.

    PubMed

    Vitale, Antonio; Rigante, Donato; Lucherini, Orso Maria; Caso, Francesco; Muscari, Isabella; Magnotti, Flora; Brizi, Maria Giuseppina; Guerrini, Susanna; Patti, Maria; Punzi, Leonardo; Galeazzi, Mauro; Cantarini, Luca

    2013-01-01

    Treatment of monogenic autoinflammatory disorders, an expanding group of hereditary diseases characterized by apparently unprovoked recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells, has been revolutionized by the discovery that several of these conditions are caused by mutations in proteins involved in the mechanisms of innate immune response, including components of the inflammasome, cytokine receptors, receptor antagonists, and oversecretion of a network of proinflammatory molecules. Aim of this review is to synthesize the current experience and the most recent evidences about the therapeutic approach with biologic drugs in pediatric and adult patients with monogenic autoinflammatory disorders.

  8. Biological Treatments: New Weapons in the Management of Monogenic Autoinflammatory Disorders

    PubMed Central

    Lucherini, Orso Maria; Muscari, Isabella; Magnotti, Flora; Brizi, Maria Giuseppina; Guerrini, Susanna; Patti, Maria; Punzi, Leonardo; Galeazzi, Mauro

    2013-01-01

    Treatment of monogenic autoinflammatory disorders, an expanding group of hereditary diseases characterized by apparently unprovoked recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells, has been revolutionized by the discovery that several of these conditions are caused by mutations in proteins involved in the mechanisms of innate immune response, including components of the inflammasome, cytokine receptors, receptor antagonists, and oversecretion of a network of proinflammatory molecules. Aim of this review is to synthesize the current experience and the most recent evidences about the therapeutic approach with biologic drugs in pediatric and adult patients with monogenic autoinflammatory disorders. PMID:23970817

  9. Genomics, Biology, and Human Illness: Advances in the Monogenic Autoinflammatory Diseases.

    PubMed

    Oda, Hirotsugu; Kastner, Daniel L

    2017-08-01

    The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically determined recurrent sterile inflammation and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines, such as interleukin 1 and tumor necrosis factor, and intracellular cytokine signaling pathways have proved effective in many cases. Emerging next-generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. This review covers several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies. Published by Elsevier Inc.

  10. IL-1 Blockade in Autoinflammatory Syndromes1

    PubMed Central

    Jesus, Adriana A.; Goldbach-Mansky, Raphaela

    2014-01-01

    Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)–regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular “molecular sensor” that forms a multimolecular platform, the NLRP3 inflammasome, which links “danger recognition” to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL-1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor–associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still’s, Behcet’s, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease. PMID:24422572

  11. Skin manifestations in autoinflammatory syndromes.

    PubMed

    Braun-Falco, Markus; Ruzicka, Thomas

    2011-03-01

    Autoinflammatory diseases encompass a group of inflammatory diseases that are non-infectious, non-allergic, non-autoimmune and non-immunodeficient. The term was initially coined for a small group of familial periodic fever syndromes of which familial Mediterranean fever (FMF) is the most common and best known. Genetic and molecular analyses demonstrated for the majority of these diseases an impairment of inflammasomes to cause an increased activity of an interleukin-1-dependent inflammatory response. Over the last years an increasing number of either rare hereditary syndromes or acquired common diseases could be summarized under the designation of autoinflammatory disease, thus creating an emerging new rubric of inflammatory diseases. Many of them display cutaneous manifestations as both concomitant or more rarely main symptoms. To name some of them like erysipelas-like erythema in FMF; urticaria-like rashes in tumor necrosis factor receptor 1- or cryopyrin-associated periodic syndromes (TRAPS, CAPS), hyperimmunoglobulin D syndrome (HIDS) or Schnitzler syndrome; pyoderma gangrenosum and acne in PAPA syndrome; or behçetoid aphthous ulcerations in HIDS and PFAPA syndrome. Based on the new insights into pathogenesis one increasingly realizes the good response of these diseases to IL-1 antagonist therapies.

  12. Monogenic Auto-inflammatory Syndromes: A Review of the Literature.

    PubMed

    Azizi, Gholamreza; Khadem Azarian, Shahin; Nazeri, Sepideh; Mosayebian, Ali; Ghiasy, Saleh; Sadri, Ghazal; Mohebi, Ali; Khan Nazer, Nikoo Hossein; Afraei, Sanaz; Mirshafiey, Abbas

    2016-12-01

    Auto-inflammatory syndromes are a new group of distinct hereditable disorders characterized by episodes of seemingly unprovoked inflammation (most commonly in skin, joints, gut, and eye), the absence of a high titer of auto-antibodies or auto-reactive T cells, and an inborn error of innate immunity. A narrative literature review was carried out of studies related to auto-inflammatory syndromes to discuss the pathogenesis and clinical manifestation of these syndromes. This review showed that the main monogenic auto-inflammatory syndromes are familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), Blau syndrome, TNF receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), and pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). The data suggest that correct diagnosis and treatment of monogenic auto-inflammatory diseases relies on the physicians' awareness. Therefore, understanding of the underlying pathogenic mechanisms of auto-inflammatory syndromes, and especially the fact that these disorders are mediated by IL-1 secretion stimulated by monocytes and macrophages, facilitated significant progress in patient management.

  13. Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1

    PubMed Central

    Goldbach-Mansky, R

    2012-01-01

    The disease-based discovery of the molecular basis for autoinflammatory diseases has led not only to a rapidly growing number of clinically and genetically identifiable disorders, but has unmantled key inflammatory pathways such as the potent role of the alarm cytokine interleukin (IL)-1 in human disease. Following its initial failures in the treatment of sepsis and the moderate success in the treatment of rheumatoid arthritis, IL-1 blocking therapies had a renaissance in the treatment of a number of autoinflammatory conditions, and IL-1 blocking therapies have been Food and Drug Administration (FDA)-approved for the treatment of the autoinflammatory conditions: cryopyrin-associated periodic syndromes (CAPS). CAPS and deficiency of the IL-1 receptor antagonist (DIRA), both genetic conditions with molecular defects in the IL-1 pathway, have provided a pathogenic rationale to IL-1 blocking therapies, and the impressive clinical results confirmed the pivotal role of IL-1 in human disease. Furthermore, IL-1 blocking strategies have shown clinical benefit in a number of other genetically defined autoinflammatory conditions, and diseases with clinical similarities to the monogenic disorders and not yet identified genetic causes. The discovery that IL-1 is not only triggered by infectious danger signals but also by danger signals released from metabolically ‘stressed’ or even dying cells has extended the concept of autoinflammation to disorders such as gout, and those that were previously not considered inflammatory, such as type 2 diabetes, coronary artery disease, obesity and some degenerative diseases, and provided the conceptual framework to target IL-1 in these diseases. Despite the tremendous success of IL-1 blocking therapy, the use of these agents in a wider spectrum of autoinflammatory conditions has uncovered disease subsets that are not responsive to IL-1 blockade, including the recently discovered proteasome-associated autoinflammatory syndromes such as

  14. Auto-inflammatory fever syndromes.

    PubMed

    Padeh, Shai; Berkun, Yakov

    2007-08-01

    Human autoinflammatory diseases (except for PFAPA) are a heterogeneous group of genetically determined diseases characterized by seemingly unprovoked inflammation in the absence of autoimmune or infective causes (Table 2). The last decade has witnessed tremendous advances in the understanding of these disorders. These advances have allowed therapeutic interventions resulting in improvement in the short-term and long-term morbidity of all of these diseases. Future research into the molecular mechanisms underlying these inflammatory diseases should lead to a better understanding of inflammatory diseases in general and, it is hoped, to better and more targeted therapies.

  15. Periodic fevers and autoinflammatory syndromes in childhood.

    PubMed

    Ostring, Genevieve T; Singh-Grewal, Davinder

    2016-09-01

    Recurrent fever is a common presentation in paediatric practice and can be caused by a wide variety of diseases including autoinflammatory conditions. The innate immune system plays an essential role in the 'first line' response to infection through mediation of inflammatory responses. Inflammasomes are part of the regulatory process for this system and result in the production of the powerful pro-inflammatory cytokine interleukin-1B. Dysregulation of inflammasomes, and Interleukin 1 production, contributes to the pathogenesis of autoinflammatory diseases. This review focuses on described periodic fever syndromes (PFS) which are now collectively referred to as autoinflammatory syndromes. Conditions discussed include periodic fever aphthous stomatitis pharyngitis and cervical adenopathy, familial Mediterranean fever, tumour necrosis factor receptor-associated periodic syndromes, hyperimmunoglobulinaemia D and the cryopyrin-associated periodic syndromes. Presenting features, complications, diagnostic and treatment approaches for these conditions are discussed. Nonetheless, as most of these conditions are rare and may have significant long-term complications, it is recommended that they be managed in consultations with a physician experienced in managing PFS.

  16. Urticarial vasculitis and urticarial autoinflammatory syndromes.

    PubMed

    Marzano, A V; Tavecchio, S; Venturini, M; Sala, R; Calzavara-Pinton, P; Gattorno, M

    2015-02-01

    Urticaria is a frequent disorder classified as acute and chronic forms, which presents with wheals that can be associated with angioedema. Several entities may manifest with urticarial skin lesions, encompassing a heterogeneous group of conditions that have to be differentiated from ordinary urticaria. This review is focused on two of these urticarial syndromes: urticarial vasculitis (UV), which represents the most important differential diagnosis with common urticaria, and autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) and Schnitzler's Syndrome, both rare multisystem forms that may masquerade as common urticaria. UV is a small-vessel vasculitis with predominant skin involvement, characterized by wheals persisting for more than 24 hours, burning rather than itching and resolving with hyperpigmentation as well as by other cutaneous manifestations including purpura, papules, vesicles, bullae and necrotic-ulcerative lesions. Histology shows a classic pattern of leukocytoclastic vasculitis, with possible presence of upper dermal edema. CAPS are classified as three distinct entities: familial cold autoinflammatory syndrome, Muckle-Wells Syndrome and chronic infantile neurological cutaneous and articular syndrome, which represent a spectrum of disorders caused by different mutations in a single gene, NLRP3 (NOD-like receptor 3). This gene encodes for cryopyrin, an inflammasome protein that activates interleukin-1β, leading to an overproduction of this pivotal proinflammatory cytokine. Histologically, urticarial lesions are generally characterized by a perivascular neutrophilic infiltrate. Unlike urticaria, neither UV nor urticarial autoinflammatory syndromes do respond to antihistamines: thus, it is important not to misdiagnose such conditions in order to give the patients specific treatments, potentially preventing serious systemic complications.

  17. Autoinflammatory Diseases in Pediatric Dermatology-Part 1: Urticaria-like Syndromes, Pustular Syndromes, and Mucocutaneous Ulceration Syndromes.

    PubMed

    Hernández-Ostiz, S; Prieto-Torres, L; Xirotagaros, G; Noguera-Morel, L; Hernández-Martín, Á; Torrelo, A

    2017-09-01

    Monogenic autoinflammatory diseases are a heterogeneous emergent group of conditions that are currently under intensive study. We review the etiopathogenesis of these syndromes and their principal manifestations. Our aim is to propose a classification system based on the clinicopathologic features of typical skin lesions for routine clinical use in dermatology. Our focus is on diagnosis in pediatric practice given that this is the period when the signs and symptoms of these syndromes first appear. In Part 1 we discuss the course of urticaria-like syndromes, which include cryopyrin-associated periodic conditions and hereditary periodic fever syndromes. Pustular syndromes are also covered in this part. Finally, we review the range of therapies available as well as the genetic mutations associated with these autoinflammatory diseases. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Immunology in clinic review series; focus on autoinflammatory diseases: role of inflammasomes in autoinflammatory syndromes

    PubMed Central

    Ozkurede, V U; Franchi, L

    2012-01-01

    Autoinflammatory syndromes are disorders characterized by the hyperactivation of the innate immune system in the absence of microbial infection or autoantibody production. Some autoinflammatory syndromes are associated with recurrent episodes of fever and systemic inflammation that are caused by dysregulated activation of inflammasomes, molecular platforms responsible for the activation of caspase-1 and the production of interleukin (IL)-1β. In this review we will discuss the role of IL-1β and the inflammasomes in host defence and how mutations of two genes, NLRP3 and PYRIN, leads to the autoinflammatory syndromes, cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF). Both CAPS and FMF are characterized by increased inflammasome activity and overproduction of IL-1β which is ultimately responsible for disease manifestations. Importantly, understanding the molecular mechanisms of these syndromes has led to effective treatment for these rare diseases with biological drugs that target IL-1β-mediated signalling. PMID:22288581

  19. Auto-inflammatory syndromes and oral health.

    PubMed

    Scully, C; Hodgson, T; Lachmann, H

    2008-11-01

    Auto-inflammatory diseases (periodic syndromes) are rare childhood-onset disorders which are characterized by fluctuating or recurrent episodes of fever and inflammation affecting serosal surfaces, joints, eyes and/or skin without significant autoantibody production or an identifiable underlying infection. They are disorders of innate immunity and the underlying genetic defect has been identified in most of the syndromes. Diagnosis relies on clinical symptoms and evidence of an elevated acute phase response during attacks, supported by finding mutations in the relevant genes. Several syndromes can lead to systemic AA amyloidosis. Aphthous-like oral ulceration has been reported as one manifestation in several of the syndromes, including periodic fever, aphthous-stomatitis, pharyngitis, adenitis (PFAPA) familial Mediterranean fever (FMF), hyperimmunoglobulinaemia D and periodic fever syndrome, tumour necrosis factor receptor associated periodic syndrome and pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA). Chronic jaw recurrent osteomyelitis has been recorded in chronic recurrent multifocal osteomyelitis. Advances in the molecular pathogenesis of these syndromes and the regulation of innate immunity have enhanced diagnosis, and rationalized therapies. This article reviews the periodic fever syndromes relevant to oral health and the suggested association of FMF with Behçet's disease.

  20. Amyloidosis and auto-inflammatory syndromes.

    PubMed

    Grateau, Gilles; Jéru, Isabelle; Rouaghe, Saad; Cazeneuve, Cécile; Ravet, Nathalie; Duquesnoy, Philippe; Cuisset, Laurence; Dodé, Catherine; Delpech, Marc; Amselem, Serge

    2005-02-01

    Amyloidosis remains currently a severe potential complication of many chronic inflammatory disorders. It is not exactly know why some patients develop a progressive amyloidosis, whereas others do not although latent deposits may be present. A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis. Genetic factors have however been recently emphasized. Among persistent or emerging causes of AA amyloidosis, hereditary periodic fever syndromes also known as auto-inflammatory syndromes are a group of diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases.

  1. The Central Role of Anti-IL-1 Blockade in the Treatment of Monogenic and Multi-Factorial Autoinflammatory Diseases

    PubMed Central

    Federici, Silvia; Martini, Alberto; Gattorno, Marco

    2013-01-01

    Inherited autoinflammatory diseases are secondary to mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to seemingly unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed new lights on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of an autoinflammatory disease. The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways responsible for the activation and secretion of the potent inflammatory cytokine interleukin-1β (IL-1β). It became clear that several multi-factorial inflammatory conditions display a number of pathogenic and clinical similarities with inherited autoinflammatory diseases. The dramatic effect of interleukin-1 (IL-1) blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders. Several IL-1 blockers are now available on the market. In this review we outline the more recent novelties in the treatment with different IL-1 blockers in inherited and multi-factorial autoinflammatory diseases. PMID:24198817

  2. Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives.

    PubMed

    Savic, Sinisa; Dickie, Laura J; Wittmann, Miriam; McDermott, Michael F

    2012-08-01

    The term 'autoinflammatory disease' was first proposed in 1999 to encompass some of the distinct clinicopathologic features of a group of monogenic conditions, characterised by recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells. It was subsequently observed that several of these conditions were caused by mutations in proteins involved in the innate immune response, including, among others, components of the NLRP3 inflammasome, cytokine receptors (tumour necrosis factor receptor 1 (TNFR1)) and receptor antagonists (interleukin 1 receptor antagonist (IL-1RA)). More recently, additional mechanisms linking innate immune-mediated inflammation with a variety of cellular processes, including protein misfolding, oxidative stress and mitochondrial dysfunction, have been recognised to play a role in the pathogenesis of some monogenic autoinflammatory conditions, and also in more common diseases such as type 2 diabetes (T2D), previously perceived as a metabolic disorder, but reclassified as a chronic inflammatory condition. NLRP3 inflammasome activation is induced by islet amyloid polypeptides (IAPPs) in T2D and this condition may, in future, be more commonly treated with targeted anti-cytokine therapies. Caspase 1 activation and release of IL-1β/IL-1 family members is central to the pathogenesis of many autoinflammatory syndromes, as evidenced by the effectiveness of anti-IL-1 biologics in treating these disorders. However, many patients continue to experience symptoms of chronic inflammation, and it will be necessary to translate discoveries on the immunopathology of these conditions into more effective therapies. For example, in tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), the pathogenesis may vary with each mutation and therefore future approaches to treatment of individual patients will require a more tailored approach based on genetic and functional studies. Copyright © 2012 Elsevier Ltd

  3. Autoinflammatory syndromes behind the scenes of recurrent fevers in children.

    PubMed

    Rigante, Donato

    2009-08-01

    Many children experience recurrent fevers with no easily identifiable source and only a careful follow-up helps in the early identification of other presenting symptoms of other defined conditions which require medical intervention. Autoinflammatory syndromes are rare childhood-onset disorders of the innate immunity in which recurrent flares of fever and inflammation affecting skin, joints, the gastrointestinal tube, or serous membranes are the most striking signs, without any evidence of autoantibody production or underlying infections. Among the pediatric conditions belonging to this group we can consider hereditary recurrent fevers (familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes), pyogenic disorders (PAPA syndrome, CRMO syndrome, Majeed syndrome), immune-mediated granulomatous diseases (Blau syndrome, Crohn's disease), and idiopathic febrile syndromes (systemic-onset juvenile idiopathic arthritis, PFAPA syndrome, Behçet syndrome). Their genetic background has only been partially elucidated and advances in their molecular pathogenesis are shedding new light on the innate immune system, whilst more and more diseases are being reconsidered at a pathogenetic level and included in this new chapter of postgenomic medicine. The diagnosis of most autoinflammatory syndromes relies on clinical history, demonstration of an increased acute-phase response during inflammatory attacks, and, possibly, genetic confirmation, which is still elusive especially for idiopathic febrile syndromes. This astonishing progress in the awareness and knowledge of autoinflammatory syndromes has anticipated the actual possibilities of medical intervention and rationalized treatment with targeted biologic agents.

  4. [Monogenic and syndromic symptoms of morbid obesity. Rare but important].

    PubMed

    Wiegand, S; Krude, H

    2015-02-01

    Monogenic and syndromic obesity are rare diseases with variable manifestation. Therefore diagnosis is difficult and often delayed. The purpose of this work was to develop a clinical diagnostic algorithm for earlier diagnosis. Available publications for clinical symptoms and molecular defects of monogenic and syndromic obesity cases were evaluated. Monogenic and syndromic obesity can be expected in cases with early manifestation before the age of 5 years and a BMI above 40 or above the 99th percentile. Syndromic cases are mostly associated with a low IQ and dwarfism. Monogenic cases are associated with additional endocrine defects. Measurement of serum leptin proves the treatable leptin deficiency. Sequencing of the melanocortin-4 receptor gene (MC4R) allows diagnosis of the most frequent monogenic form of obesity. Treatment with a melanocyte-stimulating hormone (MSH) analog can be expected in the future. Early treatment of children with Prader-Willi syndrome can prevent severe obesity. Because in some cases treatment is available, monogenic and syndromic obesity should be diagnosed early. Based on the disease symptoms, serum leptin, and MC4R sequencing, a diagnostic algorithm is proposed, which can be used to diagnose cases of morbid obesity.

  5. [Nosology of inflammatory diseases: lessons learned from the auto-inflammatory syndromes--a focus on skin manifestations].

    PubMed

    Lipsker, Dan; Ramot, Yuval; Ingber, Arieh

    2012-10-01

    Auto-inflammatory diseases were first described more than 10 years ago as inherited disorders, characterized by recurrent flares of inflammation due to an abnormality in the innate immune system. The understanding of the underlying pathogenic mechanisms of these disorders, and especially the fact that they are mediated by IL-1 secretion by stimulated monocytes/macrophages, facilitated significant progress in patient management. IL-1 inhibitors are especially effective, and indeed, a brief and complete response to IL-1 inhibition is probably one of the best signs of auto-inflammation. Cutaneous manifestations are frequent in the monogenic auto-inflammatory syndromes, and a careful analysis of those findings reveals that they are almost always the consequence of neutrophilic skin infiltration. The neutrophilic dermatoses are, therefore, the cutaneous manifestations of those disorders. Even when the neutrophilic dermatoses occur outside the setting of genetically determined auto-inflammatory disorders, they probably also result from auto-inflammatory mechanisms. The distinction between auto-inflammation and autoimmunity is essential for the proper treatment of the patients. Auto-inflammation will almost always respond to IL-1 inhibition, while immunospressors will not be beneficial. The aim of the current paper is to review these two sub-groups of inflammatory diseases, focusing on their cutaneous manifestations, and highlighting the connection between these syndromes and inflammation in general.

  6. Infevers: an evolving mutation database for auto-inflammatory syndromes.

    PubMed

    Touitou, Isabelle; Lesage, Suzanne; McDermott, Michael; Cuisset, Laurence; Hoffman, Hal; Dode, Catherine; Shoham, Nitza; Aganna, Ebun; Hugot, Jean-Pierre; Wise, Carol; Waterham, Hans; Pugnere, Denis; Demaille, Jacques; Sarrauste de Menthiere, Cyril

    2004-09-01

    The Infevers database (http://fmf.igh.cnrs.fr/infevers/) was established in 2002 to provide investigators with access to a central source of information about all sequence variants associated with periodic fevers: Familial Mediterranean fever (FMF), TNF Receptor Associated Periodic Syndrome (TRAPS), Hyper IgD Syndrome (HIDS), Familial Cold Autoinflammatory Syndrome/Muckle-Wells Syndrome/Chronic Infantile Neurological Cutaneous and Articular Syndrome (FCAS/MWS/CINCA). The prototype of this group of disorders is FMF, a recessive disease characterized by recurrent bouts of unexplained inflammation. FMF is the pivotal member of an expanding family of autoinflammatory disorders, a new term coined to describe illnesses resulting from a defect of the innate immune response. Therefore, we decided to extend the Infevers database to genes connected with autoinflammatory diseases. We present here the biological content of the Infevers database, including the introduction of two new entries: Crohn/Blau and Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA syndrome). Infevers has a range of query capabilities, allowing for simple or complex interrogation of the database. Currently, the database contains 291 sequence variants in related genes (MEFV, TNFRSF1A, MVK, CARD15, PSTPIP1, and CIAS1), consisting of published data and personal communications, which has revealed or refined the preferential mutational sites for each gene. This database will continue to evolve in its content and to improve in its presentation.

  7. PASS Syndrome: An IL-1-Driven Autoinflammatory Disease.

    PubMed

    Leuenberger, Mathieu; Berner, Jeanne; Di Lucca, Julie; Fischer, Lara; Kaparos, Nikolaos; Conrad, Curdin; Hohl, Daniel; So, Alexander; Gilliet, Michel

    2016-01-01

    PASS syndrome is a rare inflammatory disease characterized by a chronic-relapsing course of pyoderma gangrenosum, acne vulgaris, hidradenitis suppurativa and ankylosing spondylitis. Here, we describe a case of a patient with spontaneously recurrent purulent skin lesions along with seronegative spondylarthritis consistent with the PASS syndrome. During his disease exacerbation, the patient displayed episodes of fever along with elevated serum levels of interleukin (IL)-1β. Skin lesions were characterized by sterile neutrophilic infiltrates and showed a rapid response to the IL-1 receptor antagonist anakinra (Kineret®) consistent with the autoinflammatory nature of this disease. However, unlike other autoinflammatory diseases such as PAPA and PAPASH, we did not find mutations in the gene PSTPIP1, raising the possibility that other specific mutations in the IL-1 pathway may be involved.

  8. The inherited autoinflammatory syndrome: a decade of discovery.

    PubMed

    Goldfinger, Stephen

    2009-01-01

    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.

  9. Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome and early onset sarcoidosis.

    PubMed

    Caso, Francesco; Costa, Luisa; Rigante, Donato; Vitale, Antonio; Cimaz, Rolando; Lucherini, Orso Maria; Sfriso, Paolo; Verrecchia, Elena; Tognon, Sofia; Bascherini, Vittoria; Galeazzi, Mauro; Punzi, Leonardo; Cantarini, Luca

    2014-12-01

    Blau syndrome (BS) and early onset sarcoidosis (EOS) are, respectively, the familial and sporadic forms of the pediatric granulomatous autoinflammatory disease, which belong to the group of monogenic autoinflammatory syndromes. Both of these conditions are caused by mutations in the NOD2 gene, which encodes the cytosolic NOD2 protein, one of the pivotal molecules in the regulation of innate immunity, primarily expressed in the antigen-presenting cells. Clinical onset of BS and EOS is usually in the first years of life with noncaseating epithelioid granulomas mainly affecting joints, skin, and uveal tract, variably associated with heterogeneous systemic features. The dividing line between autoinflammatory and autoimmune mechanisms is probably not so clear-cut, and the relationship existing between BS or EOS and autoimmune phenomena remains unclear. There is no established therapy for the management of BS and EOS, and the main treatment aim is to prevent ocular manifestations entailing the risk of potential blindness and to avoid joint deformities. Nonsteroidal anti-inflammatory drugs, corticosteroids and immunosuppressive drugs, such as methotrexate or azathioprine, may be helpful; when patients are unresponsive to the combination of corticosteroids and immunosuppressant agents, the tumor necrosis factor-α inhibitor infliximab should be considered. Data on anti-interleukin-1 inhibition with anakinra and canakinumab is still limited and further corroboration is required. The aim of this paper is to describe BS and EOS, focusing on their genetic, clinical, and therapeutic issues, with the ultimate goal of increasing clinicians' awareness of both of these rare but serious disorders.

  10. Bariatric surgery in monogenic and syndromic forms of obesity.

    PubMed

    Alqahtani, Aayed R; Elahmedi, Mohamed; Alqahtani, Yara A

    2014-02-01

    Currently, no topic is more controversial in bariatric surgery than performing these procedures on children with monogenic and syndromic forms of obesity. The medical community and the caregivers of those patients are struggling to find a solution that can alleviate their suffering and save their life. In all forms of obesity, dieting and physical activity do not result in significant weight loss and is associated with a high rate of weight regain. Additionally, effective medical therapy is not available yet. While there is significant debate about the risks and benefits of bariatric surgery in the adolescent population, there is an increasing number of studies that demonstrate the success of this option for the appropriate patients. Similarly, our experience demonstrated the same success not only in normal children and adolescents but also in those with monogenic and syndromic form of obesity.

  11. Autoinflammatory Diseases in Pediatric Dermatology-Part 2: Histiocytic, Macrophage Activation, and Vasculitis Syndromes.

    PubMed

    Hernández-Ostiz, S; Xirotagaros, G; Prieto-Torres, L; Noguera-Morel, L; Torrelo, A

    2017-09-01

    The discovery of new autoinflammatory syndromes and novel mutations has advanced at breakneck speed in recent years. Part 2 of this review focuses on vasculitis syndromes and the group of histiocytic and macrophage activation syndromes. We also include a table showing the mutations associated with these autoinflammatory syndromes and treatment alternatives. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  12. Differentiating PFAPA syndrome from monogenic periodic fevers.

    PubMed

    Gattorno, Marco; Caorsi, Roberta; Meini, Antonella; Cattalini, Marco; Federici, Silvia; Zulian, Francesco; Cortis, Elisabetta; Calcagno, Giuseppina; Tommasini, Alberto; Consolini, Rita; Simonini, Gabriele; Pelagatti, Maria Antonietta; Baldi, Maurizia; Ceccherini, Isabella; Plebani, Alessandro; Frenkel, Joost; Sormani, Maria Pia; Martini, Alberto

    2009-10-01

    To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

  13. Blau syndrome, the prototypic auto-inflammatory granulomatous disease.

    PubMed

    Wouters, Carine H; Maes, Anne; Foley, Kevin P; Bertin, John; Rose, Carlos D

    2014-01-01

    Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the triad of granulomatous polyarthritis, dermatitis and uveitis. This paper reviews briefly the classical clinical features of the disease, as well as more recently described extra-triad symptoms. From an ongoing prospective multicenter study, we provide new data on the natural history of Blau syndrome, focusing on functional status and visual outcome. We also present an update of the range of different NOD2 mutations found in Blau syndrome as well as recent data on morphologic and immunohistochemical characteristics of the Blau granuloma. Finally, emerging insights into pathogenic mechanisms including activation of NOD2 signal transduction, and potential biomarkers of disease activity are discussed.

  14. Pathogenesis of the metabolic syndrome: insights from monogenic disorders.

    PubMed

    Murphy, Rinki; Carroll, Richard W; Krebs, Jeremy D

    2013-01-01

    Identifying rare human metabolic disorders that result from a single-gene defect has not only enabled improved diagnostic and clinical management of such patients, but also has resulted in key biological insights into the pathophysiology of the increasingly prevalent metabolic syndrome. Insulin resistance and type 2 diabetes are linked to obesity and driven by excess caloric intake and reduced physical activity. However, key events in the causation of the metabolic syndrome are difficult to disentangle from compensatory effects and epiphenomena. This review provides an overview of three types of human monogenic disorders that result in (1) severe, non-syndromic obesity, (2) pancreatic beta cell forms of early-onset diabetes, and (3) severe insulin resistance. In these patients with single-gene defects causing their exaggerated metabolic disorder, the primary defect is known. The lessons they provide for current understanding of the molecular pathogenesis of the common metabolic syndrome are highlighted.

  15. Pathogenesis of the Metabolic Syndrome: Insights from Monogenic Disorders

    PubMed Central

    Murphy, Rinki; Carroll, Richard W.; Krebs, Jeremy D.

    2013-01-01

    Identifying rare human metabolic disorders that result from a single-gene defect has not only enabled improved diagnostic and clinical management of such patients, but also has resulted in key biological insights into the pathophysiology of the increasingly prevalent metabolic syndrome. Insulin resistance and type 2 diabetes are linked to obesity and driven by excess caloric intake and reduced physical activity. However, key events in the causation of the metabolic syndrome are difficult to disentangle from compensatory effects and epiphenomena. This review provides an overview of three types of human monogenic disorders that result in (1) severe, non-syndromic obesity, (2) pancreatic beta cell forms of early-onset diabetes, and (3) severe insulin resistance. In these patients with single-gene defects causing their exaggerated metabolic disorder, the primary defect is known. The lessons they provide for current understanding of the molecular pathogenesis of the common metabolic syndrome are highlighted. PMID:23766565

  16. The Relationship between NALP3 and Autoinflammatory Syndromes

    PubMed Central

    Campbell, Lorna; Raheem, Irfan; Malemud, Charles J.; Askari, Ali D.

    2016-01-01

    The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome, which is required for synthesis of interleukin-1β, has been implicated in the pathogenesis of several autoinflammatory syndromes. This review of the literature summarizes the interconnectedness of NALP3 inflammasome with some of these disorders. Familial Mediterranean fever results from a mutation in the Mediterranean fever (MEFV) gene, which encodes the pyrin protein. Previous study results suggest that pyrin suppresses caspase-1 activation, perhaps by competing for the adaptor protein, termed, pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ACS) which therefore interferes with NALP3 inflammasome activation. The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome is constitutively activated in cryopyrin-associated periodic syndromes due to gain-of-function mutations resulting from point mutations within the neuronal apoptosis inhibitor protein/class 2 transcription factor/heterokaryon incompatibility/telomerase-associated protein-1 (NACHT) domain of the NALP3 protein. Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is caused by mutations in the genes encoding proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1). These PSTPIP1 mutants are thought to bind to pyrin causing an increase in the pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ASC) pyroptosome assembly leading to procaspase-1 recruitment and therefore its activation. Hyperimmunoglublinemia D syndrome is caused by mevalonate kinase (MVK) deficiency, which may be affected by protein accumulation that leads to NALP3 inflammasome activation. Tumor necrosis factor receptor–associated periodic syndrome is associated with mutations in the tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene which decreases the level of soluble tumor necrosis

  17. The Relationship between NALP3 and Autoinflammatory Syndromes.

    PubMed

    Campbell, Lorna; Raheem, Irfan; Malemud, Charles J; Askari, Ali D

    2016-05-13

    The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome, which is required for synthesis of interleukin-1β, has been implicated in the pathogenesis of several autoinflammatory syndromes. This review of the literature summarizes the interconnectedness of NALP3 inflammasome with some of these disorders. Familial Mediterranean fever results from a mutation in the Mediterranean fever (MEFV) gene, which encodes the pyrin protein. Previous study results suggest that pyrin suppresses caspase-1 activation, perhaps by competing for the adaptor protein, termed, pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ACS) which therefore interferes with NALP3 inflammasome activation. The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome is constitutively activated in cryopyrin-associated periodic syndromes due to gain-of-function mutations resulting from point mutations within the neuronal apoptosis inhibitor protein/class 2 transcription factor/heterokaryon incompatibility/telomerase-associated protein-1 (NACHT) domain of the NALP3 protein. Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is caused by mutations in the genes encoding proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1). These PSTPIP1 mutants are thought to bind to pyrin causing an increase in the pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ASC) pyroptosome assembly leading to procaspase-1 recruitment and therefore its activation. Hyperimmunoglublinemia D syndrome is caused by mevalonate kinase (MVK) deficiency, which may be affected by protein accumulation that leads to NALP3 inflammasome activation. Tumor necrosis factor receptor-associated periodic syndrome is associated with mutations in the tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene which decreases the level of soluble tumor necrosis factor

  18. [Hereditary systemic autoinflammatory diseases. Part II: cryopyrin-associated periodic syndromes, pediatric systemic granulomatosis and PAPA syndrome].

    PubMed

    Aróstegui, Juan I; Yagüe, Jordi

    2008-03-29

    Hereditary systemic autoinflammatory diseases result from a genetically-based dysregulated inflammatory process, and are clinically characterized by recurrent or persistent systemic inflammatory episodes, which typically occur in the absence of infectious, neoplastic or autoimmune etiology. Elucidation of their molecular basis has enabled the use of genetic analyses to achieve an accurate and definitive diagnosis, and to establish a tailored treatment. The present review is the second and last part of an updated and comprehensive overview of hereditary systemic autoinflammatory diseases, and will introduce persistent, non-periodic autoinflammatory diseases, such as: a) the group of cryopyrin-associated periodic syndromes (CAPS), which includes familial cold-induced autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and CINCA-NOMID syndrome; b) the group of pediatric systemic granulomatosis, which includes both Blau syndrome and early-onset sarcoidosis, and c) the pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome.

  19. The challenge of autoinflammatory syndromes: with an emphasis on hyper-IgD syndrome.

    PubMed

    van der Meer, Jos W M; Simon, Anna

    2016-12-01

    Autoinflammatory syndromes are disorders with an exaggerated inflammatory response, mostly in the absence of an appropriate trigger. Prototypic autoinflammatory syndromes are FMF, hyper-IgD syndrome (also known as mevalonate kinase deficiency), TNF receptor-associated periodic syndrome and cryopyrin-associated periodic syndrome. The clinical phenotypes partly overlap (with fever and acute phase response), but also differ between the various syndromes (e.g. regarding fever pattern, episodic vs chronic inflammation and accompanying clinical signs). In recent years, the genetic basis of quite a number of these relatively rare and mostly hereditary disorders has been elucidated. These genetic defects lead to either enhanced production of inflammatory mediators or to a lack of inhibition of these components of the innate immune system. Among these dysregulated inflammatory mediators, the pro-inflammatory cytokine IL-1β stands out. Hence, targeted treatment with blockers of IL-1 action, such as recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) and mAb against IL-1β has met with impressive clinical results. In this article, hyper-IgD syndrome is discussed in more detail, based on 30 years of experience with this syndrome.

  20. Response to IL-1-receptor antagonist in a child with familial cold autoinflammatory syndrome.

    PubMed

    O'Connell, Susan M; O'Regan, Grainne M; Bolger, Turlough; Hoffman, Hal M; Cant, Andrew; Irvine, Alan D; Watson, Rosemarie M

    2007-01-01

    Familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic, cutaneous, articular syndrome are related disorders associated with mutations in the CIAS1 gene. They appear to represent a continuum of one disease characterized by IL-1-mediated inflammation. Until recently, these conditions have been difficult to treat; however, with the advent of IL-1-receptor antagonist therapy, many reports of successful treatment of patients with these autoinflammatory diseases have emerged in the past 2 years. We describe an 8-year-old girl, diagnosed with Familial cold auto-inflammatory syndrome, confirmed by presence of a novel CIAS1 mutation, who was refractory to symptomatic treatment. As frequent attacks of urticaria and associated arthralgia had a debilitating effect on the child's lifestyle, a trial of IL-1-receptor antagonist (anakinra) was instituted. Dramatic sustained clinical improvement was evident within days and serum amyloid and C-reactive protein levels normalized within a month. Although several authors have reported successful use of this agent in children with chronic infantile neurologic, cutaneous, articular syndrome, we believe ours is the first report of successful treatment with anakinra in a young child with familial cold auto-inflammatory syndrome.

  1. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome.

    PubMed

    Braun-Falco, Markus; Kovnerystyy, Oleksandr; Lohse, Peter; Ruzicka, Thomas

    2012-03-01

    PAPA syndrome is a recently identified hereditary autoinflammatory syndrome clinically characterized by pyogenic arthritis, severe acne, and pyoderma gangrenosum. It is caused by mutations in the PSTPIP1 gene and may be closely linked to the aseptic abscesses syndrome, which has been shown to be associated with CCTG repeat amplification in the promoter region of PSTPIP1. We describe two unrelated patients with a clinical presentation quite similar to, yet distinct from, PAPA syndrome. Both patients had pyoderma gangrenosum and acute or remittent acne conglobata, but, in contrast to PAPA syndrome, lacked any episodes of pyogenic arthritis. Instead, they had suppurative hidradenitis. Mutations in PSTPIP1 exons 1 to 15 were excluded. In the promoter region, an increased repetition of the CCTG microsatellite motif was present on one allele in both patients. Alterations of the most commonly affected exons of the MEFV, NLRP3, and TNFRSF1A genes also were not detectable. One patient was treated with the interleukin (IL)-1 receptor antagonist anakinra and responded well, although without complete remission. This implies that IL-1ß may be of pathogenetic importance. Small number of patients, no gene mutation identified, and unclear efficacy of therapy are limitations. The clinical triad of pyoderma gangrenosum, acne, and suppurative hidradenitis represents a new disease entity within the spectrum of autoinflammatory syndromes, similar to PAPA and aseptic abscesses syndrome. For this disease, we propose the acronym "PASH" syndrome. PASH syndrome may respond to IL-1ß blockade. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  2. Autoinflammatory bone diseases.

    PubMed

    Stern, Sara M; Ferguson, Polly J

    2013-11-01

    Autoinflammatory bone disease is a new branch of autoinflammatory diseases caused by seemingly unprovoked activation of the innate immune system leading to an osseous inflammatory process. The inflammatory bone lesions in these disorders are characterized by chronic inflammation that is typically culture negative with no demonstrable organism on histopathology. The most common autoinflammatory bone diseases in childhood include chronic nonbacterial osteomyelitis (CNO), synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist, and cherubism. In this article, the authors focus on CNO and summarize the distinct genetic autoinflammatory bone syndromes.

  3. Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort.

    PubMed

    Sampson, Matthew G; Gillies, Christopher E; Robertson, Catherine C; Crawford, Brendan; Vega-Warner, Virginia; Otto, Edgar A; Kretzler, Matthias; Kang, Hyun Min

    2016-07-01

    To maximize clinical benefits of genetic screening of patients with nephrotic syndrome (NS) to diagnose monogenic causes, reliably distinguishing NS-causing variants from the background of rare, noncausal variants prevalent in all genomes is vital. To determine the prevalence of monogenic NS in a North American case cohort while accounting for background prevalence of genetic variation, we sequenced 21 implicated monogenic NS genes in 312 participants from the Nephrotic Syndrome Study Network and 61 putative controls from the 1000 Genomes Project (1000G). These analyses were extended to available sequence data from approximately 2500 subjects from the 1000G. A typical pathogenicity filter identified causal variants for NS in 4.2% of patients and 5.8% of subjects from the 1000G. We devised a more stringent pathogenicity filtering strategy, reducing background prevalence of causal variants to 1.5%. When applying this stringent filter to patients, prevalence of monogenic NS was 2.9%; of these patients, 67% were pediatric, and 44% had FSGS on biopsy. The rate of complete remission did not associate with monogenic classification. Thus, we identified factors contributing to inaccurate monogenic classification of NS and developed a more accurate variant filtering strategy. The prevalence and clinical correlates of monogenic NS in this sporadically affected cohort differ substantially from those reported for patients referred for genetic analysis. Particularly in unselected, population-based cases, considering putative causal variants in known NS genes from a probabilistic rather than a deterministic perspective may be more precise. We also introduce GeneVetter, a web tool for monogenic assessment of rare disease.

  4. Anakinra prevents symptoms of familial cold autoinflammatory syndrome and Raynaud's disease.

    PubMed

    Metyas, Samy K; Hoffman, Hal M

    2006-10-01

    Familial cold autoinflammatory syndrome (FCAS) is a rare, hereditary disorder characterized by cold-induced inflammation. We describe the successful longterm treatment of a patient with FCAS with anakinra, an interleukin 1 receptor antagonist (IL-1Ra). The remarkable response of FCAS and associated Raynaud's disease in this patient suggests that IL-1 is an important mediator of these inflammatory diseases. Our report supports increasing evidence that anakinra plays an important role in the treatment of select chronic inflammatory diseases.

  5. Advances in the genetically-complex autoinflammatory diseases

    PubMed Central

    Ombrello, Michael J.

    2015-01-01

    Monogenic diseases usually demonstrate Mendelian inheritance and are caused by highly penetrant genetic variants of a single gene. In contrast, genetically-complex diseases arise from a combination of multiple genetic and environmental factors. The concept of autoinflammation originally emerged from the identification of individual, activating lesions of the innate immune system as the molecular basis of the hereditary periodic fever syndromes. In addition to these rare, monogenic forms of autoinflammation, genetically-complex autoinflammatory diseases like the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, chronic recurrent multifocal osteomyelitis (CRMO), Behçet’s disease, and systemic arthritis also fulfill the definition of autoinflammatory diseases - namely the development of apparently unprovoked episodes of inflammation without identifiable exogenous triggers and in the absence of autoimmunity. Interestingly, investigations of these genetically-complex autoinflammatory diseases have implicated both innate and adaptive immune abnormalities, blurring the line between autoinflammation and autoimmunity. This reinforces the paradigm of concerted innate and adaptive immune dysfunction leading to genetically-complex autoinflammatory phenotypes. PMID:26077134

  6. Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA).

    PubMed

    Israeli, E

    2012-02-01

    Gulf War syndrome (GWS) is a multi-symptom condition comprising a variety of signs and symptoms described in the literature, which not been fully resolved. The various symptoms of the condition include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. In addition, excessive chemical sensitivity and odour intolerance is reported. The aetiology of the condition is unclear, but many reviews and epidemiological analyses suggest association with pyridostigmine bromide (PB), certain vaccination regimes, a variety of possible chemical exposures, including smoke from oil-well fires or depleted uranium from shells, as well as physical and psychological stress. Recently, Shoenfeld et al. suggested that four conditions--siliconosis, macrophagic myofaciitis (MMF), GWS and post-vaccination phenomena--that share clinical and pathogenic resemblances, may be incorporated into common syndrome called 'Autoimmune (Autoinflammatory) Syndrome induced by Adjuvants' (ASIA). Symptoms and signs of the four conditions described by Shoenfeld et al. show that at least eight out of ten main symptoms are in correlation in all four conditions. Namely, myalgia, arthralgias, chronic fatigue, neurological cognitive impairment, gastrointestinal symptoms, respiratory symptoms, skin manifestations and appearance of autoantibodies. Regardless of the aetiology of GWS, be it exposure to environmental factors or chemical drugs, vaccinations or the adjuvants in them, GWS fits well with the definition of ASIA and is included as part of 'Shoenfeld's syndrome'.

  7. Genetic and Epigenetic Determinants in Autoinflammatory Diseases

    PubMed Central

    Álvarez-Errico, Damiana; Vento-Tormo, Roser; Ballestar, Esteban

    2017-01-01

    The concept of autoinflammation has evolved over the past 20 years, beginning with the discovery that mutations in the Mediterranean Fever (MEFV) gene were causative of Familial Mediterranean Fever. Currently, autoinflammatory diseases comprise a wide range of disorders with the common features of recurrent fever attacks, prevalence of hyperreactive innate immune cells, and signs of inflammation that can be systemic or organ specific in the absence of pathogenic infection of autoimmunity. Innate immune cells from the myeloid compartment are the main effectors of uncontrolled inflammation that is caused in great extent by the overproduction of inflammatory cytokines such as IL-1β and IL-18. Defects in several signaling pathways that control innate immune defense, particularly the hyperreactivity of one or more inflammasomes, are at the core of pathologic autoinflammatory phenotypes. Although many of the autoinflammatory syndromes are known to be monogenic, some of them are genetically complex and are impacted by environmental factors. Recently, epigenetic dysregulation has surfaced as an additional contributor to pathogenesis. In the present review, we discuss data that are currently available to describe the contribution of epigenetic mechanisms in autoinflammatory diseases. PMID:28382039

  8. Free circulating interleukin-18 is increased in Schnitzler syndrome: a new autoinflammatory disease?

    PubMed

    Migliorini, Paola; Del Corso, Isabella; Tommasi, Cristina; Boraschi, Diana

    2009-09-01

    Schnitzler syndrome is a rare disease characterised by chronic urticaria and arthralgia. The recent evidence that the IL-1 receptor antagonist IL-1Ra could induce rapid and complete remission of Schnitzler symptoms has pointed to IL-1 as a major pathological factor in this disease. To examine the possibility that Schnitzler syndrome may be considered to be an autoinflammatory disease, in this study we measured the serum levels of IL-18, another cytokine of the IL-1 family that is cleaved by caspase-1, in two recently diagnosed Schnitzler patients before and after treatment with IL-1Ra. In parallel, mRNA expression of IL-1 family cytokines and caspase-1 were assessed in isolated blood monocytes. Treatment with IL-1Ra significantly inhibited IL-1beta gene expression, indicating that IL-1beta activity in Schnitzler syndrome is central to IL-1beta gene upregulation in a type of auto-amplification loop. While no IL-1beta was detected in serum, free circulating IL-18 was increased in patients with Schnitzler syndrome, despite low IL-18 gene expression in monocytes. This suggests constitutive activation of the IL-1beta/IL-18-producing inflammasome, and supports the hypothesis that Schnitzler's syndrome is a new autoinflammatory disease.

  9. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep.

    PubMed

    Luján, Lluís; Pérez, Marta; Salazar, Eider; Álvarez, Neila; Gimeno, Marina; Pinczowski, Pedro; Irusta, Silvia; Santamaría, Jesús; Insausti, Nerea; Cortés, Yerzol; Figueras, Luis; Cuartielles, Isabel; Vila, Miguel; Fantova, Enrique; Chapullé, José Luis Gracia

    2013-07-01

    We describe a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep, linked to the repetitive inoculation of aluminum-containing adjuvants through vaccination. The syndrome shows an acute phase that affects less than 0.5% of animals in a given herd, it appears 2-6 days after an adjuvant-containing inoculation and it is characterized by an acute neurological episode with low response to external stimuli and acute meningoencephalitis, most animals apparently recovering afterward. The chronic phase is seen in a higher proportion of flocks, it can follow the acute phase, and it is triggered by external stimuli, mostly low temperatures. The chronic phase begins with an excitatory phase, followed by weakness, extreme cachexia, tetraplegia and death. Gross lesions are related to a cachectic process with muscular atrophy, and microscopic lesions are mostly linked to a neurodegenerative process in both dorsal and ventral column of the gray matter of the spinal cord. Experimental reproduction of ovine ASIA in a small group of repeatedly vaccinated animals was successful. Detection of Al(III) in tissues indicated the presence of aluminum in the nervous tissue of experimental animals. The present report is the first description of a new sheep syndrome (ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can have devastating consequences as it happened after the compulsory vaccination against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of other similar diseases affecting both human and animals. A major research effort is needed in order to understand its complex pathogenesis.

  10. Acute coronary syndromes as auto-inflammatory disorders.

    PubMed

    Suzuki, Makoto

    2012-01-01

    From the onset to the healing stage of acute coronary syndromes, an endless inflammation has been presented with complex, multiple cross-talk mechanisms at the molecular, cellular, and organ levels. Even though the early reperfusion treatment either by thrombolysis or percutaneous coronary intervention provides the excellent clinical benefits in patients with acute coronary syndromes, ischemia/ reperfusion injury may somewhat offset those great advantages. Inflammation, although potentially protective, has been deeply associated with those detrimental conditions. The hexagonal vascular inflammatory network which is composed of activated various leukocytes, vascular endothelial cells, vascular smooth muscle cells, platelets, excess reactive oxygen species, and cholesterol may contribute these vicious circles. To address these complex syndromes with more benefits regarding the prevention and treatment, this review comprehensively updates the pathogenesis of acute coronary syndromes from the view points of vascular inflammation.

  11. A Novel Model for IFN-γ–Mediated Autoinflammatory Syndromes

    PubMed Central

    Reinhardt, R. Lee; Liang, Hong-Erh; Bao, Katherine; Price, April E.; Mohrs, Markus; Kelly, Ben L.

    2015-01-01

    Autoinflammatory disease and hyperinflammatory syndromes represent a growing number of diseases associated with inappropriately controlled inflammation in multiple organs. Systemic inflammation commonly results from dysregulated activation of innate immune cells, and therapeutic targeting of the IL-1β pathway has been used to ameliorate some of these diseases. Some hyperinflammatory syndromes, however, such as hemophagocytic lymphohistiocytosis and the newly classified proteasome disability syndromes, are refractory to such treatments, suggesting that other factors or environmental stressors may be contributing. In comparing two cytokine reporter mouse strains, we identify IFN-γ as a mediator of systemic autoinflammatory disease. Chronically elevated levels of IFN-γ resulted in progressive multiorgan inflammation and two copies of the mutant allele resulted in increased mortality accompanied by myeloproliferative disease. Disease was alleviated by genetic deletion of T-bet. These studies raise the possibility that therapeutics targeting the IFN-γ pathway might be effective in hyperinflammatory conditions refractory to IL-1β–targeted therapies. PMID:25637019

  12. Validation of the Auto-Inflammatory Diseases Activity Index (AIDAI) for hereditary recurrent fever syndromes

    PubMed Central

    Piram, Maryam; Koné-Paut, Isabelle; Lachmann, Helen J; Frenkel, Joost; Ozen, Seza; Kuemmerle-Deschner, Jasmin; Stojanov, Silvia; Simon, Anna; Finetti, Martina; Sormani, Maria Pia; Martini, Alberto; Gattorno, Marco; Ruperto, Nicolino

    2014-01-01

    Objectives To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary recurrent fever syndromes (HRFs): familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS). Methods In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient's disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0–175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%). Conclusions The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials. PMID:24026675

  13. Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

    PubMed

    Grillo, Elisa; Lo Rizzo, Caterina; Bianciardi, Laura; Bizzarri, Veronica; Baldassarri, Margherita; Spiga, Ottavia; Furini, Simone; De Felice, Claudio; Signorini, Cinzia; Leoncini, Silvia; Pecorelli, Alessandra; Ciccoli, Lucia; Mencarelli, Maria Antonietta; Hayek, Joussef; Meloni, Ilaria; Ariani, Francesca; Mari, Francesca; Renieri, Alessandra

    2013-01-01

    Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

  14. Revealing the Complexity of a Monogenic Disease: Rett Syndrome Exome Sequencing

    PubMed Central

    Grillo, Elisa; Lo Rizzo, Caterina; Bianciardi, Laura; Bizzarri, Veronica; Baldassarri, Margherita; Spiga, Ottavia; Furini, Simone; De Felice, Claudio; Signorini, Cinzia; Leoncini, Silvia; Pecorelli, Alessandra; Ciccoli, Lucia; Mencarelli, Maria Antonietta; Hayek, Joussef; Meloni, Ilaria; Ariani, Francesca; Mari, Francesca; Renieri, Alessandra

    2013-01-01

    Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought. PMID:23468869

  15. No shortcuts: new findings reinforce why nuance is the rule in genetic autoinflammatory syndromes.

    PubMed

    Tsoukas, Paul; Canna, Scott W

    2017-09-01

    Practitioners dazed by the evolving concept of autoinflammation are in good company. Despite the clinical challenges autoinflammatory patients present, their study has been fundamental to our understanding of basic human inflammation. This review will focus on the ways in which recent discoveries in genetically mediated autoinflammation broaden and refine the concept. Major developments in pyrin inflammasome biology, defective ubiquitination, and the hyperferritinemic syndromes will be highlighted. We offer a brief discussion of discordance, convergence, genotype, and phenotype in autoinflammation. Additionally, we introduce the concepts of mutation dose effect and hybrid nomenclature. Overall, we hope to provide an update on developments in the field of autoinflammation, some conceptual tools to help navigate the rising tide of discovery, and some encouragement that keeping up with developments in autoinflammation is both exciting and necessary.

  16. Screening for hormonal, monogenic, and syndromic disorders in obese infants and children.

    PubMed

    Mason, Kelly; Page, Laura; Balikcioglu, Pinar Gumus

    2014-09-01

    The prevalence of pediatric obesity in the United States is nearly 17%. Most cases are "exogenous", resulting from excess energy intake relative to energy expenditure over a prolonged period of time. However, some cases of obesity are "endogenous", associated with hormonal, genetic, or syndromic disorders such as hypothyroidism, Cushing's syndrome, growth hormone deficiency, defective leptin signaling, mutations in the melanocortin 4 receptor, and Prader-Willi and Bardet-Biedl syndromes. This article reviews the hormonal, monogenic, and syndromic causes of childhood obesity and identifies critical features that distinguish "endogenous" obesity disorders from the more common exogenous obesity. Findings that raise suspicion for endogenous obesity include onset in infancy, lack of satiety, poor linear growth, dysmorphic features, and cognitive dysfunction. Selection and interpretation of appropriate laboratory tests and indications for subspecialist referral are also discussed.

  17. Screening for Hormonal, Monogenic, and Syndromic Disorders in Obese Infants and Children

    PubMed Central

    Mason, Kelly; Page, Laura; Balikcioglu, Pinar Gumus

    2015-01-01

    The prevalence of pediatric obesity in the United States is nearly 17%. Most cases are “exogenous”, resulting from excess energy intake relative to energy expenditure over a prolonged period of time. However, some cases of obesity are “endogenous”, associated with hormonal, genetic, or syndromic disorders such as hypothyroidism, Cushing’s syndrome, growth hormone deficiency, defective leptin signaling, mutations in the melanocortin 4 receptor, and Prader-Willi and Bardet-Biedl syndromes. This article reviews the hormonal, monogenic, and syndromic causes of childhood obesity and identifies critical features that distinguish “endogenous” obesity disorders from the more common exogenous obesity. Findings that raise suspicion for endogenous obesity include onset in infancy, lack of satiety, poor linear growth, dysmorphic features, and cognitive dysfunction. Selection and interpretation of appropriate laboratory tests and indications for subspecialist referral are also discussed. PMID:25198446

  18. The sick building syndrome as a part of the autoimmune (auto-inflammatory) syndrome induced by adjuvants.

    PubMed

    Israeli, Eitan; Pardo, Asher

    2011-06-01

    Sick building syndrome (SBS) is a term coined for a set of clinically recognizable symptoms and ailments without a clear cause reported by occupants of a building. In the 1990s the term "functional somatic syndromes" was applied to several syndromes, including SBS, multiple chemical sensitivity, repetition stress injury, the side effects of silicone breast implants, the Gulf War syndrome (GWS), chronic fatigue syndrome, the irritable bowel syndrome, and fibromyalgia. Recently, Shoenfeld and Agmon-Levin suggested that four conditions--siliconosis, macrophagic myofascitis, the GWS, and post-vaccination phenomena--which share clinical and pathogenic resemblances, may be included under a common syndrome entitled the "autoimmune (auto-inflammatory) syndrome induced by adjuvants". Comparison of the clinical manifestations, symptoms, and signs of the four conditions described by Shoenfeld and Agmon-Levin with those described for SBS shows that nine out of ten main symptoms are present in all 5 conditions. Shoenfeld and Agmon-Levin further propose several major and minor criteria, which, although requiring further validation, may aid in the diagnosis of this newly defined syndrome. We propose here that SBS may also be included as a part of "Shoenfeld's syndrome".

  19. Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept.

    PubMed

    Cruz-Tapias, Paola; Agmon-Levin, Nancy; Israeli, Eitan; Anaya, Juan-Manuel; Shoenfeld, Yehuda

    2013-01-01

    ASIA syndrome, "Autoimmune (Auto-inflammatory) Syndromes Induced by Adjuvants" includes at least four conditions which share a similar complex of signs and symptoms and have been defined by hyperactive immune responses: siliconosis, macrophagic myofasciitis syndrome, Gulf war syndrome and post-vaccination phenomena. Exposure to adjuvants has been documented in these four medical conditions, suggesting that the common denominator to these syndromes is a trigger entailing adjuvant activity. An important role of animal models in proving the ASIA concept has been established. Experimentally animal models of autoimmune diseases induced by adjuvants are currently widely used to understand the mechanisms and etiology and pathogenesis of these diseases and might thus promote the development of new diagnostic, predictive and therapeutic methods. In the current review we wish to unveil the variety of ASIA animal models associated with systemic and organ specific autoimmune diseases induced by adjuvants. We included in this review animal models for rheumatoid arthritis-like disease, for systemic lupus erythematosus-like disease, autoimmune thyroid disease-like disease, antiphospholipid syndrome, myocarditis and others. All these models support the concept of ASIA, as the Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants.

  20. Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus.

    PubMed

    Kim, Hanna; Sanchez, Gina A Montealegre; Goldbach-Mansky, Raphaela

    2016-10-01

    Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of "autoinflammatory" and "autoimmune" interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.

  1. Inflammasome mediated autoinflammatory disorders

    PubMed Central

    Wilson, Shruti P.; Cassel, Suzanne L.

    2013-01-01

    The nucleotide-binding domain leucine-rich repeat containing (NLR) family of receptors are members of the innate immune system with a critical role in host defense. These molecules are key to driving inflammatory responses to abnormal cellular conditions. A number of the NLRs serve this role upon activation by forming a multi-protein complex called an inflammasome. The inflammasome drives the processing and release of cytokines such as the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. The important function of NLR molecules in autoinflammatory disorders has recently been recognized in part through the identification of the role of IL-1β in pathogenesis of several autoinflammatory diseases. Cryopyrin-associated periodic syndromes (CAPS) were the first autoinflammatory disorders found to be directly mediated by dysfunctional inflammasome activation. This finding has subsequently led to studies in both murine models and humans that have revealed several other inflammatory conditions associated with activation of NLR containing inflammasomes. Understanding of the molecular pathophysiology of these autoinflammatory disorders has further guided the successful development of targeted therapy against IL-1. In this review, we will provide an overview of the inflammasomes and describe the important role they play in the development and manifestations of autoinflammatory diseases. PMID:20861596

  2. Modeling Monogenic Human Nephrotic Syndrome in the Drosophila Garland Cell Nephrocyte.

    PubMed

    Hermle, Tobias; Braun, Daniela A; Helmstädter, Martin; Huber, Tobias B; Hildebrandt, Friedhelm

    2017-05-01

    Steroid-resistant nephrotic syndrome is characterized by podocyte dysfunction. Drosophila garland cell nephrocytes are podocyte-like cells and thus provide a potential in vivo model in which to study the pathogenesis of nephrotic syndrome. However, relevant pathomechanisms of nephrotic syndrome have not been studied in nephrocytes. Here, we discovered that two Drosophila slit diaphragm proteins, orthologs of the human genes encoding nephrin and nephrin-like protein 1, colocalize within a fingerprint-like staining pattern that correlates with ultrastructural morphology. Using RNAi and conditional CRISPR/Cas9 in nephrocytes, we found this pattern depends on the expression of both orthologs. Tracer endocytosis by nephrocytes required Cubilin and reflected size selectivity analogous to that of glomerular function. Using RNAi and tracer endocytosis as a functional read-out, we screened Drosophila orthologs of human monogenic causes of nephrotic syndrome and observed conservation of the central pathogenetic alterations. We focused on the coenzyme Q10 (CoQ10) biosynthesis gene Coq2, the silencing of which disrupted slit diaphragm morphology. Restoration of CoQ10 synthesis by vanillic acid partially rescued the phenotypic and functional alterations induced by Coq2-RNAi. Notably, Coq2 colocalized with mitochondria, and Coq2 silencing increased the formation of reactive oxygen species (ROS). Silencing of ND75, a subunit of the mitochondrial respiratory chain that controls ROS formation independently of CoQ10, phenocopied the effect of Coq2-RNAi. Moreover, the ROS scavenger glutathione partially rescued the effects of Coq2-RNAi. In conclusion, Drosophila garland cell nephrocytes provide a model with which to study the pathogenesis of nephrotic syndrome, and ROS formation may be a pathomechanism of COQ2-nephropathy. Copyright © 2017 by the American Society of Nephrology.

  3. The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders

    PubMed Central

    2014-01-01

    Background Angelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep disorders, and seizures. The disorder is caused by loss of central nervous system expression of UBE3A, a gene encoding a ubiquitin ligase. Current treatments focus on the management of symptoms, as there have not been therapies to treat the underlying molecular cause of the disease. However, this outlook is evolving with advances in molecular therapies, including artificial transcription factors a class of engineered DNA-binding proteins that have the potential to target a specific site in the genome. Results Here we review the recent progress and prospect of targeted gene expression therapies. Three main issues that must be addressed to advance toward human clinical trials are specificity, toxicity, and delivery. Conclusions Artificial transcription factors have the potential to address these concerns on a level that meets and in some cases exceeds current small molecule therapies. We examine the possibilities of such approaches in the context of Angelman syndrome, as a template for other single-gene, neurologic disorders. PMID:24946931

  4. Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives.

    PubMed

    Lopalco, Giuseppe; Cantarini, Luca; Vitale, Antonio; Iannone, Florenzo; Anelli, Maria Grazia; Andreozzi, Laura; Lapadula, Giovanni; Galeazzi, Mauro; Rigante, Donato

    2015-01-01

    A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet's disease, gout, Sjögren's syndrome, interstitial lung diseases, and Still's disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems.

  5. Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome?

    PubMed

    Meroni, Pier Luigi

    2011-02-01

    There has been considerable interest in the role of environmental factors and the induction of autoimmunity and the ways by which they facilitate loss of tolerance. Clearly both genetic and environmental factors are incriminated, as evidenced by the lack of concordance in identical twins and the relatively recent identification of the shared epitope in rheumatoid arthritis. In this issue a new syndrome called 'Asia'-autoimmune/auto-inflammatory syndrome induced by adjuvants has been proposed. It is an intriguing issue and one that is likely to be provocative and lead to further biologic and molecular investigations.

  6. [Fever of unknown cause and autoinflammatory disease].

    PubMed

    Hara, Toshiro

    2011-09-01

    Autoinflammatory diseases are often associated with various kinds of febrile episodes such as fever of unknown origin, periodic fever and recurrent fever. Therefore, in the differential diagnosis of fever of unknown cause, autoinflammatory diseases should be considered after exclusion of infections, malignancy and autoimmune diseases. As autoinflammatory diseases now include TRAPS (TNF receptor-associated periodic syndrome), CAPS (cryopyrin -associated periodic syndromes), FMF(familial Mediterranean fever), MAPS (mevalonate kinase-associated periodic fever syndrome, hyper-IgD syndrome) and many others, and show symptoms and signs of wide variations, we need to make an accurate diagnosis of them to prevent possible complications such as amyloidosis.

  7. Monogenic human obesity.

    PubMed

    Farooqi, I Sadaf

    2008-01-01

    We and others have identified several single gene defects that disrupt the molecules in the leptinmelanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterisation of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.

  8. Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome

    PubMed Central

    Marzano, A V; Fanoni, D; Antiga, E; Quaglino, P; Caproni, M; Crosti, C; Meroni, P L; Cugno, M

    2014-01-01

    Pyoderma gangrenosum (PG) and Sweet's syndrome (SS) are two inflammatory skin diseases presenting with painful ulcers and erythematous plaques, respectively; both disorders have a debilitating clinical behaviour and PG is potentially life-threatening. Recently, PG and SS have been included among the autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. However, an autoinflammatory pattern clearly supporting this inclusion has never been demonstrated. We studied 16 patients with PG, six with SS and six controls, evaluating, using a sandwich-based protein antibody array method, the expression profile of inflammatory effector molecules in PG, SS and normal skin. The expressions of interleukin (IL)-1 beta and its receptor I were significantly higher in PG (P = 0·0001 for both) and SS (P = 0·004–0·040) than in controls. In PG, chemokines such as IL-8 (P = 0·0001), chemokine (C-X-C motif) ligand (CXCL) 1/2/3 (P = 0·002), CXCL 16 (P = 0·003) and regulated upon activation normal T cell expressed and secreted (RANTES) (P = 0·005) were over-expressed. In SS, IL-8 (P = 0·018), CXCL 1/2/3 (P = 0·006) and CXCL 16 (P = 0·036) but not RANTES were over-expressed, suggesting that chemokine-mediated signals are lower than in PG. Fas/Fas ligand and CD40/CD40 ligand systems were over-expressed in PG (P = 0·0001 for Fas, P = 0·009 for Fas ligand, P = 0·012 for CD40, P = 0·0001 for CD40 ligand), contributing to tissue damage and inflammation, while their role seems to be less significant in SS. Over-expression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that PG and SS are autoinflammatory diseases. The differences in expression profile of inflammatory effectors between these two disorders may explain the stronger local aggressiveness in PG than SS. PMID:24903614

  9. Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)

    PubMed Central

    2013-01-01

    Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated. PMID:24359092

  10. Monogenic Diabetes

    MedlinePlus

    ... gene. In contrast, the most common types of diabetes—type 1 and type 2—are caused by multiple genes ( ... some children with monogenic diabetes are misdiagnosed with type 1 diabetes and are given insulin. When correctly diagnosed, some ...

  11. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early onset autoinflammatory syndrome

    PubMed Central

    Zhou, Qing; Wang, Hongying; Schwartz, Daniella M.; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J.; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T.; Zaal, Kristien; Chandrasekharappa, Settara C.; Hanson, Eric P.; Yu, Zhen; Mullikin, James C.; Hasni, Sarfaraz A.; Wertz, Ingrid; Ombrello, Amanda K.; Stone, Deborah L.; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K.; Leavis, Helen L.; van Royen-Kerkof, Annet; Sibley, Cailin; Batu, Ezgi D.; Gül, Ahmet; Siegel, Richard M.; Boehm, Manfred; Milner, Joshua D.; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M.; Kastner, Daniel L.; Aksentijevich, Ivona

    2016-01-01

    Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity1. Herein we describe a new syndrome caused by high penetrance heterozygous germline mutations in the NFκB regulatory protein TNFAIP3 (A20) in six unrelated families with early onset systemic inflammation. The syndrome resembles Behçet’s disease (BD), which is typically considered a polygenic disorder with onset in early adulthood2. A20 is a potent inhibitor of the NFκB signaling pathway3. TNFAIP3 mutant truncated proteins are likely to act by haploinsufficiency since they do not exert a dominant-negative effect in overexpression experiments. Patients’ cells show increased degradation of IκBα and nuclear translocation of NFκB p65, and increased expression of NFκB-mediated proinflammatory cytokines. A20 restricts NFκB signals via deubiquitinating (DUB) activity. In cells expressing the mutant A20 protein, there is defective removal of K63-linked ubiquitin from TRAF6, NEMO, and RIP1 after TNF stimulation. NFκB-dependent pro-inflammatory cytokines are potential therapeutic targets for these patients. PMID:26642243

  12. Fever tree revisited: From malaria to autoinflammatory diseases.

    PubMed

    Pastore, Serena; Vuch, Josef; Bianco, Anna Monica; Taddio, Andrea; Tommasini, Alberto

    2015-11-08

    Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.

  13. Fever tree revisited: From malaria to autoinflammatory diseases

    PubMed Central

    Pastore, Serena; Vuch, Josef; Bianco, Anna Monica; Taddio, Andrea; Tommasini, Alberto

    2015-01-01

    Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today’s periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin. PMID:26566482

  14. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder.

    PubMed

    Wise, Carol A; Gillum, Joseph D; Seidman, Christine E; Lindor, Noralane M; Veile, Rose; Bashiardes, Stavros; Lovett, Michael

    2002-04-15

    PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne, OMIM #604416) and familial recurrent arthritis (FRA) are rare inherited disorders of early onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction. We recently localized the genes for PAPA syndrome and FRA to chromosome 15q and suggested that they are the same disorder. We have now established this by the identification of co-segregating disease-causing mutations in the CD2-binding protein 1 (CD2BP1; GenBank accession no XM 044569) gene in the two reported families with this disorder. E250Q or A230T amino acid substitutions occur within a domain highly homologous to yeast cleavage furrow-associated protein CDC15. CD2BP1 and its murine ortholog, proline-serine-threonine phosphatase interacting protein (PSTPIP1), are adaptor proteins known to interact with PEST-type protein tyrosine phosphatases (PTP). Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins. Previous evidence supports the integral role of CD2BP1 and its interacting proteins in actin reorganization during cytoskeletal-mediated events. We hypothesize that the disease-causing mutations that we have identified compromise physiologic signaling necessary for the maintenance of proper inflammatory response. Accordingly we suggest classification of PAPA syndrome as an autoinflammatory disease. This CD2BP1-mediated biochemical pathway(s) may function in common inflammatory disorders with apparent etiological overlap, such as rheumatoid arthritis and inflammatory bowel disease.

  15. Monogenic diabetes syndromes: Locus‐specific databases for Alström, Wolfram, and Thiamine‐responsive megaloblastic anemia

    PubMed Central

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu‐Wai‐Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian‐Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis‐Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard

    2017-01-01

    Abstract We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. PMID:28432734

  16. Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

    PubMed

    Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu-Wai-Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian-Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis-Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard; Barrett, Timothy G

    2017-07-01

    We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org. © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  17. Shared functional defect in IP3R-mediated calcium signaling in diverse monogenic autism syndromes

    PubMed Central

    Schmunk, G; Boubion, B J; Smith, I F; Parker, I; Gargus, J J

    2015-01-01

    Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca2+ signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD—fragile X and tuberous sclerosis TSC1 and TSC2 syndromes—display depressed Ca2+ release through inositol trisphosphate receptors (IP3Rs). This was apparent in Ca2+ signals evoked by G protein-coupled receptors and by photoreleased IP3 at the levels of both global and local elementary Ca2+ events, suggesting fundamental defects in IP3R channel activity in ASD. Given the ubiquitous involvement of IP3R-mediated Ca2+ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP3R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca2+ screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD. PMID:26393489

  18. Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) Syndrome in Iranian Children First Report of Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR)

    PubMed Central

    Mehregan, Fatemeh Fereshteh; Ziaee, Vahid; Ahmadinejad, Zahra; Tahghighi, Fatemeh; Sabouni, Farah; Moradinejad, Mohamad-Hassan

    2014-01-01

    Objective: The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a nonhereditary idiopathic febrile syndrome belonging to the group of autoinflammatory diseases. No longtime sequel was reported in this disease. Early diagnosis can lead physicians to treatment of this disorder with a short course steroid application and provide satisfaction of the patient’s family. Methods: This study is a prospective review of patients diagnosed with PFAPA syndrome who were registered in Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR) through periodic fever clinic in the Children's Medical Center, Pediatric Center of Excellence in Tehran, Iran from January 2013 to March 2014. Findings: One hundred thirty patients were registered in our databases. Twenty-one (16.1%) patients including 15 males and 6 females had PFAPA. Normal growth was seen in all patients. The median age at onset was 18 months. The mean duration of fever was 4 days and the mean duration of intervals between fever episodes 21 days. Along with fever, all patients had characteristic symptoms. All patients were asymptomatic between fever episodes. Steroid was used in all patients and causing immediate reduction by 84.61%. Two patients received both steroid and colchicine because of their clinical feature and positive laboratory tests for PFAPA and familial Mediterranean fever. No patient received biological therapy or a tonsillectomy. Conclusion: The long diagnostic delay of PFAPA gives cause to concern indicating a need for greater awareness of the disease so that the diagnosis may be made timely. PMID:25793068

  19. Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) Syndrome in Iranian Children First Report of Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR).

    PubMed

    Mehregan, Fatemeh Fereshteh; Ziaee, Vahid; Ahmadinejad, Zahra; Tahghighi, Fatemeh; Sabouni, Farah; Moradinejad, Mohamad-Hassan

    2014-10-01

    The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a nonhereditary idiopathic febrile syndrome belonging to the group of autoinflammatory diseases. No longtime sequel was reported in this disease. Early diagnosis can lead physicians to treatment of this disorder with a short course steroid application and provide satisfaction of the patient's family. This study is a prospective review of patients diagnosed with PFAPA syndrome who were registered in Iranian Periodic Fever and Autoinflammatory Registry (IPFAIR) through periodic fever clinic in the Children's Medical Center, Pediatric Center of Excellence in Tehran, Iran from January 2013 to March 2014. One hundred thirty patients were registered in our databases. Twenty-one (16.1%) patients including 15 males and 6 females had PFAPA. Normal growth was seen in all patients. The median age at onset was 18 months. The mean duration of fever was 4 days and the mean duration of intervals between fever episodes 21 days. Along with fever, all patients had characteristic symptoms. All patients were asymptomatic between fever episodes. Steroid was used in all patients and causing immediate reduction by 84.61%. Two patients received both steroid and colchicine because of their clinical feature and positive laboratory tests for PFAPA and familial Mediterranean fever. No patient received biological therapy or a tonsillectomy. The long diagnostic delay of PFAPA gives cause to concern indicating a need for greater awareness of the disease so that the diagnosis may be made timely.

  20. Involvement of chronic epipharyngitis in autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA).

    PubMed

    Hotta, Osamu; Tanaka, Ayaki; Torigoe, Akira; Imai, Kazuaki; Ieiri, Norio

    2016-09-03

    The epipharynx is an immunologically active site even under normal conditions, and enhanced immunologic activation is prone to occur in response to an upper respiratory infection, air pollution, and possibly to vaccine adjuvants. Due to the potential link between the central nervous system and immune function, a relationship between epipharyngitis and autonomic nervous disturbance as well as autoimmune disease has been suggested. Various functional somatic symptoms have been described after human papillomavirus (HPV) vaccination, although a causal relationship has not been established. We examined the epipharynx in young women showing functional somatic symptoms following HPV vaccination. Surprisingly, despite having minimal symptoms involving the pharynx, all patients were found to have severe epipharyngitis. In addition, significant improvement in symptoms was seen in most patients who underwent epipharyngeal treatment. Thus, we speculate that the chronic epipharyngitis potentially caused by the vaccine adjuvant may be involved in the pathogenesis of functional somatic syndrome (FSS) post-HPV vaccination. Further, we suggest that epipharyngeal treatment may be effective for various types of FSS regardless of the initial cause, as well as for some autoimmune diseases, and that this may be an important direction in future research.

  1. Interleukin-1 as a Common Denominator from Autoinflammatory to Autoimmune Disorders: Premises, Perils, and Perspectives

    PubMed Central

    Lopalco, Giuseppe; Cantarini, Luca; Vitale, Antonio; Iannone, Florenzo; Anelli, Maria Grazia; Andreozzi, Laura; Lapadula, Giovanni; Galeazzi, Mauro; Rigante, Donato

    2015-01-01

    A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet's disease, gout, Sjögren's syndrome, interstitial lung diseases, and Still's disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems. PMID:25784780

  2. Autoinflammatory Diseases with Periodic Fevers.

    PubMed

    Sag, Erdal; Bilginer, Yelda; Ozen, Seza

    2017-07-01

    One purpose of this review was to raise awareness for the new autoinflammatory syndromes. These diseases are increasingly recognized and are in the differential diagnosis of many disease states. We also aimed to review the latest recommendations for the diagnosis, management, and treatment of these patients. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), and hyperimmunoglobulinemia D and periodic fever syndrome/mevalonate kinase deficiency (HIDS/MVKD) are the more common autoinflammatory diseases that are characterized by periodic fevers and attacks of inflammation. Recently much collaborative work has been done to understand the characteristics of these patients and to develop recommendations to guide the physicians in the care of these patients. These recent recommendations will be summarized for all four diseases. FMF is the most common periodic fever disease. We need to further understand the pathogenesis and the role of single mutations in the disease. Recently, the management and treatment of the disease have been nicely reviewed. CAPS is another interesting disease associated with severe complications. Anti-interleukin-1 (anti-IL-1) treatment provides cure for these patients. TRAPS is characterized by the longest delay in diagnosis; thus, both pediatricians and internists should be aware of the characteristic features and the follow-up of these patients. HIDS/MVKD is another autoinflammatory diseases characterized with fever attacks. The spectrum of disease manifestation is rather large in this disease, and we need further research on biomarkers for the optimal management of these patients.

  3. Rapid Detection of Monogenic Causes of Childhood-Onset Steroid-Resistant Nephrotic Syndrome

    PubMed Central

    Lovric, Svjetlana; Fang, Humphrey; Vega-Warner, Virginia; Sadowski, Carolin E.; Gee, Heon Yung; Halbritter, Jan; Ashraf, Shazia; Saisawat, Pawaree; Soliman, Neveen A.; Kari, Jameela A.; Otto, Edgar A.

    2014-01-01

    Background and objectives In steroid-resistant nephrotic syndrome (SRNS), >21 single-gene causes are known. However, mutation analysis of all known SRNS genes is time and cost intensive. This report describes a new high-throughput method of mutation analysis using a PCR-based microfluidic technology that allows rapid simultaneous mutation analysis of 21 single-gene causes of SRNS in a large number of individuals. Design, setting, participants, & measurements This study screened individuals with SRNS; samples were submitted for mutation analysis from international sources between 1996 and 2012. For proof of principle, a pilot cohort of 48 individuals who harbored known mutations in known SRNS genes was evaluated. After improvements to the method, 48 individuals with an unknown cause of SRNS were then examined in a subsequent diagnostic study. The analysis included 16 recessive SRNS genes and 5 dominant SRNS genes. A 10-fold primer multiplexing was applied, allowing PCR-based amplification of 474 amplicons in 21 genes for 48 DNA samples simultaneously. Forty-eight individuals were indexed in a barcode PCR, and high-throughput sequencing was performed. All disease-causing variants were confirmed via Sanger sequencing. Results The pilot study identified the genetic cause of disease in 42 of 48 (87.5%) of the affected individuals. The diagnostic study detected the genetic cause of disease in 16 of 48 (33%) of the affected individuals with a previously unknown cause of SRNS. Seven novel disease-causing mutations in PLCE1 (n=5), NPHS1 (n=1), and LAMB2 (n=1) were identified in <3 weeks. Use of this method could reduce costs to 1/29th of the cost of Sanger sequencing. Conclusion This highly parallel approach allows rapid (<3 weeks) mutation analysis of 21 genes known to cause SRNS at a greatly reduced cost (1/29th) compared with traditional mutation analysis techniques. It detects mutations in about 33% of childhood-onset SRNS cases. PMID:24742477

  4. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA).

    PubMed

    Agmon-Levin, Nancy; Zafrir, Yaron; Kivity, Shaye; Balofsky, Ari; Amital, Howard; Shoenfeld, Yehuda

    2014-12-01

    The objectives of this study were to gather information regarding demographic and clinical characteristics of patients diagnosed with either fibromyalgia (FM) or chronic fatigue (CFS) following hepatitis B vaccination (HBVv) and furthermore to apply the recently suggested criteria of autoimmune (auto-inflammatory) syndromes induced by adjuvants (ASIA), in the aim of identifying common characteristics that may suggest an association between fibromyalgia, chronic fatigue and HBV vaccination. Medical records of 19 patients with CFS and/or fibromyalgia following HBVv immunization were analyzed. All of which were immunized during 1990-2008 in different centers in the USA. All medical records were evaluated for demographics, medical history, the number of vaccine doses, as well as immediate and long term post-immunization adverse events and clinical manifestations. In addition, available blood tests, imaging results, treatments and outcomes were analyzed. ASIA criteria were applied to all patients. The mean age of patients was 28.6 ± 11 years, of which 68.4 % were females. 21.05 % had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBVv to onset of symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1 %) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2 %), musculoskeletal (78.9 %), psychiatric (63.1 %), fatigue (63.1 %), gastrointestinal complains (58 %) and mucocutaneous manifestations (36.8 %). Autoantibodies were detected in 71 % of patients tested. All patients fulfilled the ASIA criteria. This study suggests that in some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome. The appearance of adverse event during immunization, the presence of autoimmune susceptibility and higher titers of autoantibodies all can be suggested as risk

  5. A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis).

    PubMed

    Grandemange, Sylvie; Sanchez, Elodie; Louis-Plence, Pascale; Tran Mau-Them, Frédéric; Bessis, Didier; Coubes, Christine; Frouin, Eric; Seyger, Marieke; Girard, Manon; Puechberty, Jacques; Costes, Valérie; Rodière, Michel; Carbasse, Aurélia; Jeziorski, Eric; Portales, Pierre; Sarrabay, Guillaume; Mondain, Michel; Jorgensen, Christian; Apparailly, Florence; Hoppenreijs, Esther; Touitou, Isabelle; Geneviève, David

    2017-07-01

    Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined. To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients. We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome. We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity. NCT02067962; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please

  6. [Monogenic obesity in human].

    PubMed

    Onigata, Kazumichi

    2013-02-01

    Obesity is a heterogeneous pathologic condition that is driven by interactions between multiple genetic and environmental factors. The discovery of leptin has provided the useful clue to the molecular dissection of central pathways involved in the regulation of food intake and body weight. Monogenic obesity in human has been documented. Several obesity causing genes within the leptin-POMC-melanocortin axis have been identified: Leptin, leptin receptor, proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin receptor-4 (MC4-R) genes. The patients who have a mutation of such genes developed early onset of obesity and distinct metabolic abnormalities. Also, several gene mutations have been identified in some syndromes presenting hereditary symptomatic obesity.

  7. Animal models of monogenic migraine.

    PubMed

    Chen, Shih-Pin; Tolner, Else A; Eikermann-Haerter, Katharina

    2016-06-01

    Migraine is a highly prevalent and disabling neurological disorder with a strong genetic component. Rare monogenic forms of migraine, or syndromes in which migraine frequently occurs, help scientists to unravel pathogenetic mechanisms of migraine and its comorbidities. Transgenic mouse models for rare monogenic mutations causing familial hemiplegic migraine (FHM), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and familial advanced sleep-phase syndrome (FASPS), have been created. Here, we review the current state of research using these mutant mice. We also discuss how currently available experimental approaches, including epigenetic studies, biomolecular analysis and optogenetic technologies, can be used for characterization of migraine genes to further unravel the functional and molecular pathways involved in migraine.

  8. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry

    PubMed Central

    Lachmann, H J; Papa, R; Gerhold, K; Obici, L; Touitou, I; Cantarini, L; Frenkel, J; Anton, J; Kone-Paut, I; Cattalini, M; Bader-Meunier, B; Insalaco, A; Hentgen, V; Merino, R; Modesto, C; Toplak, N; Berendes, R; Ozen, S; Cimaz, R; Jansson, A; Brogan, P A; Hawkins, P N; Ruperto, N; Martini, A; Woo, P; Gattorno, M

    2014-01-01

    Objective To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. Methods A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. Results Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. Conclusions In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation. PMID:23965844

  9. Vasculitis in the autoinflammatory diseases.

    PubMed

    Peleg, Hagit; Ben-Chetrit, Eldad

    2017-01-01

    This article addresses the prevalence and relationship between autoinflammatory diseases and vasculitis. Autoimmune diseases (AIDs) are a group of syndromes characterized by episodes of unprovoked inflammation due to dysregulation of the innate immune system. Despite the common occurrence of rashes and other skin lesions in these diseases, vasculitis is reported in only a few. On the other hand, neutrophilic dermatoses are more prevalent. Large vessel vasculitis is reported in patients with Behcet's and Blau's syndromes. Small and medium size vasculitides are reported in familial Mediterranean fever mainly as Henoch-Schonlein purpura and polyarteritis nodosa, respectively. It is rarely described in hyper IgD with periodic fever syndrome, cryopyrin associated periodic syndromes, TNF receptor-associated periodic syndrome, deficiency of interleukin-1 receptor antagonist and pyoderma gangrenosum and acne syndrome. In most AID where bones and skin are mainly involved (CRMO, Majeed syndrome, Cherubism and DITRA) - vasculitis has not been described at all. In AID small vessel vasculitis affects mainly the skin with no involvement of internal organs. In AID, neutrophilic dermatoses are more common and prominent than vasculitis. This may reflect a minor role for interleukin-1 in the pathogenesis of vasculitis. The rarity of vasculitis in AID suggests that in most reported cases its occurrence has been probably coincidental rather than being an integral feature of the disease.

  10. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.

    PubMed

    Lachmann, H J; Papa, R; Gerhold, K; Obici, L; Touitou, I; Cantarini, L; Frenkel, J; Anton, J; Kone-Paut, I; Cattalini, M; Bader-Meunier, B; Insalaco, A; Hentgen, V; Merino, R; Modesto, C; Toplak, N; Berendes, R; Ozen, S; Cimaz, R; Jansson, A; Brogan, P A; Hawkins, P N; Ruperto, N; Martini, A; Woo, P; Gattorno, M

    2014-12-01

    To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence

  11. Deficiency of interleukin-1-receptor antagonist syndrome: a rare auto-inflammatory condition that mimics multiple classic radiographic findings.

    PubMed

    Thacker, Paul G; Binkovitz, Larry A; Thomas, Kristen B

    2012-04-01

    Deficiency of interleukin-1-receptor antagonist (DIRA) syndrome is a newly identified inflammatory disease of the skeleton and appendicular soft tissues presenting in early infancy that has yet to be reported in the radiology literature. The radiological manifestations of DIRA syndrome include multifocal osteitis of the ribs and long bones, heterotopic ossification and periarticular soft-tissue swelling. Thus, the pediatric radiologist should be made aware of this novel disease because its radiographic findings can mimic multiple other disease entities. With knowledge of the unique clinical presentation of DIRA syndrome and its multiple radiographic manifestations, the pediatric radiologist may be the first to suggest the correct diagnosis.

  12. Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling*

    PubMed Central

    de Jesus, Adriana Almeida; Canna, Scott W.; Liu, Yin; Goldbach-Mansky, Raphaela

    2015-01-01

    Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification. PMID:25706096

  13. Autoinflammatory pustular neutrophilic diseases.

    PubMed

    Naik, Haley B; Cowen, Edward W

    2013-07-01

    This article provides a new categorization of inflammatory pustular dermatoses in the context of recent genetic and biological insights. Monogenic diseases with pustular phenotypes are discussed, including deficiency of interleukin 1 receptor antagonist, deficiency of the interleukin 36 receptor antagonist, CARD14-associated pustular psoriasis, and pyogenic arthritis, pyoderma gangrenosum, and acne. How these new genetic advancements may inform how previously described pustular diseases are viewed, including pustular psoriasis and its clinical variants, with a focus on historical classification by clinical phenotype, is also discussed.

  14. dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure.

    PubMed

    Dos Santos, Reinaldo Sousa; Daures, Mathilde; Philippi, Anne; Romero, Sophie; Marselli, Lorella; Marchetti, Piero; Senée, Valérie; Bacq, Delphine; Besse, Céline; Baz, Baz; Marroquí, Laura; Ivanoff, Sarah; Masliah-Planchon, Julien; Nicolino, Marc; Soulier, Jean; Socié, Gérard; Eizirik, Decio L; Gautier, Jean-François; Julier, Cécile

    2017-04-01

    We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT) gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this DUT mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance. © 2017 by the American Diabetes Association.

  15. The fresco of autoinflammatory diseases from the pediatric perspective.

    PubMed

    Rigante, Donato

    2012-03-01

    Autoinflammatory diseases are genetic or acquired clinical entities globally caused by the aberrant release of the proinflammatory cytokine interleukin-1 and mostly characterized by recurrent spontaneous inflammatory events which do not produce antigen-specific T cells or autoantibodies. Within the past decade, the list of autoinflammatory diseases has included cryopyrin-associated periodic syndromes, familial Mediterranean fever, mevalonate kinase deficiency, tumor necrosis factor receptor-associated periodic syndrome, hereditary pyogenic disorders, pediatric granulomatous autoinflammatory diseases, idiopathic febrile syndromes, complement dysregulation syndromes and Behçet's disease. Most of these conditions interact with the inflammasomes, intracellular molecular complexes coordinating the phylogenetically ancient response of the innate immune system. The pathogenetic mechanisms of these diseases have shown the evidence of disrupted interleukin-1 signaling for most of them and allowed to locate interleukin-1 as an attractive therapeutic target. The whole fresco of autoinflammatory diseases in pediatrics will be discussed in this review with the aim of establishing both diagnostic clues and treatments for each condition.

  16. Developments in the scientific and clinical understanding of autoinflammatory disorders

    PubMed Central

    Lachmann, Helen J; Hawkins, Philip N

    2009-01-01

    The autoinflammatory diseases, also known as periodic fever syndromes, are disorders of innate immunity which can be inherited or acquired and which cause recurrent, self-limiting, seemingly spontaneous episodes of systemic inflammation and fever in the absence of autoantibody production or infection. There has been much recent progress in elucidating their aetiologies and treatment. With the exception of familial Mediterranean fever, which is common in certain populations, autoinflammatory diseases are mostly rare but should not be overlooked in the differential diagnosis of recurrent fevers since DNA diagnosis and effective therapies are available for many of them. PMID:19232070

  17. Hereditary auto-inflammatory disorders and biologics.

    PubMed

    Church, Leigh D; Churchman, Sarah M; Hawkins, Philip N; McDermott, Michael F

    2006-06-01

    The term auto-inflammatory disorders has been coined to describe a group of conditions characterized by spontaneously relapsing and remitting bouts of systemic inflammation without apparent involvement of antigen-specific T cells or significant production of auto-antibodies. The hereditary periodic fever syndromes are considered as the prototypic auto-inflammatory diseases, and genetic studies have yielded important new insights into innate immunity. DNA analysis has greatly enhanced the clinical characterization of these conditions, and elucidation of their molecular aetiopathogenesis has suggested that therapies may be aimed at specific targets within the immune cascade. The availability of biologic response modifiers such as inhibitors of tumour necrosis factor (TNF) and interleukin-1beta has greatly improved the outlook for some of these disorders, although effective therapies remain elusive in patients with certain conditions, including hyperimmunoglobulinaemia-D with periodic fever syndrome (HIDS) and a proportion of those with TNF-receptor associated periodic syndrome (TRAPS). Indeed, outstanding challenges and the unique potential to further elucidate molecular mechanisms in innate immunity are illustrated by the dashed early hope that TNF blockade would be a panacea for TRAPS: not only is etanercept (Enbrel) ineffective in some cases, but there are anecdotal reports of this condition being greatly exacerbated by infliximab (Remicade).

  18. Roux-en-Y gastric bypass in an adolescent patient with Bardet-Biedl syndrome, a monogenic obesity disorder.

    PubMed

    Daskalakis, Markos; Till, Holger; Kiess, Wieland; Weiner, Rudolf A

    2010-01-01

    Bardet-Biedl syndrome (BBS) is a rare genetic disorder characterized by a wide range of phenotypic variability and associated with the development of life-threatening obesity. Birth weight tends to be normal, but rapid weight gain begins after the first year, probably due to polyphagia rather than abnormalities in energy metabolism. A morbidly obese 16-year-old male patient with BBS was referred to our institution, after nonsurgical methods of weight control had failed, for surgical treatment of his obesity. His preoperative body mass index (BMI) was 52.28 kg/m(2) (height, 1.84 m; weight, 177 kg) and was above the 99th centile for age and gender. The patient underwent laparoscopic Roux-en-Y gastric bypass (RYGBP). The postoperative period was uneventful. Three and a half years after the operation, the patient's weight has decreased to 118 kg (BMI, 34.85 kg/m(2)), while significant improvement in his hypertension, hyperuricemia, and mobility has been noted. In our BBS patient, RYGBP proved to be safe and effective; nevertheless, longer follow-up is required to evaluate the weight loss durability and to assess the lasting beneficial effect of surgical intervention on genetically determined co-morbidities.

  19. Early onset (childhood) monogenic neuropathies.

    PubMed

    Landrieu, Pierre; Baets, Jonathan

    2013-01-01

    Hereditary neuropathies (HN) with onset in childhood are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission and, in selected cases, pathological findings. Especially relevant to pediatrics are the items "secondary" versus "primary" neuropathy, "syndromic versus nonsyndromic," and "period of life." Different combinations of these parameters frequently point toward specific monogenic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first concern in pediatrics. As a rule, metabolic diseases include additional, orienting symptoms or signs, and their biochemical diagnosis is based on logical algorithms. Primary, motor sensory are the most frequent HN and are dominated by demyelinating autosomal dominant (AD) forms (CMT1). Other forms include demyelinating autosomal recessive (AR) forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Peripheral motor neuron disorders are dominated by AR SMN-linked spinal muscular atrophies. (Distal) hereditary motor neuropathies represent <10% of HN but exhibit large clinical and genetic heterogeneity. Sensory/dysautonomic HN involves five classic subtypes, each one related to specific genes. However, genetic heterogeneity is larger than initially suspected. Syndromic HN distinguish "purely neurological syndromes", which are multisystemic, such as spinocerebellar atrophies +, spastic paraplegias +, etc. Peripheral neuropathy is possibly the presenting feature, including in childhood. Autosomal recessive forms, on average, start more frequently in childhood. "Multiorgan syndromes", on the other hand, are more specific to Pediatrics. AR forms, which are clearly degenerative, prompt the investigation of a large set of pleiotropic genes. Other syndromes expressed in the perinatal period are mainly developmental disorders, and can sometimes be related to specific transcription factors. Systematic

  20. Skin symptoms as diagnostic clue for autoinflammatory diseases*

    PubMed Central

    Moreira, Alvaro; Torres, Barbara; Peruzzo, Juliano; Mota, Alberto; Eyerich, Kilian; Ring, Johannes

    2017-01-01

    Autoinflammatory disorders are immune-mediated diseases with increased production of inflammatory cytokines and absence of detectable autoantibodies. They course with recurrent episodes of systemic inflammation and fever is the most common symptom. Cutaneous manifestations are prevalent and important to diagnosis and early treatment of the syndromes. The purpose of this review is to emphasize to dermatologists the skin symptoms present in these syndromes in order to provide their early diagnosis. PMID:28225960

  1. Molecular and genetic characteristics of hereditary autoinflammatory diseases.

    PubMed

    Tunca, Mehmet; Ozdogan, Huri

    2005-02-01

    Autoinflammatory diseases are defined as recurrent "unprovoked" inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.

  2. Monogenic autoimmune diseases of the endocrine system.

    PubMed

    Johnson, Matthew B; Hattersley, Andrew T; Flanagan, Sarah E

    2016-10-01

    The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. [Clinical and genetic aspects of monogenic obesity].

    PubMed

    Lesayová, D; Staník, J; Gasperíková, D; Klimes, I

    2010-10-01

    High prevalence of obesity in all of age categories is currently one of the biggest problem in medicine. Identification of etiology of obesity can individualise an approach to the patient and it is essential for choosing a target management and therapy. Beside the largest group with polygenic inheritance are clinically important also patients with "syndromic obesity", where obesity is only one of the signs and monogenic obesity, where obesity is the major clinical phenotype (patients with mutations in gene for leptin, leptine receptor, prohormone convertase 1, melanocortine receptor 4, brain-derived neurotropic factor and tyrosin kinase receptor B). The monogenic obesity includes 3-4% of all patients with obesity. This review article brings newest insight on genetics, clinical manifestation, diagnostics and therapy of these diseases.

  4. AUTOINFLAMMATORY PUSTULAR NEUTROPHILIC DISEASES

    PubMed Central

    Naik, Haley B.; Cowen, Edward W.

    2013-01-01

    SYNOPSIS The inflammatory pustular dermatoses constitute a spectrum of non-infectious conditions ranging from localized involvement to generalized disease with associated acute systemic inflammation and multi-organ involvement. Despite the variability in extent and severity of cutaneous presentation, each of these diseases is characterized by non-infectious neutrophilic intra-epidermal microabscesses. Many share systemic findings including fever, elevated inflammatory markers, inflammatory bowel disease and/or osteoarticular involvement, suggesting potential common pathogenic links (Figure 1). The recent discoveries of several genes responsible for heritable pustular diseases have revealed a distinct link between pustular skin disease and regulation of innate immunity. These genetic advances have led to a deeper exploration of common pathways in pustular skin disease and offer the potential for a new era of biologic therapy which targets these shared pathways. This chapter provides a new categorization of inflammatory pustular dermatoses in the context of recent genetic and biologic insights. We will discuss recently-described monogenic diseases with pustular phenotypes, including deficiency of IL-1 receptor antagonist (DIRA), deficiency of the IL-36 receptor antagonist (DITRA), CARD14-associated pustular psoriasis (CAMPS), and pyogenic arthritis, pyoderma gangrenosum, acne (PAPA). We will then discuss how these new genetic advancements may inform how we view previously described pustular diseases, including pustular psoriasis and its clinical variants, with a focus on historical classification by clinical phenotype. PMID:23827244

  5. Autoinflammatory Skin Disorders: The Inflammasomme in Focus

    PubMed Central

    Gurung, Prajwal; Kanneganti, Thirumala-Devi

    2016-01-01

    Autoinflammatory skin disorders are a group of heterogeneous diseases that include diseases such as cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF). Therapeutic strategies targeting IL-1 cytokines have proved helpful in ameliorating some of these diseases. While inflammasomes are the major regulators of IL-1 cytokines, inflammasome-independent complexes can also process IL-1 cytokines. Herein, we focus on recent advances in our understanding of how IL-1 cytokines, stemming from inflammasome-dependent and -independent pathways are involved in the regulation of skin conditions. Importantly, we discuss several mouse models of skin inflammation generated to help elucidate the basic cellular and molecular effects and modulation of IL-1 in the skin. Such models offer perspectives on how these signaling pathways could be targeted to improve therapeutic approaches in the treatment of these rare and debilitating inflammatory skin disorders. PMID:27267764

  6. Autoinflammatory Skin Disorders: The Inflammasomme in Focus.

    PubMed

    Gurung, Prajwal; Kanneganti, Thirumala-Devi

    2016-07-01

    Autoinflammatory skin disorders are a group of heterogeneous diseases that include diseases such as cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF). Therapeutic strategies targeting IL-1 cytokines have proved helpful in ameliorating some of these diseases. While inflammasomes are the major regulators of IL-1 cytokines, inflammasome-independent complexes can also process IL-1 cytokines. Herein, we focus on recent advances in our understanding of how IL-1 cytokines, stemming from inflammasome-dependent and -independent pathways are involved in the regulation of skin conditions. Importantly, we discuss several mouse models of skin inflammation generated to help elucidate the basic cellular and molecular effects and modulation of IL-1 in the skin. Such models offer perspectives on how these signaling pathways could be targeted to improve therapeutic approaches in the treatment of these rare and debilitating inflammatory skin disorders.

  7. Basic Characteristics of Adults with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome in Comparison with the Typical Pediatric Expression of Disease

    PubMed Central

    Cattalini, Marco; Soliani, Martina; Rigante, Donato; Lopalco, Giuseppe; Iannone, Florenzo; Galeazzi, Mauro; Cantarini, Luca

    2015-01-01

    Autoinflammatory diseases are caused by inflammasome dysregulation leading to overproduction of proinflammatory cytokines and a pathological delay in the inflammation switching off. The progress of cellular biology has partially clarified pathogenic mechanisms behind monogenic autoinflammatory diseases, whereas little is known about the polygenic ones. Although the genetic susceptibility of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is still obscure, the presence of overlapping symptoms with monogenic periodic fevers, the recurrence in family members, the important role played by dysregulated interleukin- (IL-) 1β secretion during flares, the overexpression of inflammasome-associated genes during attacks, and, last but not least, the therapeutic efficacy of IL-1β blockade strongly indicate a potential genetic involvement in its pathogenesis, probably linked with environmental factors. PFAPA syndrome has a typical inception in the pediatric age, but a delayed onset during adulthood has been described as well. Treatments required as well as effectiveness of tonsillectomy remain controversial, even if the disease seems to have a self-limited course mostly in children. The purpose of this review is to provide an overview of this complex polygenic/multifactorial autoinflammatory disorder in which the innate immune system undoubtedly plays a basic role. PMID:26357457

  8. Basic Characteristics of Adults with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome in Comparison with the Typical Pediatric Expression of Disease.

    PubMed

    Cattalini, Marco; Soliani, Martina; Rigante, Donato; Lopalco, Giuseppe; Iannone, Florenzo; Galeazzi, Mauro; Cantarini, Luca

    2015-01-01

    Autoinflammatory diseases are caused by inflammasome dysregulation leading to overproduction of proinflammatory cytokines and a pathological delay in the inflammation switching off. The progress of cellular biology has partially clarified pathogenic mechanisms behind monogenic autoinflammatory diseases, whereas little is known about the polygenic ones. Although the genetic susceptibility of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is still obscure, the presence of overlapping symptoms with monogenic periodic fevers, the recurrence in family members, the important role played by dysregulated interleukin- (IL-) 1β secretion during flares, the overexpression of inflammasome-associated genes during attacks, and, last but not least, the therapeutic efficacy of IL-1β blockade strongly indicate a potential genetic involvement in its pathogenesis, probably linked with environmental factors. PFAPA syndrome has a typical inception in the pediatric age, but a delayed onset during adulthood has been described as well. Treatments required as well as effectiveness of tonsillectomy remain controversial, even if the disease seems to have a self-limited course mostly in children. The purpose of this review is to provide an overview of this complex polygenic/multifactorial autoinflammatory disorder in which the innate immune system undoubtedly plays a basic role.

  9. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*).

    PubMed

    Masters, Seth L; Simon, Anna; Aksentijevich, Ivona; Kastner, Daniel L

    2009-01-01

    The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of autoinflammatory disease: IL-1beta activation disorders (inflammasomopathies), NF-kappaB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.

  10. Horror Autoinflammaticus: The Molecular Pathophysiology of Autoinflammatory Disease*

    PubMed Central

    Masters, Seth L.; Simon, Anna; Aksentijevich, Ivona; Kastner, Daniel L.

    2010-01-01

    The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of autoinflammatory disease: IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside. PMID:19302049

  11. Neuro-Behçet disease and autoinflammatory disorders.

    PubMed

    Miller, Julie J; Venna, Nagagopal; Siva, Aksel

    2014-09-01

    Misregulation of innate immunity leads to autoinflammation. Behçet disease is an autoinflammatory condition involving recurrent attacks of inflammation in skin, eyes, joints, and even the nervous system. The etiology may involve vascular inflammation. Central nervous system involvement in neuro-Behçet disease (NBD) comes in the form of parenchymal NBD or nonparenchymal NBD. The parenchymal form has a predilection for the brainstem, diencephalon and cerebral hemispheres, and represents a meningoencephalitis thought to be related to small vessel vasculitis. Cerebral venous sinus thrombosis, arising from a vasculitic process of large veins, comprises the majority of vascular NBD cases. The rarer monogenetic autoinflammatory syndromes are characterized by periodic fever, and typically present in the pediatric population. Neurologic involvement in these syndromes typically presents in the form of an aseptic meningitis. Treatment of autoinflammatory disorders involves immune modulation with corticosteroids, disease-modifying antirheumatic medications, and increasingly antibodies targeting cytokines like tumor necrosis factor α and interleukin 1. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  12. [Autoinflammatory diseases as cause of wound healing defects].

    PubMed

    Löhrer, R; Eming, R; Wolfrum, N; Krieg, T; Eming, S A

    2011-07-01

    Ulcerations of the skin and mucosal membranes are a common feature of autoinflammatory diseases. They can give raise to chronic wound healing defects and should be considered in the differential diagnosis of chronic skin ulcers. The increased activation of the innate immune system in the absence of an apparent provocation for inflammation is a hallmark of autoinflammatory diseases. Mutations and alterations of signaling pathways regulating the innate immune response to physical trauma/tissue damage result into an unrestrained activation of the inflammasome, which leads to increased activation of Interleukin-1. Uncontrolled recruitment and activation of myeloid effector cells within the wound site lead to the release of potent proteases that cause the degradation of structural components of the skin. The majority of these diseases respond well to immunosuppressive and immunomodulatory treatment regimes. Therapeutic resistance converts the acute inflammatory response into a chronic and non-resolving inflammatory process that leads to tissue degeneration. In this article we will focus on the review of those autoinflammatory diseases that often display ulcerative cutaneous and aphthous lesions including pyoderma gangrenosum, Behçet disease, PAPA syndrome and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). Furthermore, the article will be complemented by an overview of those inflammatory diseases that are associated with non-ulcerative cutaneous manifestations.

  13. Autoinflammatory conditions: when to suspect? How to treat?

    PubMed

    Grateau, Gilles; Duruöz, Mehmet Tuncay

    2010-06-01

    The term 'autoinflammatory disease' encompasses an enlarging group of inflammatory disorders defined as Mendelian genetic diseases of the innate immune system. This group is growing considering the fact that diseases sharing strong similarities with this core group can be defined as autoinflammatory. The core group consists now of six disorders also known as hereditary recurrent fever syndromes. Thez most common is familial Mediterranean fever, an autosomal recessive disease affecting mainly populations of Mediterranean ancestry. All these six diseases are characterised by inflammatory attacks both at the clinical and at the biological level. The diagnosis of each of these diseases relies first on clinical features and second on genetic testing, which is guided by the clinical results. Deciphering the role of interleukin-1 in the regulation of the inflammatory response through the inflammasome represents a major advance in the knowledge of the mechanisms of these diseases with, as a main consequence, treatment with interleukin-1 inhibitors.

  14. Clinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center.

    PubMed

    Hernández-Rodríguez, José; Ruíz-Ortiz, Estíbaliz; Tomé, Adrià; Espinosa, Gerard; González-Roca, Eva; Mensa-Vilaró, Anna; Prieto-González, Sergio; Espígol-Frigolé, Georgina; Mensa, Josep; Cardellach, Francesc; Grau, Josep M; Cid, Maria C; Yagüe, Jordi; Aróstegui, Juan I; Cervera, Ricard

    2016-01-01

    Autoinflammatory diseases (AID) are usually diagnosed during the pediatric age. However, adult-onset disease or diagnosis during adulthood has been occasionally described. To assess the clinical and genetic characteristics of adult patients diagnosed with an AID in an adult referral center for AID. We retrospectively evaluated clinical and genetic features of adult patients (≥16 years) diagnosed with an AID or referred after AID diagnosis to the Clinical Unit of AID, at the Department of Autoimmune Diseases, Hospital Clínic of Barcelona, from 2008 to 2014. During the study period, a genetic study for suspected AID was requested to 90 patients at the Department of Autoimmune Diseases. A final diagnosis of monogenic AID was achieved in 17 patients (19% of patients tested). Five additional cases were diagnosed with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and 10 patients with AID were referred from other adult departments. Finally, a total of 32 patients with AID were finally diagnosed or monitored in our Clinical Unit. These included 12 (37.5%) familial Mediterranean fever, 6 (18.8%) tumour necrosis factor-receptor associated periodic syndrome, 8 (25%) cryopirin-associated periodic syndromes (Muckle-Wells syndrome [MWS] or overlap familial cold-associated periodic syndrome/MWS), 1 (3.1%) mevalonate kinase deficiency, and 5 (15.6%) PFAPA. Clinical evidence of disease-onset during childhood and adulthood was observed in 15 (47%) and 17 (53%) patients, respectively. Overall, the final diagnosis was obtained after a delay of a mean of 12 years (range 0-47 years). Compared to children, adult patients with AID in our series presented more frequently with non-severe manifestations and none of them developed amyloidosis during follow-up. Adult patients also carried higher proportion of low-penetrance mutations or polymorphisms and all genetic variants were presented in heterozygosis or as heterozygous compounds. Adult disease

  15. Treating young adults with type 2 diabetes or monogenic diabetes.

    PubMed

    Owen, Katharine R

    2016-06-01

    It is increasingly recognised that diabetes in young adults has a wide differential diagnosis. There are many monogenic causes, including monogenic beta-cell dysfunction, mitochondrial diabetes and severe insulin resistance. Type 2 diabetes in the young is becoming more prevalent, particularly after adolescence. It's important to understand the clinical features and diagnostic tools available to classify the different forms of young adult diabetes. Classic type 1 diabetes is characterised by positive β-cell antibodies and absence of endogenous insulin secretion. Young type 2 diabetes is accompanied by metabolic syndrome with obesity, hypertension and dyslipidaemia. Monogenic β-cell dysfunction is characterised by non-autoimmune, C-peptide positive diabetes with a strong family history, while mitochondrial diabetes features deafness and other neurological involvement. Severe insulin resistance involves a young-onset metabolic syndrome often with a disproportionately low BMI. A suspected diagnosis of monogenic diabetes is confirmed with genetic testing, which is widely available in specialist centres across the world. Treatment of young adult diabetes is similarly diverse. Mutations in the transcription factors HNF1A and HNF4A and in the β-cell potassium ATP channel components cause diabetes which responds to low dose and high dose sulfonylurea agents, respectively, while glucokinase mutations require no treatment. Monogenic insulin resistance and young-onset type 2 diabetes are both challenging to treat, but first line management involves insulin sensitisers and aggressive management of cardiovascular risk. Outcomes are poor in young-onset type 2 diabetes compared to both older onset type 2 and type 1 diabetes diagnosed at a similar age. The evidence base for treatments in monogenic and young-onset type 2 diabetes relies on studies of moderate quality at best and largely on extrapolation from work conducted in older type 2 diabetes subjects. Better quality

  16. Monogenic obesity in humans.

    PubMed

    Farooqi, I Sadaf; O'Rahilly, Stephen

    2005-01-01

    Until relatively recently, the small number of identifiable inherited human diseases associated with marked obesity were complex, pleiotropic developmental disorders, the molecular basis for which were entirely obscure. The molecular basis for many of these complex syndromes, such as Bardet Beidl syndrome, has been revealed, providing novel insights into processes essential for human hypothalamic function and energy balance. In addition to these discoveries, which were the fruits of positional cloning, the molecular constituents of the signaling pathways responsible for the control of mammalian energy homeostasis have been identified, largely through the study of natural or artificial mutations in mice. We discuss the increasing number of human disorders that result from genetic disruption of the leptin-melanocortin pathways that have been identified. Practical implications of these findings for genetic counseling, prognostication, and even therapy have already emerged.

  17. Monogenic forms of childhood obesity due to mutations in the leptin gene.

    PubMed

    Funcke, Jan-Bernd; von Schnurbein, Julia; Lennerz, Belinda; Lahr, Georgia; Debatin, Klaus-Michael; Fischer-Posovszky, Pamela; Wabitsch, Martin

    2014-12-01

    Congenital leptin deficiency is a rare autosomal recessive monogenic obesity syndrome caused by mutations in the leptin gene. This review describes the molecular and cellular characteristics of the eight distinct mutations found so far in humans.

  18. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome

    PubMed Central

    Gioia, Silvio Alessandro Di; Bedoni, Nicola; von Scheven-Gête, Annette; Vanoni, Federica; Superti-Furga, Andrea; Hofer, Michaël; Rivolta, Carlo

    2015-01-01

    PFAPA syndrome is the most common autoinflammatory syndrome in children from Western countries. In spite of its strong familial clustering, its genetic basis and inheritance pattern are still unknown. We performed a comprehensive genetic study on 68 individuals from 14 families. Linkage analysis suggested a susceptibility locus on chromosome 8, but direct molecular sequencing did not support this initial statistical finding. Exome sequencing revealed the absence of any gene that was mutated in all patients. Exhaustive screening of genes involved in other autoinflammatory syndromes or encoding components of the human inflammasome showed no DNA variants that could be linked to PFAPA molecular pathology. Among these, the previously-reported missense mutation V198M in the NLRP3 gene was clearly shown not to co-segregate with PFAPA. Our results on this relatively large cohort indicate that PFAPA syndrome is unlikely to be a monogenic condition. Moreover, none of the several genes known to be involved in inflammation or in autoinflammatory disorders seem to be relevant, alone, to its etiology, suggesting that PFAPA results from oligogenic or complex inheritance of variants in multiple disease genes and/or non-genetic factors. PMID:25988833

  19. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.

    PubMed

    Di Gioia, Silvio Alessandro; Bedoni, Nicola; von Scheven-Gête, Annette; Vanoni, Federica; Superti-Furga, Andrea; Hofer, Michaël; Rivolta, Carlo

    2015-05-19

    PFAPA syndrome is the most common autoinflammatory syndrome in children from Western countries. In spite of its strong familial clustering, its genetic basis and inheritance pattern are still unknown. We performed a comprehensive genetic study on 68 individuals from 14 families. Linkage analysis suggested a susceptibility locus on chromosome 8, but direct molecular sequencing did not support this initial statistical finding. Exome sequencing revealed the absence of any gene that was mutated in all patients. Exhaustive screening of genes involved in other autoinflammatory syndromes or encoding components of the human inflammasome showed no DNA variants that could be linked to PFAPA molecular pathology. Among these, the previously-reported missense mutation V198M in the NLRP3 gene was clearly shown not to co-segregate with PFAPA. Our results on this relatively large cohort indicate that PFAPA syndrome is unlikely to be a monogenic condition. Moreover, none of the several genes known to be involved in inflammation or in autoinflammatory disorders seem to be relevant, alone, to its etiology, suggesting that PFAPA results from oligogenic or complex inheritance of variants in multiple disease genes and/or non-genetic factors.

  20. Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia

    PubMed Central

    Benussi, Alberto; Padovani, Alessandro; Borroni, Barbara

    2015-01-01

    Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease. PMID:26388768

  1. An Update on Autoinflammatory Diseases

    PubMed Central

    Ciccarelli, F.; Martinis, M. De; Ginaldi, L.

    2013-01-01

    Autoinflammatory diseases area group of clinical conditions other than autoimmune diseases, characterized by recurrent inflammatory episodes. From apathogenetic point of view they are determined by a dys regulation of innate immunity, without involvement of specific immunity (auto reactive T cells and auto antibodies). Recently, the increased knowledge in the field of auto inflammation highlighted shared immune mechanisms in the pathogenesis of both classical monogenetic and multifactorial auto inflammatory diseases and a broad spectrum of chronic age-related inflammatory pathologies. The current increase in the prevalence of chronic inflammatory diseases makes this subject of topical interest. In the light of these considerations, we propose an update of auto inflammatory diseases and a new interpretation of auto inflammation with both theoretical and clinical implications. PMID:24164192

  2. Many faces of monogenic diabetes.

    PubMed

    Schwitzgebel, Valerie M

    2014-03-23

    Monogenic diabetes represents a heterogeneous group of disorders resulting from defects in single genes. Defects are categorized primarily into two groups: disruption of β-cell function or a reduction in the number of β-cells. A complex network of transcription factors control pancreas formation, and a dysfunction of regulators high in the hierarchy leads to pancreatic agenesis. Dysfunction among factors further downstream might cause organ hypoplasia, absence of islets of Langerhans or a reduction in the number of β-cells. Many transcription factors have pleiotropic effects, explaining the association of diabetes with other congenital malformations, including cerebellar agenesis and pituitary agenesis. Monogenic diabetes variants are classified conventionally according to age of onset, with neonatal diabetes occurring before the age of 6 months and maturity onset diabetes of the young (MODY) manifesting before the age of 25 years. Recently, certain familial genetic defects were shown to manifest as neonatal diabetes, MODY or even adult onset diabetes. Patients with neonatal diabetes require a thorough genetic work-up in any case, and because extensive phenotypic overlap exists between monogenic, type 2, and type 1 diabetes, genetic analysis will also help improve diagnosis in these cases. Next generation sequencing will facilitate rapid screening, leading to the discovery of digenic and oligogenic diabetes variants, and helping to improve our understanding of the genetics underlying other types of diabetes. An accurate diagnosis remains important, because it might lead to a change in the treatment of affected subjects and influence long-term complications.

  3. Monogenic diseases that can be cured by liver transplantation.

    PubMed

    Fagiuoli, Stefano; Daina, Erica; D'Antiga, Lorenzo; Colledan, Michele; Remuzzi, Giuseppe

    2013-09-01

    While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia). This review focuses on principles of diagnosis, management

  4. Clinical and biochemical landmarks in systemic autoinflammatory diseases.

    PubMed

    Cantarini, Luca; Rigante, Donato; Brizi, Maria Giuseppina; Lucherini, Orso Maria; Sebastiani, Gian Domenico; Vitale, Antonio; Gianneramo, Valentina; Galeazzi, Mauro

    2012-11-01

    Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases.

  5. From the Mediterranean to the Sea of Japan: The Transcontinental Odyssey of Autoinflammatory Diseases

    PubMed Central

    Frediani, Bruno; Galeazzi, Mauro

    2013-01-01

    Autoinflammatory diseases are comprehensively caused by aberrant production of proinflammatory cytokines and are revealed by cyclically and spontaneously occurring inflammatory events. Over the last decade, there has been a revolution in the understanding of periodic fever syndromes, cryopyrinopathies, and skin disorders with pyogenic, granulomatous, or dystrophic features, which have been recognized across different countries spanning from the Mediterranean basin to the Japanese archipelago. Many children and adults with autoinflammatory diseases continue to elude diagnosis, and the diagnostic delay of many years puts these patients at risk of long-term severe complications, such as amyloidosis. Any hint of suspicion of autoinflammatory disease thus needs to be highlighted in various medical specialties, and this review examines their frequencies around the world, trying to match them with geographic location, ethnic and genetic data, in an attempt to realize a geoepidemiologic map for most of these conditions. PMID:23971037

  6. Development of the autoinflammatory disease damage index (ADDI).

    PubMed

    Ter Haar, Nienke M; Annink, Kim V; Al-Mayouf, Sulaiman M; Amaryan, Gayane; Anton, Jordi; Barron, Karyl S; Benseler, Susanne M; Brogan, Paul A; Cantarini, Luca; Cattalini, Marco; Cochino, Alexis-Virgil; De Benedetti, Fabrizio; Dedeoglu, Fatma; De Jesus, Adriana A; Della Casa Alberighi, Ornella; Demirkaya, Erkan; Dolezalova, Pavla; Durrant, Karen L; Fabio, Giovanna; Gallizzi, Romina; Goldbach-Mansky, Raphaela; Hachulla, Eric; Hentgen, Veronique; Herlin, Troels; Hofer, Michaël; Hoffman, Hal M; Insalaco, Antonella; Jansson, Annette F; Kallinich, Tilmann; Koné-Paut, Isabelle; Kozlova, Anna; Kuemmerle-Deschner, Jasmin B; Lachmann, Helen J; Laxer, Ronald M; Martini, Alberto; Nielsen, Susan; Nikishina, Irina; Ombrello, Amanda K; Ozen, Seza; Papadopoulou-Alataki, Efimia; Quartier, Pierre; Rigante, Donato; Russo, Ricardo; Simon, Anna; Trachana, Maria; Uziel, Yosef; Ravelli, Angelo; Gattorno, Marco; Frenkel, Joost

    2017-05-01

    Autoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency. We developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds. More than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain. An instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  7. A Pilot Study to Evaluate the Safety and Efficacy of the Long-acting IL-1 Inhibitor, Rilonacept (IL-1 Trap) in Patients with Familial Cold Autoinflammatory Syndrome (FCAS)

    PubMed Central

    Goldbach-Mansky, Raphaela; Shroff, Sharukh; Wilson, Mildred; Snyder, Christopher; Plehn, Sara; Barham, Beverly; Pham, Tuyet Hang; Kastner, Daniel L.; Pucino, Frank; Wesley, Robert A.; Papadopoulos, Joanne; Weinstein, Steven; Mellis, Scott

    2009-01-01

    Objective Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in CIAS1 leading to excessive secretion of IL-1β, which is associated with cold induced fevers, joint pain and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of the long acting IL-1 receptor fusion protein, rilonacept (IL-1 Trap), in patients with FCAS. Methods Five Caucasian patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injections, were evaluated 6 and 10 days later for clinical efficacy and remained off drug until a clinical flare occurred. At the time of flare patients were retreated with 300 mg of rilonacept and then maintained on weekly doses of 100 mg per week. Patients who were not completely controlled could have their dose increased to 160 mg per week and further to 320 mg per week during an intra-patient dose escalation phase. Safety, disease activity measures, (daily diary reports of rash, joint pain and/or swelling, fevers) and quality of health measures (SF-36 questionnaire) as well as various serum markers of inflammation (ESR, CRP, SAA and IL-6) were measured at 3, 6, 9, 12 and 24 months after initiation of rilonacept administration and compared with baseline values. Results In all patients, clinical symptoms typically induced by cold (rash, fever, joint pain and swelling) improved within days of rilonacept administration. Inflammatory markers (ESR, CRP and SAA) showed a statistically significant reduction (p < 0.01 for ESR and p<0.001 for CRP and SAA) at doses of 100 mg. Although dose escalation to 160 mg and 320 mg resulted in subjectively better control of rash and joint pain, the lower measurements at the higher doses differed only significantly for the ESR, and a non-significant trend towards lower CRP and SAA levels was observed. All patients remained on study drug. The drug was well tolerated. Weight gain in two patients was

  8. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease.

    PubMed

    Uhlig, Holm H

    2013-12-01

    Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, has multifactorial aetiology with complex interactions between genetic and environmental factors. Over 150 genetic loci are associated with IBD. The genetic contribution of the majority of those loci towards explained heritability is low. Recent studies have reported an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. A substantial proportion of patients with those genetic defects present with very early onset of intestinal inflammation. The 40 monogenic defects with IBD-like pathology selected in this review can be grouped into defects in intestinal epithelial barrier and stress response, immunodeficiencies affecting granulocyte and phagocyte activity, hyper- and autoinflammatory disorders as well as defects with disturbed T and B lymphocyte selection and activation. In addition, there are defects in immune regulation affecting regulatory T cell activity and interleukin (IL)-10 signalling. Related to the variable penetrance of the IBD-like phenotype, there is a likely role for modifier genes and gene-environment interactions. Treatment options in this heterogeneous group of disorders range from anti-inflammatory and immunosuppressive therapy to blockade of tumour necrosis factor α and IL-1β, surgery, haematopoietic stem cell transplantation or gene therapy. Understanding of prototypic monogenic 'orphan' diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD.

  9. Monogenic mouse models of social dysfunction: implications for autism.

    PubMed

    Oddi, D; Crusio, W E; D'Amato, F R; Pietropaolo, S

    2013-08-15

    Autism is a pervasive disorder characterized by a complex symptomatology, based principally on social dysfunction. The disorder has a highly complex, largely genetic etiology, involving an impressive variety of genes, the precise contributions of which still remain to be determined. For this reason, a reductionist approach to the study of autism has been proposed, employing monogenic animal models of social dysfunction, either by targeting a candidate gene, or by mimicking a single-gene disorder characterized by autistic symptoms. In the present review, we discuss this monogenic approach by comparing examples of each strategy: the mu opioid receptor knock-out (KO) mouse line, which targets the opioid system (known to be involved in the control of social behaviors); and the Fmr1-KO mouse, a model for Fragile X syndrome (a neurodevelopmental syndrome that includes autistic symptoms). The autistic-relevant behavioral phenotypes of the mu-opioid and Fmr1-KO mouse lines are described here, summarizing previous work by our research group and others, but also providing novel experimental evidence. Relevant factors influencing the validity of the two models, such as sex differences and age at testing, are also addressed, permitting an extensive evaluation of the advantages and limits of monogenic mouse models for autism. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Transition to adult life in the monogenic epilepsies.

    PubMed

    Scheffer, Ingrid E; Dravet, Charlotte

    2014-08-01

    There are many monogenic disorders associated with epilepsy that begin in childhood and persist into adult life. Each of these disorders raises specific issues for transition, in addition to common issues facing this group of patients as they move from pediatric to adult care. Such comorbidities include psychiatric and movement disorders. Epileptic encephalopathies may be caused by monogenic disorders, with Dravet syndrome being the best characterized. Although some patients have a relatively good adult outcome, others have persisting severe epilepsy complicated by autistic spectrum disorder and problems with gait. When reevaluating a patient as they transition to adult care, a thorough reconsideration of the genetic etiology of their epilepsy should be performed. This should be followed by genetic counseling for the patient and their family members.

  11. From Genes to Mechanisms: The Expanding Spectrum of Monogenic Disorders Associated with Inflammatory Bowel Disease.

    PubMed

    Uhlig, Holm H; Schwerd, Tobias

    2016-01-01

    Inborn errors of the intestinal epithelial barrier function as well as the innate and adaptive mucosal immune responses toward the intestinal microbiota are a group of genetic disorders that confer susceptibility to monogenic and syndromal forms of inflammatory bowel disease (IBD). There is a continuous spectrum of genetic susceptibility from monogenic causative variants with complete Mendelian inheritance, over NOD2 variants with moderate penetrance to minute penetrance in most common susceptibility variants predisposing to conventional polygenic IBD. We discuss advances to understand monogenic IBD and review recently identified genetic defects. We describe an integrative model for genetic susceptibility variants of conventional IBD and monogenic IBD-like intestinal inflammation in the context of microbial commensal colonization and infection susceptibility.

  12. Interleukin-1: Ariadne's Thread in Autoinflammatory and Autoimmune Disorders.

    PubMed

    Cantarini, Luca; Lopalco, Giuseppe; Cattalini, Marco; Vitale, Antonio; Galeazzi, Mauro; Rigante, Donato

    2015-02-01

    Autoinflammatory and autoimmune disorders are characterized by chronic activation of the immune system, which leads to systemic self-directed inflammation in genetically predisposed individuals. Mutations in inflammasome-related proteins have been associated with autoinflammatory disorders, and the link between inflammasome and autoimmune disorders is becoming increasingly clear. As researchers learn more about these two areas, other disorders that were once thought to be autoimmune are now being considered autoinflammatory, or as having at least an autoinflammatory component. This review depicts the role of interleukin-1 as "Ariadne's thread" on the path through the labyrinth of autoinflammatory and autoimmune disorders and emphasizes the blurred boundary between innate and adaptive immune systems.

  13. Cryopyrin-Associated Autoinflammatory Syndromes (CAPS) - Juvenile

    MedlinePlus

    ... MACRA Glossary MACRA Resources Position Statements Insurance Advocacy Current Issues Tools & Resources Practice Resources Practice Publications Audit Programs Coding Coding Guidelines ICD-10 E/M CPT Coding Support Evaluation & Management FAQs Infusion FAQs Incident-to FAQs Injection FAQs ...

  14. Cryopyrin-Associated Autoinflammatory Syndromes (CAPS) - Juvenile

    MedlinePlus

    ... Clinician Researchers Six Minute Walk Test (SMWT) Arthritis Impact Measurement Scales (AIMS) Evidence Based Practice (EBP) Fibromyalgia Impact Questionnaire (FIQ) Fracture Risk Assessment Tool (FRAX) Multidimensional ...

  15. [Auto-inflammatory syndromes and pregnancy].

    PubMed

    Stankovic, Katia; Hentgen, Véronique; Grateau, Gilles

    2008-11-01

    In familial mediterranean fever (FMF), fertility is normal in treated patients. There is no abnormality of spermatogenesis under usual therapeutic doses of colchicine. The risk of early abortion is increased if inflammatory attacks occur during the pregnancy. It is recommended to continue colchicine treatment during the conception and the pregnancy. Careful follow-up must be organized, even more in patients with renal amyloidosis. Breast-feeding is allowed under colchicine with no risk for the baby. There is no indication for systematic amniocentesis in FMF patients treated with colchicine.

  16. OTULIN deficiency causes auto-inflammatory syndrome.

    PubMed

    Fiil, Berthe Katrine; Gyrd-Hansen, Mads

    2016-11-01

    Ubiquitin chains assembled via the N-terminal methionine (Met1 or linear ubiquitin), conjugated by the linear ubiquitin chain assembly complex (LUBAC), participate in NF-κΒ-dependent inflammatory signaling and immune responses. A recent report in Cell finds that OTULIN, a deubiquitinase that selectively cleaves Met1-linked ubiquitin chains, is essential for restraining inflammation in vivo.

  17. Monogenic diabetes: implications for therapy of rare types of disease.

    PubMed

    Malecki, Maciej T; Mlynarski, Wojciech

    2008-08-01

    There are two major forms of diabetes: type 1 and type 2. However, monogenic diabetes, associated with severe beta-cell dysfunction or with severe resistance to insulin action, is diagnosed with increasing frequency by genetic testing. The list of such forms of diabetes includes MODY, mitochondrial diabetes, permanent neonatal diabetes (PNDM) and transient neonatal diabetes, familial lipodystrophies and some others. These rare forms constitute probably at least a few per cent of all diabetes cases seen in diabetic clinics. The identification of the molecular background of specific forms of diabetes gives new insight into the underlying aetiology. This knowledge helps to optimize treatment in specific clinical situations. The proper differential diagnosis also helps to predict the progress of diabetes in affected individuals and defines the prognosis in the family. For example, in patients with MODY2 because of glucokinase mutations who have very mild diabetes characterized by modest fasting, hyperglycaemia diet is frequently sufficient. Some other forms of monogenic diabetes associated with impaired function of the beta-cell, such as MODY3 and PNDM linked to mutations in Kir6.2 and SUR1 genes, can be successfully managed by sulphonylurea agents. Although the examples of pharmacogenetics seem to be less spectacular in rare syndromes of insulin resistance, those patients can also benefit from genetic testing. In this paper, the aetiology of some monogenic diabetes forms is reviewed together with the clinical aspects of management of the affected individuals.

  18. Lung Involvement in Children with Hereditary Autoinflammatory Disorders

    PubMed Central

    Tarantino, Giusyda; Esposito, Susanna; Andreozzi, Laura; Bracci, Benedetta; D’Errico, Francesca; Rigante, Donato

    2016-01-01

    Short-lived systemic inflammatory reactions arising from disrupted rules in the innate immune system are the operating platforms of hereditary autoinflammatory disorders (HAIDs). Multiple organs may be involved and aseptic inflammation leading to disease-specific phenotypes defines most HAIDs. Lungs are infrequently involved in children with HAIDs: the most common pulmonary manifestation is pleuritis in familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), respectively caused by mutations in the MEFV and TNFRSF1A genes, while interstitial lung disease can be observed in STING-associated vasculopathy with onset in infancy (SAVI), caused by mutations in the TMEM173 gene. The specific pleuropulmonary diseases may range from sub-clinical abnormalities during inflammatory flares of FMF and TRAPS to a severe life-threatening disorder in children with SAVI. PMID:27983684

  19. Pyrin Inflammasome Activation and RhoA Signaling in the Autoinflammatory Diseases FMF and HIDS

    PubMed Central

    Park, Yong Hwan; Wood, Geryl; Kastner, Daniel L.; Chae, Jae Jin

    2016-01-01

    Mutations of pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases, familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutated or in response to bacterial modification of the GTPase RhoA. Here we show that RhoA activates the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin binds 14-3-3 proteins, which block the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin is substantially decreased, and the constitutive IL-1β release from FMF or HIDS patients’ peripheral blood mononuclear cells is attenuated by activating PKN1 and PKN2. Defects in prenylation, seen in HIDS, lead to RhoA inactivation and consequent pyrin inflammasome activation. These data indicate a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders. PMID:27270401

  20. Lombardia GENS: a collaborative registry for monogenic diseases associated with stroke.

    PubMed

    Bersano, Anna; Baron, Pierluigi; Lanfranconi, Silvia; Trobia, Nadia; Sterzi, Roberto; Motto, Cristina; Comi, Giancarlo; Sessa, Maria; Martinelli-Boneschi, Filippo; Micieli, Giuseppe; Ferrarese, Carlo; Santoro, Patrizia; Parati, Eugenio; Boncoraglio, Giorgio; Padovani, Alessandro; Pezzini, Alessandro; Candelise, Livia

    2012-01-01

    The Italian region of Lombardy, with its existing stroke centers and high-technology laboratories, provides a favorable context for studying monogenic diseases associated with stroke. The Lombardia GENS project was set up to create a regional network for the diagnosis of six monogenic diseases associated with stroke: CADASIL, Fabry disease, MELAS, familial and sporadic hemiplegic migraine, hereditary cerebral amyloid angiopathy and Marfan syndrome. The network comprises 36 stroke centers and seven high-technology laboratories, performing molecular analysis. In this context, all stroke/TIA patients fulfilling clinical criteria for monogenic diseases are currently being included in an ongoing study. Demographic, clinical and family data and diagnostic criteria are collected using standardized forms. On the basis of stroke incidence in Lombardy and the reported prevalence of the diseases considered, we expect, during the course of the study, to collect datasets and DNA samples from more than 200 stroke patients suspected of having monogenic diseases. This will allow evaluation of the regional burden and better phenotype characterization of monogenic diseases associated with stroke.

  1. Untangling the Web of Systemic Autoinflammatory Diseases

    PubMed Central

    Rigante, Donato; Lopalco, Giuseppe; Vitale, Antonio; Lucherini, Orso Maria; Caso, Francesco; De Clemente, Caterina; Molinaro, Francesco; Messina, Mario; Costa, Luisa; Atteno, Mariangela; Laghi-Pasini, Franco; Lapadula, Giovanni; Galeazzi, Mauro; Iannone, Florenzo; Cantarini, Luca

    2014-01-01

    The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment. PMID:25132737

  2. Deep brain stimulation for monogenic dystonia.

    PubMed

    Aravamuthan, Bhooma R; Waugh, Jeff L; Stone, Scellig S

    2017-09-12

    Deep brain stimulation (DBS) has recently emerged as an important management option in children with medically refractory dystonia. DBS is most commonly used, best studied, and thought to be most efficacious for a select group of childhood or adolescent onset monogenic dystonias (designated with a standard 'DYT' prefix). We review how to clinically recognize these types of dystonia and the relative efficacy of DBS for key monogenic dystonias. Though used for dystonia in adults for several years, DBS has only lately been used in children. Recent evidence shows that patients with shorter duration of dystonia often experience greater benefit following DBS. This suggests that early recognition of the appropriate dystonic phenotypes and consideration of DBS in these patients may improve the management of dystonia. DBS should be considered early in patients who have medically refractory dystonia, especially for the monogenic dystonias that have a high response rate to DBS. It is important to differentiate between these monogenic dystonias and dystonias of other causes to properly prognosticate for these patients and to determine whether DBS is an appropriate management option.

  3. Precision diabetes: learning from monogenic diabetes.

    PubMed

    Hattersley, Andrew T; Patel, Kashyap A

    2017-05-01

    The precision medicine approach of tailoring treatment to the individual characteristics of each patient or subgroup has been a great success in monogenic diabetes subtypes, MODY and neonatal diabetes. This review examines what has led to the success of a precision medicine approach in monogenic diabetes (precision diabetes) and outlines possible implications for type 2 diabetes. For monogenic diabetes, the molecular genetics can define discrete aetiological subtypes that have profound implications on diabetes treatment and can predict future development of associated clinical features, allowing early preventative or supportive treatment. In contrast, type 2 diabetes has overlapping polygenic susceptibility and underlying aetiologies, making it difficult to define discrete clinical subtypes with a dramatic implication for treatment. The implementation of precision medicine in neonatal diabetes was simple and rapid as it was based on single clinical criteria (diagnosed <6 months of age). In contrast, in MODY it was more complex and slow because of the lack of single criteria to identify patients, but it was greatly assisted by the development of a diagnostic probability calculator and associated smartphone app. Experience in monogenic diabetes suggests that successful adoption of a precision diabetes approach in type 2 diabetes will require simple, quick, easily accessible stratification that is based on a combination of routine clinical data, rather than relying on newer technologies. Analysing existing clinical data from routine clinical practice and trials may provide early success for precision medicine in type 2 diabetes.

  4. On Convergence Aspects of Spheroidal Monogenics

    NASA Astrophysics Data System (ADS)

    Georgiev, S.; Morais, J.

    2011-09-01

    Orthogonal polynomials have found wide applications in mathematical physics, numerical analysis, and other fields. Accordingly there is an enormous amount of variety of such polynomials and relations that describe their properties. The paper's main results are the discussion of approximation properties for monogenic functions over prolate spheroids in R3 in terms of orthogonal monogenic polynomials and their interdependences. Certain results are stated without proof for now. The motivation for the present study stems from the fact that these polynomials play an important role in the calculation of the Bergman kernel and Green's monogenic functions in a spheroid. Once these functions are known, it is possible to solve both basic boundary value and conformal mapping problems. Interestingly, most of the used methods have a n-dimensional counterpart and can be extended to arbitrary ellipsoids. But such a procedure would make the further study of the underlying ellipsoidal monogenics somewhat laborious, and for this reason we shall not discuss these general cases here. To the best of our knowledge, this does not appear to have been done in literature before.

  5. Incidence of hereditary amyloidosis and autoinflammatory diseases in Sweden: endemic and imported diseases

    PubMed Central

    2013-01-01

    Background Amyloidoses are a heterogeneous group of progressive diseases caused by tissue deposition of misfolded proteins. According to the International Classification of Diseases, hereditary amyloidosis is divided into neuropathic and non-neuropathic forms. In Sweden, neuropathic heredofamilial amyloidosis has been identified as familial amyloidotic polyneuropathy (FAP), a fatal disease that is treated by liver transplantation. The non-neuropathic form includes familial autoinflammatory diseases. As no incidence data on these hereditary diseases are available and as even diagnostic data on non-neuropathic forms are lacking we determined the incidence of these diseases and characterized non-neuropathic conditions. Methods Patients were identified using data from the Swedish Hospital Discharge Register and from the Outpatient Register for 2001 through 2008. All patients discharged with hereditary amyloidosis diagnoses were included and standardized incidence rates were calculated. Results Non-neuropathic disease was diagnosed in 210 patients, with an incidence of 2.83 per million. FAP was diagnosed in 221 patients, with an incidence of 2.02 per million. Two northern provinces that are home to 5% of the Swedish population accounted for 77% of FAP cases; the incidence in one of them, West Bothnia, was 100 times that in the rest of Sweden. Approximately 98% of non-neuropathic disease patients were immigrants, most of whom were from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500-fold higher than that in individuals with Swedish parents. Even the early onset of these conditions identified them as familial autoinflammatory diseases. Conclusions FAP cases were highly concentrated in the two northernmost provinces. Non-neuropathic familial autoinflammatory diseases were of early-onset and immigrant origin most likely related to periodic fever syndromes. Paradoxically, FAP has remained endemic, in spite of

  6. The revolution in human monogenic disease mapping.

    PubMed

    Duncan, Emma; Brown, Matthew; Shore, Eileen M

    2014-09-05

    The successful completion of the Human Genome Project (HGP) was an unprecedented scientific advance that has become an invaluable resource in the search for genes that cause monogenic and common (polygenic) diseases. Prior to the HGP, linkage analysis had successfully mapped many disease genes for monogenic disorders; however, the limitations of this approach were particularly evident for identifying causative genes in rare genetic disorders affecting lifespan and/or reproductive fitness, such as skeletal dysplasias. In this review, we illustrate the challenges of mapping disease genes in such conditions through the ultra-rare disorder fibrodysplasia ossificans progressiva (FOP) and we discuss the advances that are being made through current massively parallel ("next generation") sequencing (MPS) technologies.

  7. A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis.

    PubMed

    Ferguson, Polly J; Bing, Xinyu; Vasef, Mohammed A; Ochoa, Luis A; Mahgoub, Amar; Waldschmidt, Thomas J; Tygrett, Lorraine T; Schlueter, Annette J; El-Shanti, Hatem

    2006-01-01

    Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that primarily affects bone but is often accompanied by inflammation of the skin and/or gastrointestinal tract. The etiology is unknown but evidence suggests a genetic component to disease susceptibility. Although most cases of CRMO are sporadic, there is an autosomal recessive syndromic form of the disease, called Majeed syndrome, which is due to homozygous mutations in LPIN2. In addition, there is a phenotypically similar mouse, called cmo (chronic multifocal osteomyelitis) in which the disease is inherited as an autosomal recessive disorder. The cmo locus has been mapped to murine chromosome 18. In this report, we describe phenotypic abnormalities in the cmo mouse that include bone, cartilage and skin inflammation. Utilizing a backcross breeding strategy, we refined the cmo locus to a 1.3 Mb region on murine chromosome 18. Within the refined region was the gene pstpip2, which shares significant sequence homology to the PSTPIP1. Mutations in PSTPIP1 have been shown to cause the autoinflammatory disorder PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne). Mutation analysis, utilizing direct sequencing, revealed a single base pair change c.293T --> C in the pstpip2 gene resulting in a highly conserved leucine at amino acid 98 being replaced by a proline (L98P). No other mutations were found in the coding sequence of the remaining genes in the refined interval, although a 50 kb gap remains unexplored. These data suggest that mutations in pstpip2 may be the genetic explanation for the autoinflammatory phenotype seen in the cmo mouse.

  8. Neutrophilic dermatoses and autoinflammatory diseases with skin involvement--innate immune disorders.

    PubMed

    Navarini, Alexander A; Satoh, Takashi K; French, Lars E

    2016-01-01

    Neutrophilic dermatoses (NDs) such as Sweet's syndrome and pyoderma gangrenosum were first described more than 50 years ago and grouped based on their clinical features combined with the typical, neutrophil-rich cutaneous inflammation. In contrast, the recently identified autoinflammatory diseases (ADs) that are also associated with neutrophil granulocyte infiltration of the skin were first characterized based on their genetic architecture. Though both the older ND and the newer AD encompass distinct conditions, they can be seen as parts of a spectrum of innate inflammation. Both groups of diseases show so many overlapping clinical, pathogenetic, histologic, and genetic features that together they should likely be considered as innate immune disorders.

  9. Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

    PubMed

    Bersano, Anna; Markus, Hugh Stephen; Quaglini, Silvana; Arbustini, Eloisa; Lanfranconi, Silvia; Micieli, Giuseppe; Boncoraglio, Giorgio B; Taroni, Franco; Gellera, Cinzia; Baratta, Silvia; Penco, Silvana; Mosca, Lorena; Grasso, Maurizia; Carrera, Paola; Ferrari, Maurizio; Cereda, Cristina; Grieco, Gaetano; Corti, Stefania; Ronchi, Dario; Bassi, Maria Teresa; Obici, Laura; Parati, Eugenio A; Pezzini, Alessando; De Lodovici, Maria Luisa; Verrengia, Elena P; Bono, Giorgio; Mazucchelli, Francesca; Zarcone, Davide; Calloni, Maria Vittoria; Perrone, Patrizia; Bordo, Bianca Maria; Colombo, Antonio; Padovani, Alessandro; Cavallini, Anna; Beretta, Simone; Ferrarese, Carlo; Motto, Cristina; Agostoni, Elio; Molini, Graziella; Sasanelli, Francesco; Corato, Manuel; Marcheselli, Simona; Sessa, Maria; Comi, Giancarlo; Checcarelli, Nicoletta; Guidotti, Mario; Uccellini, Davide; Capitani, Erminio; Tancredi, Lucia; Arnaboldi, Marco; Incorvaia, Barbara; Tadeo, Carlo Sebastiano; Fusi, Laura; Grampa, Giampiero; Merlini, Giampaolo; Trobia, Nadia; Comi, Giacomo Pietro; Braga, Massimiliano; Vitali, Paolo; Baron, Pierluigi; Grond-Ginsbach, Caspar; Candelise, Livia

    2016-07-01

    Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series. © 2016 American Heart Association, Inc.

  10. The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases

    PubMed Central

    de Torre-Minguela, Carlos; Mesa del Castillo, Pablo; Pelegrín, Pablo

    2017-01-01

    Inflammasomes are multiprotein complexes that critically control different aspects of innate and adaptive immunity. Among them we could highlight the release of pro-inflammatory cytokines that induce and maintain the inflammatory response. Usually, inflammasomes result from oligomerization of a nucleotide-binding domain-like receptor (NLR) after sensing different pathogenic or endogenous sterile dangerous signals; however, other proteins such as absent in melanoma 2, retinoic acid-inducible gene I, or pyrin could also form inflammasome platforms. Inflammasome oligomerization leads to caspase-1 activation and the processing and release of the pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Mutations in different inflammasomes are causative for multiple periodic hereditary syndromes or autoinflammatory diseases, characterized by acute systemic inflammatory flares not associated with infections, tumors, or autoimmunity. This review focuses on germline mutations that have been described in cryopyrin-associated periodic syndrome (CAPS) for NLRP3 or in familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) for MEFV. Besides the implication of inflammasomes in autoinflammatory syndromes, these molecular platforms are involved in the pathophysiology of different illnesses, including chronic inflammatory diseases, degenerative processes, fibrosis, or metabolic diseases. Therefore, drug development targeting inflammasome activation is a promising field in expansion. PMID:28191008

  11. An Up-to-date Approach to a Patient with a Suspected Autoinflammatory Disease

    PubMed Central

    Lidar, Merav; Giat, Eitan

    2017-01-01

    Autoinflammatory diseases (AID) are characterized by seemingly unprovoked self-limited attacks of fever and systemic inflammation potentially leading to amyloidosis. Familial Mediterranean fever (FMF) is the most common AID and therefore the most studied. Besides FMF, the other main hereditary AID are tumor necrosis factor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic fever syndrome (CAPS). These hereditary diseases result from a mutant gene that is involved in the regulation of inflammation, resulting in a characteristic clinical phenotype. The differential diagnosis of AID can be challenging due to a wide overlap in clinical manifestations. Moreover, a considerable proportion of patients present with autoinflammatory symptoms but without a pathogenetic variant on genetic analysis. Furthermore, non-hereditary AID, such as the periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, which is the most common AID in children worldwide, must be excluded in certain circumstances. Herein we shall review the main AID and describe a practical approach to diagnosis in a patient with a clinical suspicion of AID. PMID:28178435

  12. The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases.

    PubMed

    de Torre-Minguela, Carlos; Mesa Del Castillo, Pablo; Pelegrín, Pablo

    2017-01-01

    Inflammasomes are multiprotein complexes that critically control different aspects of innate and adaptive immunity. Among them we could highlight the release of pro-inflammatory cytokines that induce and maintain the inflammatory response. Usually, inflammasomes result from oligomerization of a nucleotide-binding domain-like receptor (NLR) after sensing different pathogenic or endogenous sterile dangerous signals; however, other proteins such as absent in melanoma 2, retinoic acid-inducible gene I, or pyrin could also form inflammasome platforms. Inflammasome oligomerization leads to caspase-1 activation and the processing and release of the pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Mutations in different inflammasomes are causative for multiple periodic hereditary syndromes or autoinflammatory diseases, characterized by acute systemic inflammatory flares not associated with infections, tumors, or autoimmunity. This review focuses on germline mutations that have been described in cryopyrin-associated periodic syndrome (CAPS) for NLRP3 or in familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) for MEFV. Besides the implication of inflammasomes in autoinflammatory syndromes, these molecular platforms are involved in the pathophysiology of different illnesses, including chronic inflammatory diseases, degenerative processes, fibrosis, or metabolic diseases. Therefore, drug development targeting inflammasome activation is a promising field in expansion.

  13. An Up-to-date Approach to a Patient with a Suspected Autoinflammatory Disease.

    PubMed

    Lidar, Merav; Giat, Eitan

    2017-01-30

    Autoinflammatory diseases (AID) are characterized by seemingly unprovoked self-limited attacks of fever and systemic inflammation potentially leading to amyloidosis. Familial Mediterranean fever (FMF) is the most common AID and therefore the most studied. Besides FMF, the other main hereditary AID are tumor necrosis factor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic fever syndrome (CAPS). These hereditary diseases result from a mutant gene that is involved in the regulation of inflammation, resulting in a characteristic clinical phenotype. The differential diagnosis of AID can be challenging due to a wide overlap in clinical manifestations. Moreover, a considerable proportion of patients present with autoinflammatory symptoms but without a pathogenetic variant on genetic analysis. Furthermore, non-hereditary AID, such as the periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, which is the most common AID in children worldwide, must be excluded in certain circumstances. Herein we shall review the main AID and describe a practical approach to diagnosis in a patient with a clinical suspicion of AID.

  14. [Whole-Exome Sequencing for monogenic disorders affecting the orthopaedic system].

    PubMed

    Imagawa, Eri; Miyake, Noriko; Matsumoto, Naomichi

    2016-04-01

    Next-generation sequencing technologies enable comprehensive genetic analyses in monogenic and oligonenic diseases. Especially whole-exome sequencing(WES)targeting exonic regions of protein coding genes is mainly used for Mendelian diseases. Here we describe a case of Hand-foot-genital syndrome arising from a HOXA13 mutation[c.1102A>T(p.Ile368Phe)]as one of successful examples in our successful WES analyses.

  15. Exome Sequencing in Suspected Monogenic Dyslipidemias

    PubMed Central

    Stitziel, Nathan O.; Peloso, Gina M.; Abifadel, Marianne; Cefalu, Angelo B.; Fouchier, Sigrid; Motazacker, M. Mahdi; Tada, Hayato; Larach, Daniel B.; Awan, Zuhier; Haller, Jorge F.; Pullinger, Clive R.; Varret, Mathilde; Rabès, Jean-Pierre; Noto, Davide; Tarugi, Patrizia; Kawashiri, Masa-aki; Nohara, Atsushi; Yamagishi, Masakazu; Risman, Marjorie; Deo, Rahul; Ruel, Isabelle; Shendure, Jay; Nickerson, Deborah A.; Wilson, James G.; Rich, Stephen S.; Gupta, Namrata; Farlow, Deborah N.; Neale, Benjamin M.; Daly, Mark J.; Kane, John P.; Freeman, Mason W.; Genest, Jacques; Rader, Daniel J.; Mabuchi, Hiroshi; Kastelein, John J.P.; Hovingh, G. Kees; Averna, Maurizio R.; Gabriel, Stacey; Boileau, Catherine; Kathiresan, Sekar

    2015-01-01

    Background Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies. PMID:25632026

  16. Monogenic causes of stroke: now and the future.

    PubMed

    Tan, Rhea Y Y; Markus, Hugh S

    2015-12-01

    Most stroke is multifactorial with multiple polygenic risk factors each conferring small increases in risk interacting with environmental risk factors, but it can also arise from mutations in a single gene. This review covers single-gene disorders which lead to stroke as a major phenotype, with a focus on those which cause cerebral small vessel disease (SVD), an area where there has been significant recent progress with findings that may inform us about the pathogenesis of SVD more broadly. We also discuss the impact that next generation sequencing technology (NGST) is likely to have on clinical practice in this area. The most common form of monogenic SVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, due to the mutations in the NOTCH3 gene. Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV α1 and α2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. These monogenic forms of SVD, with overlapping clinical phenotypes, are beginning to provide insights into how the small arteries in the brain can be damaged and some of the mechanisms identified may also be relevant to more common sporadic SVD. Despite the discovery of these disorders, it is often challenging to clinically and radiologically distinguish between syndromes, while screening multiple genes for causative mutations that can be costly and time-consuming. The rapidly falling cost of NGST may allow quicker diagnosis of these rare causes of SVD, and can also identify previously unknown disease-causing variants.

  17. Harmonic and Monogenic Potentials in Euclidean Halfspace

    NASA Astrophysics Data System (ADS)

    Brackx, F.; De Bie, H.; De Schepper, H.

    2011-09-01

    In the framework of Clifford analysis a chain of harmonic and monogenic potentials is constructed in the upper half of Euclidean space Rm+1. Their distributional limits at the boundary are computed, obtaining in this way well-known distributions in Rm such as the Dirac distribution, the Hilbert kernel, the square root of the negative Laplace operator, and the like. It is shown how each of those potentials may be recovered from an adjacent kernel in the chain by an appropriate convolution with such a distributional limit.

  18. Monogenic Forms of Diabetes: Neonatal Diabetes Mellitus and Maturity-Onset Diabetes of the Young

    MedlinePlus

    ... Diabetes Monogenic Forms of Diabetes Monogenic Forms of Diabetes The most common forms of diabetes, type 1 ... is inherited from each parent. Monogenic Forms of Diabetes Some rare forms of diabetes result from mutations ...

  19. [Monogenic causes of X-linked mental retardation].

    PubMed

    Guillén-Navarro, E; Glóver-López, G

    2006-01-07

    The term X-linked mental retardation (XLMR) refers to a heterogeneous group of conditions that, on the basis of their presenting symptoms, have traditionally been classified as being syndromic (SMR) and non-syndromic or non-specific (XMR). The prevalence of XLMR in males is estimated to be 10%, excluding fragile X syndrome, which is the most common monogenic cause. There are over 100 genes involved in XLMR. In this work we review some of the phenotypes and genes involved in SMR. A small stature and coarse features indicate a suspected case of Coffin-Lowry syndrome, which is secondary to mutations of the RPS6KA3 or RSK2 genes. Cerebellar hypoplasia points towards alterations of the OPHN1 gene. In males with coarse features and genital abnormalities screening for alpha thalassemia must be carried out; this association results from mutations in the ATRX gene. Of the genes involved in mental retardation and epilepsy, the most notable are SLC6A8 (which triggers a deficit in creatine transport when altered and which is easily detected with respect to its biochemistry) and ARX (also associated to lissencephaly and dystonia of the hands). Mutations in the PQBP1 and JARID1C genes have been identified in patients with mental retardation associated to microcephaly and short stature. A high level of T3 hormone points towards defects in the SLC16A2 gene. Some of these genes have also been implicated in XMR, which makes this distinction less clear molecularly speaking. Systematic screening of all the genes involved in XLMR is not possible in clinical praxis today. It is important to search for differential phenotypic features in males with mental retardation that guide the study towards specific genes. Identification of the molecular defect will allow for correct genetic counselling. DNA microarrays for the study of different mutations in a large number of genes involved in mental retardation are the great hope for the future.

  20. PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders.

    PubMed

    Veillette, André; Rhee, Inmoo; Souza, Cleiton Martins; Davidson, Dominique

    2009-03-01

    The proline-, glutamic acid-, serine- and threonine-rich (PEST) family of protein tyrosine phosphatases (PTPs) includes proline-enriched phosphatase (PEP)/lymphoid tyrosine phosphatase (LYP), PTP-PEST, and PTP-hematopoietic stem cell fraction (HSCF). PEP/LYP is a potent inhibitor of T-cell activation, principally by suppressing the activity of Src family protein tyrosine kinases (PTKs). This function seems to be dependent, at least in part, on the ability of PEP to bind C-terminal Src kinase (Csk), a PTK also involved in inactivating Src kinases. Interestingly, a polymorphism of LYP in humans (R620W) is a significant risk factor for autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and lupus. The R620W mutation may be a 'gain-of-function' mutation. In non-hematopoietic cells, PTP-PEST is a critical regulator of adhesion and migration. This effect correlates with the aptitude of PTP-PEST to dephosphorylate cytoskeletal proteins such as Cas, focal adhesion associated-kinase (FAK), Pyk2, and PSTPIP. While not established, a similar function may also exist in immune cells. Additionally, overexpression studies provided an indication that PTP-PEST may be a negative regulator of lymphocyte activation. Interestingly, mutations in a PTP-PEST- and PTP-HSCF-interacting protein, PSTPIP1, were identified in humans with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and familial recurrent arthritis, two autoinflammatory diseases. These mutations abrogate the ability of PSTPIP1 to bind PTP-PEST and PTP-HSCF, suggesting that these two PTPs may be negative regulators of inflammation.

  1. Clinical, biological, and imaging features of monogenic Alzheimer's Disease.

    PubMed

    Pilotto, Andrea; Padovani, Alessandro; Borroni, Barbara

    2013-01-01

    The discovery of monogenic forms of Alzheimer's Disease (AD) associated with mutations within PSEN1, PSEN2, and APP genes is giving a big contribution in the understanding of the underpinning mechanisms of this complex disorder. Compared with sporadic form, the phenotype associated with monogenic cases is somewhat broader including behavioural disturbances, epilepsy, myoclonus, and focal presentations. Structural and functional imaging show typical early changes also in presymptomatic monogenic carriers. Amyloid imaging and CSF tau/A β ratio may be useful in the differential diagnosis with other neurodegenerative dementias, especially, in early onset cases. However, to date any specific biomarkers of different monogenic cases have been identified. Thus, in clinical practice, the early identification is often difficult, but the copresence of different elements could help in recognition. This review will focus on the clinical and instrumental markers useful for the very early identification of AD monogenic cases, pivotal in the development, and evaluation of disease-modifying therapy.

  2. Myocarditis in auto-immune or auto-inflammatory diseases.

    PubMed

    Comarmond, Cloé; Cacoub, Patrice

    2017-08-01

    Myocarditis is a major cause of heart disease in young patients and a common precursor of heart failure due to dilated cardiomyopathy. Some auto-immune and/or auto-inflammatory diseases may be accompanied by myocarditis, such as sarcoidosis, Behçet's disease, eosinophilic granulomatosis with polyangiitis, myositis, and systemic lupus erythematosus. However, data concerning myocarditis in such auto-immune and/or auto-inflammatory diseases are sparse. New therapeutic strategies should better target the modulation of the immune system, depending on the phase of the disease and the type of underlying auto-immune and/or auto-inflammatory disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Autoinflammatory diseases in dermatology: CAPS, TRAPS, HIDS, FMF, Blau, CANDLE.

    PubMed

    Tripathi, Shivani V; Leslie, Kieron S

    2013-07-01

    Autoinflammatory diseases, including CAPS, TRAPS, HIDS, FMF, Blau, and CANDLE, have unique dermatologic presentations that can be a clue to diagnosis. Although these conditions are rare, the morbidity and mortality can be severe, and well-informed physicians can place these conditions in their differential diagnosis when familiar with the dermatologic manifestations. This review article presents a brief overview of each condition, clues to diagnosis that focus of dermatologic manifestations and clinical images, basic laboratory tests and follow-up, a brief review of treatments, and concludes with an overview for these autoinflammatory conditions and their differential diagnoses. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.

    PubMed

    Park, Yong Hwan; Wood, Geryl; Kastner, Daniel L; Chae, Jae Jin

    2016-08-01

    Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin was substantially decreased, and the constitutive IL-1β release from peripheral blood mononuclear cells of patients with FMF or HIDS was attenuated by activation of PKN1 and PKN2. Defects in prenylation, seen in HIDS, led to RhoA inactivation and consequent pyrin inflammasome activation. These data suggest a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders.

  5. Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders.

    PubMed

    Lopalco, Giuseppe; Rigante, Donato; Giannini, Margherita; Galeazzi, Mauro; Lapadula, Giovanni; Iannone, Florenzo; Cantarini, Luca

    2016-01-01

    Anakinra is a biologic response modifier that competitively antagonises the biologic effects of interleukin-1, the ancestor pleiotropic proinflammatory cytokine produced by numerous cell types, found in excess in the serum, synovial fluid and any involved tissues of patients with many inflammatory diseases. The magnitude of the risk of different infections, including Mycobacterium tuberculosis (Mtb) infection, associated with the large use of anakinra in many rheumatologic, metabolic or autoinflammatory disorders is still unknown. In addition, it is unclear whether this effect is modified by the concomitant use of antirheumatic drugs and corticosteroids. The rates of development of Mtb disease in patients treated with anakinra due to rheumatoid arthritis, systemic autoinflammatory diseases, Schnitzler's syndrome, Behçet's disease, adult-onset Still disease, systemic juvenile idiopathic arthritis, gout and diabetes mellitus have been usually very low. However, clinicians must carefully weigh the benefits of biological drugs against their risks, particularly in patients prone to infections. Additional data are needed to understand whether this risk of Mtb infection and reactivation are representative of a class effect related to biologics or whether anakinra bears specifically an intrinsic lower risk in comparison with other biologic drugs.

  6. Live birth after PGD with confirmation by a comprehensive approach (karyomapping) for simultaneous detection of monogenic and chromosomal disorders.

    PubMed

    Natesan, Senthilkumar A; Handyside, Alan H; Thornhill, Alan R; Ottolini, Christian S; Sage, Karen; Summers, Michael C; Konstantinidis, Michalis; Wells, Dagan; Griffin, Darren K

    2014-11-01

    Preimplantation genetic diagnosis (PGD) for monogenic disorders has the drawback of time and cost associated with tailoring a specific test for each couple, disorder, or both. The inability of any single assay to detect the monogenic disorder in question and simultaneously the chromosomal complement of the embryo also limits its application as separate tests may need to be carried out on the amplified material. The first clinical use of a novel approach ('karyomapping') was designed to circumvent this problem. In this example, karyomapping was used to confirm the results of an existing PGD case detecting both chromosomal abnormalities and a monogenic disorder (Smith-Lemli-Opitz [SLO] syndrome) simultaneously. The family underwent IVF, ICSI and PGD, and both polar body and cleavage stage biopsy were carried out. Following whole genome amplification, array comparative genomic hybridisation of the polar bodies and minisequencing and STR analysis of single blastomeres were used to diagnose maternal aneuploidies and SLO status, respectively. This was confirmed, by karyomapping. Unlike standard PGD, karyomapping required no a-priori test development. A singleton pregnancy and live birth, unaffected with SLO syndrome and with no chromosome abnormality, ensued. Karyomapping is potentially capable of detecting a wide spectrum of monogenic and chromosome disorders and, in this context, can be considered a comprehensive approach to PGD.

  7. Gene therapy for monogenic disorders of the bone marrow.

    PubMed

    Ghosh, Sujal; Thrasher, Adrian J; Gaspar, H Bobby

    2015-06-05

    Ex-vivo gene transfer of autologous haematopoietic stem cells in patients with monogenic diseases of the bone marrow has emerged as a new therapeutic approach, mainly in patients lacking a suitable donor for transplant. The encouraging results of initial clinical trials of gene therapy for primary immunodeficiencies were tempered by the occurrence of genotoxicity in a number of patients. Over the last decade, safer viral vectors have been developed to overcome the risk of insertional mutagenesis and have led to impressive clinical outcomes with considerably improved safety. We review the efforts in specific immunodeficiencies including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease and Wiskott Aldrich syndrome. Major recent progress has also been made in haemoglobinopathies, such as beta-thalassaemia, sickle cell disease and Fanconi anaemia, and also specific lysosomal storage diseases, which, although not strictly bone marrow specific conditions, have been effectively treated by bone marrow-based treatment. The success of these recent studies and the advent of new technologies, such as gene editing, suggest that gene therapy could become a more generally applied treatment modality for a number of haematopoietic disorders.

  8. Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases.

    PubMed

    Marzano, Angelo V; Ceccherini, Isabella; Gattorno, Marco; Fanoni, Daniele; Caroli, Francesco; Rusmini, Marta; Grossi, Alice; De Simone, Clara; Borghi, Orietta M; Meroni, Pier Luigi; Crosti, Carlo; Cugno, Massimo

    2014-12-01

    The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1β and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1β, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin.

  9. The RH boundary value problem of the k-monogenic functions

    NASA Astrophysics Data System (ADS)

    Bu, Yude; Du, Jinyuan

    2008-11-01

    In this paper we study the Riemann and Hilbert problems of k-monogenic functions. By using Euler operator, we transform the boundary value problem of k-monogenic functions into the boundary value problems of monogenic functions. Then by the Almansi-type theorem of k-monogenic functions, we get the solutions of these problems.

  10. New insights from monogenic diabetes for "common" type 2 diabetes.

    PubMed

    Tallapragada, Divya Sri Priyanka; Bhaskar, Seema; Chandak, Giriraj R

    2015-01-01

    Boundaries between monogenic and complex genetic diseases are becoming increasingly blurred, as a result of better understanding of phenotypes and their genetic determinants. This had a large impact on the way complex disease genetics is now being investigated. Starting with conventional approaches like familial linkage, positional cloning and candidate genes strategies, the scope of complex disease genetics has grown exponentially with scientific and technological advances in recent times. Despite identification of multiple loci harboring common and rare variants associated with complex diseases, interpreting and evaluating their functional role has proven to be difficult. Information from monogenic diseases, especially related to the intermediate traits associated with complex diseases comes handy. The significant overlap between traits and phenotypes of monogenic diseases with related complex diseases provides a platform to understand the disease biology better. In this review, we would discuss about one such complex disease, type 2 diabetes, which shares marked similarity of intermediate traits with different forms of monogenic diabetes.

  11. On the Bargmann-Radon transform in the monogenic setting

    NASA Astrophysics Data System (ADS)

    Colombo, Fabrizio; Sabadini, Irene; Sommen, Franciscus

    2017-10-01

    In this paper, we introduce and study a Bargmann-Radon transform on the real monogenic Bargmann module. This transform is defined as the projection of the real Bargmann module on the closed submodule of monogenic functions spanned by the monogenic plane waves. We prove that this projection can be written in integral form in terms the so-called Bargmann-Radon kernel. Moreover, we have a characterization formula for the Bargmann-Radon transform of a function in the real Bargmann module in terms of its complex extension and then its restriction to the nullcone in Cm. We also show that the formula holds for the Szegő-Radon transform that we introduced in Colombo et al. (2016) and we define the dual transform and we provide an inversion formula. Finally, in Theorem 5.6, we prove an integral formula for the monogenic part of an entire function.

  12. Thiamine transporter mutation: an example of monogenic diabetes mellitus.

    PubMed

    Alzahrani, Ali S; Baitei, Essa; Zou, Minging; Shi, Yufei

    2006-12-01

    Thiamine-responsive megaloblastic anemia (TRMA) is a rare syndrome characterized by diabetes mellitus (DM), anemia, and sensorineural deafness. We describe the clinical course and the molecular defect of a young woman who was diagnosed to have this syndrome. The patient is an 18-year-old girl who was born to non-consanguous parents. She was noted to be deaf-mute in the first year of life. She was diagnosed with DM at the age of 9 months and with severe anemia at the age of 2 years. An extensive work up could not identify the cause. She was treated with blood transfusions every 3-4 weeks for the past 16 years. A diagnosis of TRMA was suspected and the patient was treated with thiamine hydrochloride. Hemoglobin and platelets increased to normal values after a few weeks of thiamine therapy. Diabetic control significantly improved but she had no noticeable changes in the deafness. Peripheral blood DNA was extracted from the patient, her mother, aunt, and a healthy sister. Exons and exon-intron boundaries of the thiamine transporter gene SLC19A2 were PCR amplified and directly sequenced. A G515C homozygous mutation was identified in the SLC19A2 gene of the patient. This mutation changes Gly to Arg at codon 172 (G172R). The mother, an aunt, and a sister had a heterozygous G172R mutation. Mutations in thiamine transporter gene, SLC19A2, causes a rare form of monogenic diabetes, anemia, and sensorineural deafness. Thiamine induces a remarkable hematological response and improvement in the diabetic control but has no effect on deafness.

  13. Monogenic neurological disorders of sphingolipid metabolism.

    PubMed

    Sabourdy, Frédérique; Astudillo, Leonardo; Colacios, Céline; Dubot, Patricia; Mrad, Marguerite; Ségui, Bruno; Andrieu-Abadie, Nathalie; Levade, Thierry

    2015-08-01

    Sphingolipids comprise a wide variety of molecules containing a sphingoid long-chain base that can be N-acylated. These lipids are particularly abundant in the central nervous system, being membrane components of neurons as well as non-neuronal cells. Direct evidence that these brain lipids play critical functions in brain physiology is illustrated by the dramatic consequences of genetic disturbances of their metabolism. Inherited defects of both synthesis and catabolism of sphingolipids are now identified in humans. These monogenic disorders are due to mutations in the genes encoding for the enzymes that catalyze either the formation or degradation of simple sphingolipids such as ceramides, or complex sphingolipids like glycolipids. They cause varying degrees of central nervous system dysfunction, quite similarly to the neurological disorders induced in mice by gene disruption of the corresponding enzymes. Herein, the enzyme deficiencies and metabolic alterations that underlie these diseases are reviewed. Their possible pathophysiological mechanisms and the functions played by sphingolipids one can deduce from these conditions are discussed. This article is part of a Special Issue entitled Brain Lipids.

  14. Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease.

    PubMed

    Ahn, Jeonghyun; Barber, Glen N

    2014-12-01

    Self-DNA has long been considered a key cause of inflammatory and autoimmune disease, although the exact origin and general mechanisms of action have remained to be elucidated. Recently, new insight has been gained into our understanding of those innate immune pathways and sensors that are responsible for instigating self-DNA triggered autoinflammatory events in the cell. One such sensor referred to as STING (for stimulator of interferon genes) has been found to be seminal for controlling cytosolic-DNA induced cytokine production, and may be responsible for a wide variety of inflammatory diseases including systemic lupus erythematosus (SLE), Aicardi-Goutieres syndrome (AGS) and STING-associated vasculopathy with onset of infancy (SAVI). STING may also be involved with augmenting certain types of carcinogen induced cancer. Aside from generating valuable information into mechanisms underlining innate immune gene regulation, these findings offer new opportunities to generate innovative therapeutics which may help treat such diseases.

  15. From monogenic to polygenic obesity: recent advances

    PubMed Central

    Vogel, Carla I. G.; Hebebrand, Johannes

    2010-01-01

    The heritability of obesity and body weight in general is high. A small number of confirmed monogenic forms of obesity—the respective mutations are sufficient by themselves to cause the condition in food abundant societies—have been identified by molecular genetic studies. The elucidation of these genes, mostly based on animal and family studies, has led to the identification of important pathways to the disorder and thus to a deeper understanding of the regulation of body weight. The identification of inborn deficiency of the mostly adipocyte-derived satiety hormone leptin in extremely obese children from consanguineous families paved the way to the first pharmacological therapy for obesity based on a molecular genetic finding. The genetic predisposition to obesity for most individuals, however, has a polygenic basis. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Common variants in the first intron of the ‘fat mass and obesity associated’ gene (FTO) result in an elevated body mass index (BMI) equivalent to approximately +0.4 kg/m² per risk allele. The FTO variants were originally detected in a genome wide association study (GWAS) pertaining to type 2 diabetes mellitus. Large meta-analyses of GWAS have subsequently identified additional polygenic variants. Up to December 2009, polygenic variants have been confirmed in a total of 17 independent genomic regions. Further study of genetic effects on human body weight regulation should detect variants that will explain a larger proportion of the heritability. The development of new strategies for diagnosis, treatment and prevention of obesity can be anticipated. PMID:20127379

  16. Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient

    PubMed Central

    2006-01-01

    Monogenic diabetes results from one or more mutations in a single gene which might hence be rare but has great impact leading to diabetes at a very young age. It has resulted in great challenges for researchers elucidating the aetiology of diabetes and related features in other organ systems, for clinicians specifying a diagnosis that leads to improved genetic counselling, predicting of clinical course and changes in treatment, and for patients to altered treatment that has lead to coming off insulin and injections with no alternative (Glucokinase mutations), insulin injections being replaced by tablets (e.g. low dose in HNFα or high dose in potassium channel defects -Kir6.2 and SUR1) or with tablets in addition to insulin (e.g. metformin in insulin resistant syndromes). Genetic testing requires guidance to test for what gene especially given limited resources. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis (unspecified neonatal diabetes, type 1 or type 2 diabetes) and clinical features of a specific subtype of monogenic diabetes (neonatal diabetes, familial diabetes, mild hyperglycaemia, syndromes). Guidance is given by clinical and physiological features in patient and family and the likelihood of the proposed mutation altering clinical care. In this article, I aimed to provide insight in the genes and mutations involved in insulin synthesis, secretion, and resistance, and to provide guidance for genetic testing by showing the clinical and physiological features and tests for each specified diagnosis as well as the opportunities for treatment. PMID:17186387

  17. An autoinflammatory neurological disease due to interleukin 6 hypersecretion

    PubMed Central

    2013-01-01

    Autoinflammatory diseases are rare illnesses characterized by apparently unprovoked inflammation without high-titer auto-antibodies or antigen-specific T cells. They may cause neurological manifestations, such as meningitis and hearing loss, but they are also characterized by non-neurological manifestations. In this work we studied a 30-year-old man who had a chronic disease characterized by meningitis, progressive hearing loss, persistently raised inflammatory markers and diffuse leukoencephalopathy on brain MRI. He also suffered from chronic recurrent osteomyelitis of the mandible. The hypothesis of an autoinflammatory disease prompted us to test for the presence of mutations in interleukin-1−pathway genes and to investigate the function of this pathway in the mononuclear cells obtained from the patient. Search for mutations in genes associated with interleukin-1−pathway demonstrated a novel NLRP3 (CIAS1) mutation (p.I288M) and a previously described MEFV mutation (p.R761H), but their combination was found to be non-pathogenic. On the other hand, we uncovered a selective interleukin-6 hypersecretion within the central nervous system as the likely pathogenic mechanism. This is also supported by the response to the anti-interleukin-6−receptor monoclonal antibody tocilizumab, but not to the recombinant interleukin-1−receptor antagonist anakinra. Exome sequencing failed to identify mutations in other genes known to be involved in autoinflammatory diseases. We propose that the disease described in this patient might be a prototype of a novel category of autoinflammatory diseases characterized by prominent neurological involvement. PMID:23432807

  18. Monogenic polyarteritis: the lesson of ADA2 deficiency.

    PubMed

    Caorsi, Roberta; Penco, Federica; Schena, Francesca; Gattorno, Marco

    2016-09-08

    The deficiency of Adenosine Deaminase 2 (DADA2) is a new autoinflammatory disease characterised by an early onset vasculopathy with livedoid skin rash associated with systemic manifestations, CNS involvement and mild immunodeficiency.This condition is secondary to autosomal recessive mutations of CECR1 (Cat Eye Syndrome Chromosome Region 1) gene, mapped to chromosome 22q11.1, that encodes for the enzymatic protein adenosine deaminase 2 (ADA2). By now 19 different mutations in CECR1 gene have been detected.The pathogenetic mechanism of DADA2 is still unclear. ADA2 in a secreted protein mainly expressed by cells of the myeloid lineage; its enzymatic activity is higher in conditions of hypoxia, inflammation and oncogenesis. Moreover ADA2 is able to induce macrophages proliferation and differentiation; it's deficiency is in fact associated with a reduction of anti-inflammatory macrophages (M2). The deficiency of ADA2 is also associated with an up-regulation of neutrophils-expressed genes and an increased secretion of pro-inflammatory cytokines. The mild immunodeficiency detected in many DADA2 patients suggests a role of this protein in the adaptive immune response; an increased mortality of B cells and a reduction in the number of memory B cells, terminally differentiated B cells and plasmacells has been described in many patients. The lack of the protein is associated with endothelium damage; however the function of this protein in the endothelial homeostasis is still unknown.From the clinical point of view, this disease is characterized by a wide spectrum of severity. Chronic or recurrent systemic inflammation with fever, elevation of acute phase reactants and skin manifestations (mainly represented by livedo reticularis) is the typical clinical picture. While in some patients the disease is mild and skin-limited, others present a severe, even lethal, disease with multi-organ involvement; the CNS involvement is rather common with ischemic or hemorrhagic strokes. In

  19. AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune-Mediated Hearing Loss.

    PubMed

    Vambutas, Andrea; Pathak, Shresh

    2016-10-01

    Autoinflammatory diseases are a family of immune-mediated, rare diseases, some of which, exhibit sensorineural hearing loss (SNHL), suggesting potentially similar mechanisms of molecular pathogenesis between autoinflammatory-mediated hearing loss and autoimmune inner ear disease (AIED) may exist. The purpose of this review is to compare the clinical features of autoimmune and autoinflammatory diseases that affect hearing, discuss the limitations of our knowledge, and highlight potential new disease mechanisms and therapeutics. Pubmed Literature Review; Google Scholar Literature review. A focused comparison of AIED with a number of autoinflammatory diseases that manifest with sensorineural hearing loss was performed. The pathogenesis of these diseases is reviewed in the context of the innate and adaptive immune system, cytokine expression and genetic polymorphisms. AIED, since first described by Cogan and Lehnhardt and first clinically characterized by McCabe, has remained an enigmatic disease, with limited advances in both new diagnostics and new therapeutics. Since the discovery of autoinflammatory diseases, a number of systemic autoimmune diseases have either been re-classed as autoinflammatory diseases or identified to have features of autoinflammatory disease. AIED has clinical features of both autoimmune and autoinflammatory disease. It is critical that autoinflammatory diseases be correctly identified, as failure to do so may result in systemic amyloidosis and kidney damage.

  20. Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes

    ClinicalTrials.gov

    2017-02-28

    Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature (CANDLE); Juvenile Dermatomyositis (JDM); Stimulator of Interferon Genes (STING)-Associated Vasculopathy With Onset During Infancy (SAVI)

  1. The diagnostic evaluation of patients with potential adult-onset autoinflammatory disorders: our experience and review of the literature.

    PubMed

    Muscari, Isabella; Iacoponi, Francesca; Cantarini, Luca; Lucherini, Orso Maria; Simonini, Gabriele; Brizi, Maria Giuseppina; Vitale, Antonio; Frediani, Bruno; Cimaz, Rolando; Galeazzi, Mauro

    2012-11-01

    Hereditary periodic fever syndromes (HPFSs) are a group of inherited disorders of the innate immune system caused by mutations of genes involved in the regulation or activation of the inflammatory response, which belong to the category of autoinflammatory disorders. Most HPFs typically have an onset in pediatric age, while a limited number of patients experience disease onset during adulthood. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that genetic testing is often inconclusive. Recently, we have identified a set of variables related to the probability of detecting gene mutations in MEFV, responsible for familial Mediterranean fever, and TNFRSF1A, responsible for tumor necrosis factor receptor-associated periodic syndrome. In addition, we have proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. However, before the score can be recommended for application, further evaluation by means of longitudinal studies on different ethnicities and different populations deriving from other geographical areas is needed in order to definitively verify both its sensitivity and its specificity. The present manuscript offers our suggestions on how to establish a differential diagnosis for adult-onset HPFs, as well as a review of the literature, and we also provide a score revision available online. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. AAO: Autoimmune and Autoinflammatory (Disease) in Otology: What is New in Immune‐Mediated Hearing Loss

    PubMed Central

    Pathak, Shresh

    2016-01-01

    Objectives Autoinflammatory diseases are a family of immune‐mediated, rare diseases, some of which, exhibit sensorineural hearing loss (SNHL), suggesting potentially similar mechanisms of molecular pathogenesis between autoinflammatory‐mediated hearing loss and autoimmune inner ear disease (AIED) may exist. The purpose of this review is to compare the clinical features of autoimmune and autoinflammatory diseases that affect hearing, discuss the limitations of our knowledge, and highlight potential new disease mechanisms and therapeutics. Data sources Pubmed Literature Review; Google Scholar Literature review. Review methods A focused comparison of AIED with a number of autoinflammatory diseases that manifest with sensorineural hearing loss was performed. The pathogenesis of these diseases is reviewed in the context of the innate and adaptive immune system, cytokine expression and genetic polymorphisms. Results AIED, since first described by Cogan and Lehnhardt and first clinically characterized by McCabe, has remained an enigmatic disease, with limited advances in both new diagnostics and new therapeutics. Since the discovery of autoinflammatory diseases, a number of systemic autoimmune diseases have either been re‐classed as autoinflammatory diseases or identified to have features of autoinflammatory disease. Conclusion AIED has clinical features of both autoimmune and autoinflammatory disease. It is critical that autoinflammatory diseases be correctly identified, as failure to do so may result in systemic amyloidosis and kidney damage. PMID:27917401

  3. More than Meets the Eye: Monogenic Autoimmunity Strikes Again.

    PubMed

    Anderson, Mark S; Casanova, Jean-Laurent

    2015-06-16

    Autoimmunity is often familial, suggesting that inborn genetic variations might underlie its development. Curiously, autoimmunity has long been thought to be typically polygenic. Contrary to this prediction and consistent with growing discoveries of monogenic autoimmunity, Oftedal et al. discovered heterozygous dominant-negative AIRE mutations in patients with certain forms of autoimmunity. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Autoinflammatory diseases in adults. Clinical characteristics and prognostic implications.

    PubMed

    González García, A; Patier de la Peña, J L; Ortego Centeno, N

    2017-03-01

    Autoinflammatory diseases are clinical conditions with inflammatory manifestations that present in a periodic or persistent manner and are caused by acquired or hereditary disorders of the innate immune response. In general, these diseases are more common in childhood, but cases have been reported in adults and are therefore important for all specialists. There are few references on these diseases in adults due to their low prevalence and underdiagnosis. The aim of this study is to review the scientific literature on these disorders to systematise their clinical, prognostic and treatment response characteristics in adults.

  5. Network-Informed Gene Ranking Tackles Genetic Heterogeneity in Exome-Sequencing Studies of Monogenic Disease.

    PubMed

    Dand, Nick; Schulz, Reiner; Weale, Michael E; Southgate, Laura; Oakey, Rebecca J; Simpson, Michael A; Schlitt, Thomas

    2015-12-01

    Genetic heterogeneity presents a significant challenge for the identification of monogenic disease genes. Whole-exome sequencing generates a large number of candidate disease-causing variants and typical analyses rely on deleterious variants being observed in the same gene across several unrelated affected individuals. This is less likely to occur for genetically heterogeneous diseases, making more advanced analysis methods necessary. To address this need, we present HetRank, a flexible gene-ranking method that incorporates interaction network data. We first show that different genes underlying the same monogenic disease are frequently connected in protein interaction networks. This motivates the central premise of HetRank: those genes carrying potentially pathogenic variants and whose network neighbors do so in other affected individuals are strong candidates for follow-up study. By simulating 1,000 exome sequencing studies (20,000 exomes in total), we model varying degrees of genetic heterogeneity and show that HetRank consistently prioritizes more disease-causing genes than existing analysis methods. We also demonstrate a proof-of-principle application of the method to prioritize genes causing Adams-Oliver syndrome, a genetically heterogeneous rare disease. An implementation of HetRank in R is available via the Website http://sourceforge.net/p/hetrank/.

  6. [Personalized therapy in cardiology. Biomarkers, pharmacogenetics and therapy of monogenic diseases].

    PubMed

    Eschenhagen, T; Blankenberg, S

    2013-02-01

    Improved therapy and prophylaxis of cardiovascular diseases have contributed to an increase in life expectancy like no other field of medicine. However, many cardiological diseases remain untreatable and standard therapies often work only in a minority of patients or cause more harm than benefit. Personalized approaches appear to be a promising solution. Monogenic heart diseases are paradigmatic for this approach and can in rare cases be treated mutation specifically. Overall, however, success remains limited. Next generation sequencing will facilitate the identification of mutations causing diseases. Cell culture models based on induced pluripotent stem cells open the perspective of individualized testing of disease severity and pharmacological or genetic therapy. In contrast to monogenic diseases genetic testing plays no practical role yet in the management of multifactorial cardiovascular diseases. Biomarkers can identify individuals with increased cardiovascular risk. Furthermore, biomarker-guided therapy represents an attractive option with troponin-guided therapy of acute coronary syndromes as a successful example. Individual responses to drugs vary and are partly determined by genes. Simple genetic analyses can improve response prediction and minimize side effects in cases such as warfarin and high doses of simvastatin. Taken together personalized approaches will gain importance in the cardiovascular field but this requires the development of better methods and research that quantifies the true value of the new knowledge.

  7. Network‐Informed Gene Ranking Tackles Genetic Heterogeneity in Exome‐Sequencing Studies of Monogenic Disease

    PubMed Central

    Schulz, Reiner; Weale, Michael E.; Southgate, Laura; Oakey, Rebecca J.; Simpson, Michael A.; Schlitt, Thomas

    2015-01-01

    ABSTRACT Genetic heterogeneity presents a significant challenge for the identification of monogenic disease genes. Whole‐exome sequencing generates a large number of candidate disease‐causing variants and typical analyses rely on deleterious variants being observed in the same gene across several unrelated affected individuals. This is less likely to occur for genetically heterogeneous diseases, making more advanced analysis methods necessary. To address this need, we present HetRank, a flexible gene‐ranking method that incorporates interaction network data. We first show that different genes underlying the same monogenic disease are frequently connected in protein interaction networks. This motivates the central premise of HetRank: those genes carrying potentially pathogenic variants and whose network neighbors do so in other affected individuals are strong candidates for follow‐up study. By simulating 1,000 exome sequencing studies (20,000 exomes in total), we model varying degrees of genetic heterogeneity and show that HetRank consistently prioritizes more disease‐causing genes than existing analysis methods. We also demonstrate a proof‐of‐principle application of the method to prioritize genes causing Adams‐Oliver syndrome, a genetically heterogeneous rare disease. An implementation of HetRank in R is available via the Website http://sourceforge.net/p/hetrank/. PMID:26394720

  8. Translational research network and patient registry for auto-inflammatory diseases.

    PubMed

    Lainka, Elke; Bielak, Maria; Hilger, Volker; Basu, Oliver; Neudorf, Ulrich; Wittkowski, Helmut; Holzinger, Dirk; Roth, Johannes; Niehues, Tim; Foell, Dirk

    2011-01-01

    Auto-inflammatory diseases (AIDs) are characterized by recurrent self-limiting systemic inflammation. In a multicentre effort, we set out to register genetic, epidemiological and clinical features as well as prognostic factors of these diseases by prospective longitudinal and long-term documentation, in order to define novel AIDs and to better understand treatment responses and outcome. In 2009, a federally funded clinical and research consortium (AID-Net) was established, including an online registry for AIDs (http://www.aid-register.uk-essen.de). Inclusion criteria are disease-associated mutations for hereditary periodic fever syndromes [FMF, hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), TNF receptor 1-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS)], or, alternatively, clinically confirmed AID, systemic-onset JIA (SoJIA) and periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome with unknown genetic background. Patients were recruited to the registry and patient material was deposited in biomaterial banks (DNA/serum). In addition, basic research projects were initiated that focus on molecular mechanisms of AID. During the first 9 months, 117 patients (65 males, 52 females; age 1-21 years) have been recorded and classified as FMF (n=84), HIDS (n=1), TRAPS (n=3) and CAPS (n=1); clinically confirmed AID (n=5); SoJIA (n=22); and PFAPA (n=1). One hundred and fifty blood samples of 18 patients were included in biomaterial banks. Recruitment and follow-up of patients with AID will enable us to comprehensively address the correlation between clinical and epidemiological data, genetics and biomarkers. The translational approach may help to identify genetic or inflammatory markers relevant for the course and outcome of diseases.

  9. A novel assessment tool for clinical care of patients with autoinflammatory disease: juvenile autoinflammatory disease multidimensional assessment report.

    PubMed

    Konukbay, Dilek; Gattorno, Marco; Yildiz, Dilek; Frenkel, Joost; Acikel, Cengizhan; Sozeri, Betul; Makay, Balahan; Aktay Ayaz, Nuray; Barut, Kenan; Kisaarslan, Aysenur; Bilginer, Yelda; Karaman, Dursun; Peru, Harun; Simsek, Dogan; Aydog, Ozlem; Unsal, Erbil; Gunduz, Zubeyde; Fidanci, Berna Eren; Kone-Paut, Isabelle; Kasapcopur, Ozgur; Ravelli, Angelo; Ozen, Seza; Demirkaya, Erkan

    2016-01-01

    To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care. The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report. 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989). The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.

  10. Association of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Shares Genetic and Cytokine Profiles With Other Autoinflammatory Diseases

    PubMed Central

    Marzano, Angelo V.; Ceccherini, Isabella; Gattorno, Marco; Fanoni, Daniele; Caroli, Francesco; Rusmini, Marta; Grossi, Alice; De Simone, Clara; Borghi, Orietta M.; Meroni, Pier Luigi; Crosti, Carlo; Cugno, Massimo

    2014-01-01

    Abstract The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1β and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1β, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin. PMID:25501066

  11. Monogenic diabetes: old and new approaches to diagnosis.

    PubMed

    Owen, Katharine R

    2013-06-01

    Up to 5% of young adults diagnosed with diabetes have a monogenic aetiology, the most common of which is maturity-onset diabetes of the young (MODY). A definitive molecular diagnosis is important, as this affects treatment, prognosis and family screening. Currently, however, rates of diagnosis are low due to a combination of lack of awareness of the benefits of making the diagnosis and the challenges of differentiating patients with MODY from those with common forms of diabetes. This article aims to introduce general physicians to the characteristics of monogenic diabetes and the clinical features that can be used to diagnose patients. Recently, genomewide association studies have resulted in the identification of C-reactive protein and glycan profile as specific biomarkers for the most common MODY subtype due to HNF1A mutations, and the potential translation of these findings are discussed.

  12. An additional monogenic disorder that masquerades as multiple sclerosis

    SciTech Connect

    Vahedi, K.; Tournier-Lasserve, E.; Vahedi, K.

    1996-11-11

    In their comprehensive differential diagnosis of monogenic diseases that can mimic multiple sclerosis, Natowicz and Bejjani did not include a newly recognized monogenic disorder known under the acronym of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy); this disorder can mimic MS clinically and radiologically to a remarkable extent. The underlying histopathological lesion of CADASIL is a non-atherosclerotic, non-amyloid arteriopathy affecting mainly the penetrating medullary arteries to the subcortical white matter and basal ganglia. Electron microscopy shows an abnormal deposit of granular osmiophilic material in the arterial wall. These arterial changes are observed in various tissues even though clinical manifestations seem to be restricted to the central nervous system. The CADASIL gene was mapped recently to chromosome 19 and gene identification is ongoing. 6 refs., 1 fig.

  13. Monogenic models: what have the single gene disorders taught us?

    PubMed

    Klupa, Tomasz; Skupien, Jan; Malecki, Maciej T

    2012-12-01

    Monogenic diabetes constitutes a heterogeneous group of single gene disorders. The molecular background and clinical picture of many of these diseases have been described. While each of these forms is much less prevalent than multifactorial type 1 and type 2 diabetes mellitus (T2DM), together they affect millions of patients worldwide. Genetic diagnosis, which has become widely available, is of great clinical importance for patients with single gene diabetes. It helps to fully understand the pathophysiology of the disease, tailor the optimal hypoglycemic treatment, and define the prognosis for the entire family. Monogenic diabetes forms can be divided into 2 large groups, resulting from impaired insulin secretion or from an abnormal response to insulin. There are several lessons we have been taught by single-gene diabetes. We learned that the gene responsible for the occurrence of diabetes can be identified if an appropriate search strategy is used. In addition, discoveries of genes responsible for monogenic disorders pointed to them as susceptibility candidates for T2DM. Moreover, establishing that some families of proteins or biological pathways, such as transcription factors or potassium channel subunits, are involved in monogenic diabetes sparked research on their involvement in multifactorial diabetes. Finally, the example of single gene diabetes, particularly HNF1A MODY and permanent neonatal diabetes associated with the KCNJ11 and ABCC8 genes, all efficiently controlled on sulfonylurea, inspires us to continue the efforts to tailor individual treatment for T2DM patients. In this review paper, we summarize the impact of single gene disease discoveries on diabetes research and clinical practice.

  14. Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis.

    PubMed

    Halbritter, Jan; Baum, Michelle; Hynes, Ann Marie; Rice, Sarah J; Thwaites, David T; Gucev, Zoran S; Fisher, Brittany; Spaneas, Leslie; Porath, Jonathan D; Braun, Daniela A; Wassner, Ari J; Nelson, Caleb P; Tasic, Velibor; Sayer, John A; Hildebrandt, Friedhelm

    2015-03-01

    Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.

  15. Genetic contributors to frontotemporal lobar degeneration: beyond monogenic disease.

    PubMed

    Borroni, B; Pilotto, A; Bianchi, M; Gilberti, N; Padovani, A

    2011-10-01

    Frontotemporal Lobar Degeneration (FTLD) is a genetically and pathologically heterogeneous disorder characterized by behavioral change, executive dysfunction and language impairment associated with frontal and temporal lobe degeneration. Three major clinical subtypes have been identified so far, namely behaviour variant Frontotemporal dementia (bvFTD), Semantic Dementia (SD) and Progressive Non-Fluent Aphasia (PNFA). FTLD might also overlap with atypical parkinsonisms or motor neuron disease. Several pathogenetic mutations have been associated with specific pathological and clinical correlates. FTLD associated with either Microtuble Associated Protein Tau (MAPT) or Progranulin (PGRN) mutations is recognised as the most common form of autosomal dominant inherited disorder. However, monogenic mutations account for only about one third of all FTLD cases. Several studies have evaluated the contribution of genetic background in non-monogenic forms of FTLD, with the attempt to establish its role in increasing disease risk and in modulating clinical phenotypes. Specific MAPT and PGRN polymorphisms have been demonstrated to affect disease onset, clinical features and prognosis of FTLD, and genetic variations within other genes appear to play a role in influencing disease risk and clinical expression of FTLD. The aim of the present review is to discuss the impact and the role of genetic background in non-monogenic forms of FTLD, to highlight new potential pathogenetic and therapeutic targets.

  16. Identifying mutations in autoinflammatory diseases: towards novel genetic tests and therapies?

    PubMed

    Touitou, Isabelle; Notarnicola, Cécile; Grandemange, Sylvie

    2004-01-01

    Autoinflammatory diseases are defined as illnesses caused by primary dysfunction of the innate immune system. This new concept includes a broad number of disorders, but the spotlight has been focused for the past two years on periodic fevers (familial Mediterranean fever [FMF]; mevalonate kinase deficiency [MVK]; tumor necrosis factor [TNF] receptor-associated periodic syndrome [TRAPS]; cryopyrin-associated periodic syndrome [CAPS]), Crohn's disease and Blau syndrome, thanks to the recent understanding of their molecular basis. Indeed, until recently, these conditions were defined only by phenotypical features, the main ones being recurrent attacks of fever, abdominal pain, arthritis, and cutaneous signs, which sometimes overlap, obscuring diagnosis. The search for distinguishing signs such as periorbital edema in TRAPS, and the use of specific functional tests where available, are valuable. Needless to say, molecular screening of the causative genes has dramatically improved patient quality-of-life by providing early and accurate diagnosis, subsequently allowing for the appropriate treatment. Some patients, however, remain hard to manage despite the advent of new genetic tests, and/or due to the lack of effective treatment. The original clinical link between the aforementioned diseases can now be confirmed by a molecular one, following the exciting discovery that most of the altered proteins are related to the death domain fold (DDF) superfamily involved in inflammation and apoptosis. These molecules mediate the regulation of nuclear factor-kappa B (NF-kappa B) activation, cell apoptosis, and interleukin-1 beta secretion through cross-regulated and, sometimes, common signaling pathways. Knowledge of the defective step in autoinflammation has already led to the elucidation of the mechanisms of action of existing drugs and may allow the development of new therapies.

  17. A Novel Mutation of IL1RN in the Deficiency of Interleukin-1 Receptor Antagonist Syndrome

    PubMed Central

    Jesus, Adriana A.; Osman, Mazen; Silva, Clovis A.; Kim, Peter W.; Pham, Tuyet-Hang; Gadina, Massimo; Yang, Barbara; Bertola, Débora R.; Carneiro-Sampaio, Magda; Ferguson, Polly J.; Renshaw, Blair R.; Schooley, Ken; Brown, Michael; Al-Dosari, Asma; Al-Alami, Jamil; Sims, John E.; Goldbach-Mansky, Raphaela; El-Shanti, Hatem

    2012-01-01

    Objective Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN. Methods Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild-type protein. Results Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute-phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15-bp (in-frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1α or IL-1β led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients. Conclusion The presence of

  18. Current Progress in Therapeutic Gene Editing for Monogenic Diseases

    PubMed Central

    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-01-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects. PMID:26765770

  19. Current Progress in Therapeutic Gene Editing for Monogenic Diseases.

    PubMed

    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-03-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects.

  20. Genetics of inflammatory bowel disease from multifactorial to monogenic forms

    PubMed Central

    Bianco, Anna Monica; Girardelli, Martina; Tommasini, Alberto

    2015-01-01

    Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn’s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6th year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies. PMID:26604638

  1. Height matters-from monogenic disorders to normal variation.

    PubMed

    Durand, Claudia; Rappold, Gudrun A

    2013-03-01

    Height is a classic polygenic quantitative trait with a high level of heritability. As it is a simple and stable parameter to measure, height is a model for both common, complex disorders and monogenic, Mendelian disease. In this Review, we examine height from the perspective of monogenic and complex genetics and discuss the lessons learned so far. We explore several examples of rare sequence variants with large effects on height and compare these variants to the common variants identified in genome-wide association studies that have small effects on height. We discuss how copy number changes or genetic interactions might contribute to the unidentified aspects of the heritability of height. We also ask whether information derived from genome-wide association studies on specific loci in the vicinity of genes can be used for further research in clinical paediatric endocrinology. Furthermore, we address key challenges that remain for gene discovery and for the transition of moving from genomic localization to mechanistic insights, with an emphasis on using next-generation sequencing to identify causative variants of people at the extremes of height distribution.

  2. Genetics of inflammatory bowel disease from multifactorial to monogenic forms.

    PubMed

    Bianco, Anna Monica; Girardelli, Martina; Tommasini, Alberto

    2015-11-21

    Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn's disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

  3. Human monogenic disease genes have frequently functionally redundant paralogs.

    PubMed

    Chen, Wei-Hua; Zhao, Xing-Ming; van Noort, Vera; Bork, Peer

    2013-01-01

    Mendelian disorders are often caused by mutations in genes that are not lethal but induce functional distortions leading to diseases. Here we study the extent of gene duplicates that might compensate genes causing monogenic diseases. We provide evidence for pervasive functional redundancy of human monogenic disease genes (MDs) by duplicates by manifesting 1) genes involved in human genetic disorders are enriched in duplicates and 2) duplicated disease genes tend to have higher functional similarities with their closest paralogs in contrast to duplicated non-disease genes of similar age. We propose that functional compensation by duplication of genes masks the phenotypic effects of deleterious mutations and reduces the probability of purging the defective genes from the human population; this functional compensation could be further enhanced by higher purification selection between disease genes and their duplicates as well as their orthologous counterpart compared to non-disease genes. However, due to the intrinsic expression stochasticity among individuals, the deleterious mutations could still be present as genetic diseases in some subpopulations where the duplicate copies are expressed at low abundances. Consequently the defective genes are linked to genetic disorders while they continue propagating within the population. Our results provide insight into the molecular basis underlying the spreading of duplicated disease genes.

  4. Human Monogenic Disease Genes Have Frequently Functionally Redundant Paralogs

    PubMed Central

    van Noort, Vera; Bork, Peer

    2013-01-01

    Mendelian disorders are often caused by mutations in genes that are not lethal but induce functional distortions leading to diseases. Here we study the extent of gene duplicates that might compensate genes causing monogenic diseases. We provide evidence for pervasive functional redundancy of human monogenic disease genes (MDs) by duplicates by manifesting 1) genes involved in human genetic disorders are enriched in duplicates and 2) duplicated disease genes tend to have higher functional similarities with their closest paralogs in contrast to duplicated non-disease genes of similar age. We propose that functional compensation by duplication of genes masks the phenotypic effects of deleterious mutations and reduces the probability of purging the defective genes from the human population; this functional compensation could be further enhanced by higher purification selection between disease genes and their duplicates as well as their orthologous counterpart compared to non-disease genes. However, due to the intrinsic expression stochasticity among individuals, the deleterious mutations could still be present as genetic diseases in some subpopulations where the duplicate copies are expressed at low abundances. Consequently the defective genes are linked to genetic disorders while they continue propagating within the population. Our results provide insight into the molecular basis underlying the spreading of duplicated disease genes. PMID:23696728

  5. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism.

    PubMed

    Hooper, Amanda J; van Bockxmeer, Frank M; Burnett, John R

    2005-01-01

    The study of apolipoprotein (apo) B metabolism is central to our understanding of human lipoprotein metabolism. Moreover, the assembly and secretion of apoB-containing lipoproteins is a complex process. Increased plasma concentrations of apoB-containing lipoproteins are an important risk factor for the development of atherosclerotic coronary heart disease. In contrast, decreased levels of, but not the absence of, these apoB-containing lipoproteins is associated with resistance to atherosclerosis and potential long life. The study of inherited monogenic dyslipidaemias has been an effective means to elucidate key metabolic steps and biologically relevant mechanisms. Naturally occurring gene mutations in affected families have been useful in identifying important domains of apoB and microsomal triglyceride transfer protein (MTP) governing the metabolism of apoB-containing lipoproteins. Truncation-causing mutations in the APOB gene cause familial hypobetalipoproteinaemia, whereas mutations in MTP result in abetalipoproteinaemia; both rare conditions are characterised by marked hypocholesterolaemia. The purpose of this review is to examine the role of apoB in lipoprotein metabolism and to explore the key biochemical, clinical, metabolic and genetic features of the monogenic hypocholesterolaemic lipid disorders affecting apoB metabolism.

  6. Preimplantation genetic diagnosis for monogenic diseases: overview and emerging issues.

    PubMed

    Renwick, Pamela; Ogilvie, Caroline Mackie

    2007-01-01

    Preimplantation genetic diagnosis (PGD) is an established reproductive option for couples at risk of conceiving a pregnancy affected with a known genetic disease, who wish to avoid an (additional) affected child, termination of pregnancy or recurrent miscarriages. Early technologies concentrated on different approaches to direct mutation testing for monogenic diseases using single cell PCR protocols, or sex selection by fluorescent in situ hybridization for X-linked monogenic disease. Development of multiplex fluorescent PCR allowed simultaneously testing of linked markers alongside the mutation test, increasing the accuracy by controlling for contamination and identifying allele drop-out. The advent of highly effective whole genome amplification methods has opened the way for new technologies such as preimplantation genetic haplotyping and microarrays, thus increasing the number of genetic defects that can be detected in preimplantation embryos; the number of cases carried out and the new indications tested increases each year. Different countries have taken very different approaches to legislating and regulating PGD, giving rise to the phenomenon of reproductive tourism. PGD is now being performed for scenarios previously not undertaken using prenatal diagnosis, some of which raise significant ethical concerns. While PGD has benefited many couples aiming to have healthy children, ethical concerns remain over inappropriate use of this technology.

  7. Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children.

    PubMed

    Ozen, Seza; Demirkaya, Erkan; Amaryan, Gayane; Koné-Paut, Isabelle; Polat, Adem; Woo, Pat; Uziel, Yosef; Modesto, Consuelo; Finetti, Martina; Quartier, Pierre; Papadopoulou-Alataki, Efimia; Al-Mayouf, Sulaiman M; Fabio, Giovanna; Gallizzi, Romina; Cantarini, Luca; Frenkel, Joost; Nielsen, Susan; Hofer, Michael; Insalaco, Antonella; Acikel, C; Ozdogan, Huri; Martini, Alberto; Ruperto, Nicolino; Gattorno, Marco

    2014-04-01

    Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry. Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated. Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p<0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history. Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.

  8. SHANK3 haploinsufficiency: a "common" but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders.

    PubMed

    Betancur, Catalina; Buxbaum, Joseph D

    2013-06-11

    Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome appears to be one of the more penetrant causes of ASD. In this companion review, we show that in samples ascertained for ASD, SHANK3 haploinsufficiency is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. We note that SHANK3 haploinsufficiency remains underdiagnosed in ASD and developmental delay, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise.

  9. Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach.

    PubMed

    Alkorta-Aranburu, G; Carmody, D; Cheng, Y W; Nelakuditi, V; Ma, L; Dickens, Jazzmyne T; Das, S; Greeley, S A W; del Gaudio, D

    2014-12-01

    Single gene mutations that primarily affect pancreatic β-cell function account for approximately 1-2% of all cases of diabetes. Overlapping clinical features with common forms of diabetes makes diagnosis of monogenic diabetes challenging. A genetic diagnosis often leads to significant alterations in treatment, allows better prediction of disease prognosis and progression, and has implications for family members. Currently, genetic testing for monogenic diabetes relies on selection of appropriate individual genes for analysis based on the availability of often-limited phenotypic information, decreasing the likelihood of making a genetic diagnosis. We thus developed a targeted next-generation sequencing (NGS) assay for the detection of mutations in 36 genes known to cause monogenic forms of diabetes, including transient or permanent neonatal diabetes mellitus (TNDM or PNDM), maturity-onset diabetes of the young (MODY) and rare syndromic forms of diabetes. A total of 95 patient samples were analyzed: 19 with known causal mutations and 76 with a clinically suggestive phenotype but lacking a genetic diagnosis. All previously identified mutations were detected, validating our assay. Pathogenic sequence changes were identified in 19 out of 76 (25%) patients: 7 of 32 (22%) NDM cases, and 12 of 44 (27%) MODY cases. In 2 NDM patients the causal mutation was not expected as consanguinity was not reported and there were no clinical features aside from diabetes. A 3 year old patient with NDM diagnosed at 3 months of age, who previously tested negative for INS, KCNJ11 and ABCC8 mutations, was found to carry a novel homozygous mutation in EIF2AK3 (associated with Wolcott-Rallison syndrome), a gene not previously suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported. Similarly, another infant without a history of consanguinity was found to have a homozygous GCK mutation causing PNDM at birth. This study

  10. WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.

    PubMed

    Zalloua, Pierre A; Azar, Sami T; Delépine, Marc; Makhoul, Nadine J; Blanc, Hervé; Sanyoura, May; Lavergne, Anne; Stankov, Karmen; Lemainque, Arnaud; Baz, Patrick; Julier, Cécile

    2008-12-15

    Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1(LIB), encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.

  11. [Autoinflammatory Diseases as a Differential Diagnosis of Fever of Unknown Origin].

    PubMed

    Kümmerle-Deschner, Jasmin Beate

    2017-07-01

    Fever is the most leading symptom of autoinflammatory diseases (AID). Therefore, AID have to be considered in differential diagnosis concerning fever of unknown origin. Unspecific Inflammatory manifestations may lead to misinterpretations that possibly cause irreversible organ damage. Effective treatment options are available and imply profound diagnostics. © Georg Thieme Verlag KG Stuttgart · New York.

  12. New insights from monogenic diabetes for “common” type 2 diabetes

    PubMed Central

    Tallapragada, Divya Sri Priyanka; Bhaskar, Seema; Chandak, Giriraj R.

    2015-01-01

    Boundaries between monogenic and complex genetic diseases are becoming increasingly blurred, as a result of better understanding of phenotypes and their genetic determinants. This had a large impact on the way complex disease genetics is now being investigated. Starting with conventional approaches like familial linkage, positional cloning and candidate genes strategies, the scope of complex disease genetics has grown exponentially with scientific and technological advances in recent times. Despite identification of multiple loci harboring common and rare variants associated with complex diseases, interpreting and evaluating their functional role has proven to be difficult. Information from monogenic diseases, especially related to the intermediate traits associated with complex diseases comes handy. The significant overlap between traits and phenotypes of monogenic diseases with related complex diseases provides a platform to understand the disease biology better. In this review, we would discuss about one such complex disease, type 2 diabetes, which shares marked similarity of intermediate traits with different forms of monogenic diabetes. PMID:26300908

  13. Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism.

    PubMed

    Bennett, James T; Vasta, Valeria; Zhang, Min; Narayanan, Jaya; Gerrits, Peter; Hahn, Si Houn

    2015-03-01

    Genetic sequencing has become a critical part of the diagnosis of certain forms of pancreatic beta cell dysfunction. Despite great advances in the speed and cost of DNA sequencing, determining the pathogenicity of variants remains a challenge, and requires sharing of sequence and phenotypic data between laboratories. We reviewed all diabetes and hyperinsulinism-associated molecular testing done at the Seattle Children's Molecular Genetics Laboratory from 2009 to 2013. 331 probands were referred to us for molecular genetic sequencing for Neonatal Diabetes (NDM), Maturity-Onset Diabetes of the Young (MODY), or Congenital Hyperinsulinism (CHI) during this period. Reportable variants were identified in 115 (35%) patients with 91 variants in one of 6 genes: HNF1A, GCK, HNF4A, ABCC8, KCNJ11, or INS. In addition to identifying 23 novel variants, we identified unusual mechanisms of inheritance, including mosaic and digenic MODY presentations. Re-analysis of all reported variants using more recently available databases led to a change in variant interpretation from the original report in 30% of cases. These results represent a resource for molecular testing of monogenic forms of diabetes and hyperinsulinism, providing a mutation spectrum for these disorders in a large North American cohort. In addition, they highlight the importance of periodic review of molecular testing results.

  14. Brief Report: Sensory Reactivity in Children with Phelan-McDermid Syndrome

    ERIC Educational Resources Information Center

    Mieses, A. M.; Tavassoli, T.; Li, E.; Soorya, L.; Lurie, S.; Wang, A. T.; Siper, P. M.; Kolevzon, A.

    2016-01-01

    Phelan-McDermid syndrome (PMS), a monogenic form of autism spectrum disorder (ASD), results from deletion or mutation of the "SHANK3" gene. Atypical sensory reactivity is now included in the diagnostic criteria for ASD. Examining the sensory phenotype in monogenic forms of ASD, such as PMS, may help identify underlying mechanisms of…

  15. Brief Report: Sensory Reactivity in Children with Phelan-McDermid Syndrome

    ERIC Educational Resources Information Center

    Mieses, A. M.; Tavassoli, T.; Li, E.; Soorya, L.; Lurie, S.; Wang, A. T.; Siper, P. M.; Kolevzon, A.

    2016-01-01

    Phelan-McDermid syndrome (PMS), a monogenic form of autism spectrum disorder (ASD), results from deletion or mutation of the "SHANK3" gene. Atypical sensory reactivity is now included in the diagnostic criteria for ASD. Examining the sensory phenotype in monogenic forms of ASD, such as PMS, may help identify underlying mechanisms of…

  16. Association between inherited monogenic liver disorders and chronic hepatitis C

    PubMed Central

    Piekuse, Linda; Kreile, Madara; Zarina, Agnese; Steinberga, Zane; Sondore, Valentina; Keiss, Jazeps; Lace, Baiba; Krumina, Astrida

    2014-01-01

    AIM: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C. METHODS: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing. RESULTS: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087). CONCLUSION: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail. PMID:24575168

  17. Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions.

    PubMed

    Tan, Tiong Yang; Dillon, Oliver James; Stark, Zornitza; Schofield, Deborah; Alam, Khurshid; Shrestha, Rupendra; Chong, Belinda; Phelan, Dean; Brett, Gemma R; Creed, Emma; Jarmolowicz, Anna; Yap, Patrick; Walsh, Maie; Downie, Lilian; Amor, David J; Savarirayan, Ravi; McGillivray, George; Yeung, Alison; Peters, Heidi; Robertson, Susan J; Robinson, Aaron J; Macciocca, Ivan; Sadedin, Simon; Bell, Katrina; Oshlack, Alicia; Georgeson, Peter; Thorne, Natalie; Gaff, Clara; White, Susan M

    2017-09-01

    additional diagnosis (95% CI, A$4304-A$15 404 [US$3263-US$11 678]) compared with the standard diagnostic pathway. Even if WES were performed at the first genetics appointment, there would be an incremental cost savings of A$5461 (US$4140) (95% CI, A$1433-A$10 557 [US$1086- US$8004]) per additional diagnosis compared with the standard diagnostic pathway. Singleton WES in children with suspected monogenic conditions has high diagnostic yield, and cost-effectiveness is maximized by early application in the diagnostic pathway. Pediatricians should consider early referral of children with undiagnosed syndromes to clinical geneticists.

  18. Complete remission of Schnitzler syndrome and Waldenström macroglobulinemia under rituximab-cyclophosphamide-dexamethasone.

    PubMed

    Aouba, Achille; Pressiat, Claire; Pricopi, Maria; Georgin-Lavialle, Sophie; Boue, François; Lievre-Castilla, Maria-Angela; Marfaing-Koka, Anne; Prevot, Sophie; Decottignies, Audrey

    2015-01-01

    In Schnitzler syndrome, which is mostly diagnosed with a low and asymptomatic monoclonal peak, anakinra has always exhibited a complete but only transient control of the auto-inflammatory signs, which are induced by interleukin (IL)-1 auto-activation. We focused on the treatment of a case of Schnitzler syndrome with moderate macroglobulinemia peak. Anakinra failed to improve the severe inflammatory anaemia and the dysglobulinemia, but rituximab-dexamethasone-cyclophosphamide chemotherapy alone allowed a complete response. The correlation between the clinical, pro-inflammatory cytokines and dysglobulinemia complete controls with chemotherapy proves the following: (1) the dual action of this treatment in both the auto-inflammatory and dysglobulinemia components of the syndrome and (2) a different but entangled cytokine network in the pathogenesis of the auto-inflammatory and dysglobulinemia components of the syndrome.

  19. Auto-inflammatory diseases in ileal pouch patients with NOD2/CARD15 mutations.

    PubMed

    Seril, Darren N; Yao, Qingping; Shen, Bo

    2016-02-01

    Pouchitis is common in ulcerative colitis patients undergoing total proctocolectomy with ileal pouch-anal anastomosis, and chronic antibiotic-refractory pouchitis occurs in a subgroup of the patients. Auto-inflammatory diseases are characterized by systemic inflammation, manifesting as periodic fever, rash, arthritis, and serositis. We describe two cases with ulcerative colitis and an ileal pouch, who presented with extra-intestinal manifestations and genetic features atypical for inflammatory bowel disease alone. Case 1 had a spectrum of clinical manifestations including refractory pouchitis, intermittent fevers, polyarthralgia, and pericarditis. Case 2 presented with oral ulcers, migratory oligoarthritis, and periodic papular rash. Genetic testing in both cases revealed mutations of the NOD2/CARD15 gene, including the IVS8(+158) mutation commonly detected among patients with NOD2-associated auto-inflammatory disease. Both of the patients demonstrated clinical improvement of these diverse systemic complaints following treatment with immunosuppressive and anti-inflammatory therapies.

  20. Auto-inflammatory diseases in ileal pouch patients with NOD2/CARD15 mutations

    PubMed Central

    Seril, Darren N.; Yao, Qingping; Shen, Bo

    2016-01-01

    Pouchitis is common in ulcerative colitis patients undergoing total proctocolectomy with ileal pouch-anal anastomosis, and chronic antibiotic-refractory pouchitis occurs in a subgroup of the patients. Auto-inflammatory diseases are characterized by systemic inflammation, manifesting as periodic fever, rash, arthritis, and serositis. We describe two cases with ulcerative colitis and an ileal pouch, who presented with extra-intestinal manifestations and genetic features atypical for inflammatory bowel disease alone. Case 1 had a spectrum of clinical manifestations including refractory pouchitis, intermittent fevers, polyarthralgia, and pericarditis. Case 2 presented with oral ulcers, migratory oligoarthritis, and periodic papular rash. Genetic testing in both cases revealed mutations of the NOD2/CARD15 gene, including the IVS8+158 mutation commonly detected among patients with NOD2-associated auto-inflammatory disease. Both of the patients demonstrated clinical improvement of these diverse systemic complaints following treatment with immunosuppressive and anti-inflammatory therapies. PMID:25313006

  1. Monogenic Diabetes Accounts for 6.3% of Cases Referred to 15 Italian Pediatric Diabetes Centers During 2007 to 2012.

    PubMed

    Delvecchio, Maurizio; Mozzillo, Enza; Salzano, Giuseppina; Iafusco, Dario; Frontino, Giulio; Patera, Patrizia I; Rabbone, Ivana; Cherubini, Valentino; Grasso, Valeria; Tinto, Nadia; Giglio, Sabrina; Contreas, Giovanna; Di Paola, Rosa; Salina, Alessandro; Cauvin, Vittoria; Tumini, Stefano; d'Annunzio, Giuseppe; Iughetti, Lorenzo; Mantovani, Vilma; Maltoni, Giulio; Toni, Sonia; Marigliano, Marco; Barbetti, Fabrizio

    2017-06-01

    An etiologic diagnosis of diabetes can affect the therapeutic strategy and prognosis of chronic complications. The aim of the present study was to establish the relative percentage of different diabetes subtypes in patients attending Italian pediatric diabetes centers and the influence of an etiologic diagnosis on therapy. This was a retrospective study. The clinical records of 3781 consecutive patients (age, 0 to 18 years) referred to 15 pediatric diabetes clinics with a diagnosis of diabetes or impaired fasting glucose from January 1, 2007 to December 31, 2012 were examined. The clinical characteristics of the patients at their first referral to the centers, type 1 diabetes-related autoantibodies, molecular genetics records, and C-peptide measurements, if requested for the etiologic diagnosis, were acquired. The primary outcome was to assess the percentage of each diabetes subtype in our sample. Type 1 diabetes represented the main cause (92.4%) of diabetes in this group of patients, followed by monogenic diabetes, which accounted for 6.3% of cases [maturity onset diabetes of the young (MODY), 5.5%; neonatal diabetes mellitus, 0.6%, genetic syndromes, 0.2%]. A genetic diagnosis prompted the transfer from insulin to sulphonylureas in 12 patients bearing mutations in the HNF1A or KCNJ11 genes. Type 2 diabetes was diagnosed in 1% of the patients. Monogenic diabetes is highly prevalent in patients referred to Italian pediatric diabetes centers. A genetic diagnosis guided the therapeutic decisions, allowed the formulation of a prognosis regarding chronic diabetic complications for a relevant number of patients (i.e.,GCK/MODY), and helped to provide genetic counseling.

  2. Novel genomic techniques open new avenues in the analysis of monogenic disorders.

    PubMed

    Kuhlenbäumer, Gregor; Hullmann, Julia; Appenzeller, Silke

    2011-02-01

    The molecular genetic cause of over 3,000 monogenic disorders is currently unknown. This review discusses how novel genomic techniques like Next-Generation DNA Sequencing (NGS) and genotyping arrays open new avenues in the elucidation of genetic defects causing monogenic disorders. They will not only speed up disease gene identification but will enable us to systematically tackle previously intractable monogenic disorders. These are mainly disorders not amenable to classic linkage analysis, for example, due to insufficient family size. Most monogenic diseases are caused by exonic mutations or splice-site mutations changing the amino acid sequence of the affected gene. These mutations can be identified by sequencing of all exons in the human genome (exome sequencing) rendering whole genome sequencing unnecessary in most cases. Genotyping arrays containing 10⁵ -2×10⁶ single nucleotide polymorphisms (SNPs) and nonpolymorphic markers allow highly accurate mapping of genomic deletions and duplications not detectable by exome sequencing, which are the second most common cause of monogenic disorders. However, several hundred rare, previously unknown sequence variants affecting the amino acid sequence of the encoded protein are found in the exome of every human individual. Therefore, the main challenge will be the differentiation between the many rare benign variants detected by novel genomic techniques and disease causing mutations.

  3. [Nonsense-mediated mRNA decay and human monogenic disease].

    PubMed

    Guo, Wen-Ting; Xu, Wang-Yang; Gu, Ming-Min

    2012-08-01

    Nonsense-mediated mRNA decay (NMD) is a widespread quality control mechanism in eukaryotic cells. It can recognize and degrade aberrant transcripts harbouring a premature translational termination codon (PTC), and thereby prevent the production of C-terminally truncated proteins which might be deleterious. Approximately, 30% of human genetic diseases are caused by transcripts containing PTCs. These transcripts are potential targets of NMD. As for monogenic diseases, NMD has effects on the phenotype or mode of inheritance. Here, we explain the mechanism of this surveillance pathway, and take several neuromuscular disorders as examples to discuss its influence for human monogenic diseases. The deeper understanding for NMD will shed light on the nosogenesis and therapies of monogenic diseases.

  4. [Exome sequencing: an efficient strategy for identifying the causative genes of monogenic disorders].

    PubMed

    Rebiya, Nuli; Patamu, Mohemaiti

    2011-10-01

    The development of new generation sequencing technologies has brought new opportunities for the study of diseases. Exome sequencing has shown to be an effective, rapid, high performance technique that has already been used in research of inherited diseases such as monogenic disorders. It has already been approved by scientists in the field of monogenic disorder study, and will become widely used. This approach will accelerate discovery of the causative genes of Mendelian disorders. This article reviews some recent applications of exome sequencing in the study of gene-related diseases.

  5. Hyper-IgD syndrome/mevalonate kinase deficiency: what is new?

    PubMed

    Mulders-Manders, C M; Simon, A

    2015-07-01

    Mevalonate kinase deficiency or hyper-IgD syndrome is a hereditary autoinflammatory syndrome caused by mutations in the mevalonate kinase gene. In this review, we will discuss new findings in this disorder that have been published in the last 2 years. This includes new insights into pathophysiology, treatment, and the clinical phenotype linked to the genetic defect.

  6. Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance.

    PubMed

    Carta, Sonia; Penco, Federica; Lavieri, Rosa; Martini, Alberto; Dinarello, Charles Anthony; Gattorno, Marco; Rubartelli, Anna

    2015-03-03

    Cell stress is implicated in triggering bouts of systemic inflammation in patients with autoinflammatory disorders. Blood monocytes from patients affected by NLRP3-mediated cryopyrin-associated periodic syndromes (CAPS) release greater amounts of IL-1β than monocytes from unaffected subjects. Here we show that stress lowers the threshold of activation; blood monocytes from CAPS patients maintain the high levels of secreted IL-1β (fivefold) and IL-18 (10-fold) when stimulated with 1,000-fold less LPS than that required for full IL-1β secretion in control subjects. Unexpectedly, IL-1α secretion is increased 10-fold, indicating that inflammatory episodes in CAPS may not be entirely a result of IL-1β but may also involve IL-1α. In CAPS monocytes, LPS induces the externalization of copious amounts of ATP (10-fold), which drive IL-1β, IL-18, and IL-1α release via activation of the P2X purinoceptor 7. This enhanced ATP release appears to be the link between cell stress and increased cytokine secretion in CAPS. In the later phase after LPS stimulation, CAPS monocytes undergo oxidative stress, which impairs production of the anti-inflammatory IL-1 receptor antagonist (IL-1Ra). Remarkably, IL-1Ra secretion is fully restored by treatment with antioxidants. In two patients with the same NLRP3 mutation, but different disease severity, monocytes from the mildly affected patient exhibited more efficient redox response, lower ATP secretion, and more balanced cytokine production. Thus, the robustness of the individual antioxidant response increases the tolerance to stress and reduces the negative effect of the disease. Pharmacologic block of P2X purinoceptor 7 and improved stress tolerance may represent novel treatment strategies in stress-associated inflammatory diseases.

  7. Allelic variation, aneuploidy, and nongenetic mechanisms suppress a monogenic trait in yeast.

    PubMed

    Sirr, Amy; Cromie, Gareth A; Jeffery, Eric W; Gilbert, Teresa L; Ludlow, Catherine L; Scott, Adrian C; Dudley, Aimée M

    2015-01-01

    Clinically relevant features of monogenic diseases, including severity of symptoms and age of onset, can vary widely in response to environmental differences as well as to the presence of genetic modifiers affecting the trait's penetrance and expressivity. While a better understanding of modifier loci could lead to treatments for Mendelian diseases, the rarity of individuals harboring both a disease-causing allele and a modifying genotype hinders their study in human populations. We examined the genetic architecture of monogenic trait modifiers using a well-characterized yeast model of the human Mendelian disease classic galactosemia. Yeast strains with loss-of-function mutations in the yeast ortholog (GAL7) of the human disease gene (GALT) fail to grow in the presence of even small amounts of galactose due to accumulation of the same toxic intermediates that poison human cells. To isolate and individually genotype large numbers of the very rare (∼0.1%) galactose-tolerant recombinant progeny from a cross between two gal7Δ parents, we developed a new method, called "FACS-QTL." FACS-QTL improves upon the currently used approaches of bulk segregant analysis and extreme QTL mapping by requiring less genome engineering and strain manipulation as well as maintaining individual genotype information. Our results identified multiple distinct solutions by which the monogenic trait could be suppressed, including genetic and nongenetic mechanisms as well as frequent aneuploidy. Taken together, our results imply that the modifiers of monogenic traits are likely to be genetically complex and heterogeneous.

  8. An online monogenic diabetes discussion group: supporting families and fueling new research.

    PubMed

    Perrone, Marie E; Carmody, David; Philipson, Louis H; Greeley, Siri Atma W

    2015-11-01

    Many online support groups are available for patients with rare disorders, but scant evidence is available on how effectively such groups provide useful information or valuable psychosocial support to their participants. It is also unclear to what extent physicians and researchers may learn more about these disorders by participating in such groups. To formally assess the utility of the Kovler Monogenic Diabetes Registry online discussion group for patients and families affected by KATP channel-related monogenic neonatal diabetes in providing psychosocial and informational support and in identifying concerns unique to patients with this rare form of diabetes. We qualitatively analyzed all 1,410 messages from the online group that consisted of 64 participants affected by KATP channel monogenic diabetes and 11 researchers. We utilized the Social Behavior Support Code to assign each message to a support category and deductive thematic analysis to identify discussion topics addressed by each message. 44% of messages provided/requested informational support, whereas 31.4% of the messages contained psychosocial/emotional support. The most popular topics of postings to the forums were diabetes treatment (503 messages) and neurodevelopmental concerns (472 messages). Participation in the discussion led researchers to modify survey instruments and design new studies focusing on specific topics of concern, such as sleep. We demonstrate that an online support group for a monogenic form of diabetes is an effective informational tool that also provides psychosocial support. Participation by researchers and care providers can inform future research directions and highlight issues of patient concern.

  9. Characterization of rice blast resistance genes in rice germplasm with monogenic lines and pathogenicity assays

    USDA-ARS?s Scientific Manuscript database

    Resistance (R) genes have been effectively deployed in preventing rice crop losses due to the fungus Magnaporthe oryzae. In the present study, we studied the interaction between 24 monogenic lines carrying at least one major R gene, Pia, Pib, Pii, Pik, Pik-h, Pik-m, Pik-p, Pik-s, Pish, Pit, Pita, Pi...

  10. Clinical genetics in 2014: New monogenic diseases span the immunological disease continuum.

    PubMed

    Savic, Sinisa; McDermott, Michael F

    2015-02-01

    Three monogenic diseases, with features of both autoinflammation and autoimmunity, were described for the first time in 2014. As well as providing insights into the molecular basis of several rare immunological disorders, the discoveries have implications for their diagnosis and treatment.

  11. Development of an economic evaluation of diagnostic strategies: the case of monogenic diabetes.

    PubMed

    Peters, Jaime L; Anderson, Rob; Hyde, Chris

    2013-05-28

    To describe the development process for defining an appropriate model structure for the economic evaluation of test-treatment strategies for patients with monogenic diabetes (caused by mutations in the GCK, HNF1A or HNF4A genes). Experts were consulted to identify and define realistic test-treatment strategies and care pathways. A systematic assessment of published diabetes models was undertaken to inform the model structure. National Health Service in England and Wales. Experts in monogenic diabetes whose collective expertise spans the length of the patient care pathway. A defined model structure, including the test-treatment strategies, and the selection of a published diabetes model appropriate for the economic evaluation of strategies to identify patients with monogenic diabetes. Five monogenic diabetes test-treatment strategies were defined: no testing of any kind, referral for genetic testing based on clinical features as noted by clinicians, referral for genetic testing based on the results of a clinical prediction model, referral for genetic testing based on the results of biochemical and immunological tests, referral for genetic testing for all patients with a diagnosis of diabetes under the age of 30 years. The systematic assessment of diabetes models identified the IMS CORE Diabetes Model (IMS CDM) as a good candidate for modelling the long-term outcomes and costs of the test-treatment strategies for monogenic diabetes. The short-term test-treatment events will be modelled using a decision tree which will feed into the IMS CDM. Defining a model structure for any economic evaluation requires decisions to be made. Expert consultation and the explicit use of critical appraisal can inform these decisions. Although arbitrary choices have still been made, decision modelling allows investigation into such choices and the impact of assumptions that have to be made due to a lack of data.

  12. Monogenic and chromosomal causes of isolated speech and language impairment.

    PubMed

    Barnett, C P; van Bon, B W M

    2015-11-01

    The importance of a precise molecular diagnosis for children with intellectual disability, autism spectrum disorder and epilepsy has become widely accepted and genetic testing is an integral part of the diagnostic evaluation of these children. In contrast, children with an isolated speech or language disorder are not often genetically evaluated, despite recent evidence supporting a role for genetic factors in the aetiology of these disorders. Several chromosomal copy number variants and single gene disorders associated with abnormalities of speech and language have been identified. Individuals without a precise genetic diagnosis will not receive optimal management including interventions such as early testosterone replacement in Klinefelter syndrome, otorhinolaryngological and audiometric evaluation in 22q11.2 deletion syndrome, cardiovascular surveillance in 7q11.23 duplications and early dietary management to prevent obesity in proximal 16p11.2 deletions. This review summarises the clinical features, aetiology and management options of known chromosomal and single gene disorders that are associated with speech and language pathology in the setting of normal or only mildly impaired cognitive function. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia

    PubMed Central

    Panopoulos, Athanasia D.; Stirzaker, Roslynn A.; Hacking, Douglas F.; Tahtamouni, Lubna H.; Willson, Tracy A.; Mielke, Lisa A.; Henley, Katya J.; Zhang, Jian-Guo; Wicks, Ian P.; Stevenson, William S.; Nurden, Paquita; Watowich, Stephanie S.; Justice, Monica J.

    2007-01-01

    A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow–derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types. PMID:17515402

  14. Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.

    PubMed

    Agyemang, Amma F; Harrison, Stephanie R; Siegel, Richard M; McDermott, Michael F

    2015-07-01

    Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of "self-eating" where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.

  15. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease

    PubMed Central

    Zhou, Qing; Yu, Xiaomin; Demirkaya, Erkan; Deuitch, Natalie; Stone, Deborah; Tsai, Wanxia Li; Kuehn, Hye Sun; Wang, Hongying; Yang, Dan; Park, Yong Hwan; Ombrello, Amanda K.; Blake, Mary; Romeo, Tina; Remmers, Elaine F.; Chae, Jae Jin; Mullikin, James C.; Güzel, Ferhat; Milner, Joshua D.; Boehm, Manfred; Rosenzweig, Sergio D.; Gadina, Massimo; Welch, Steven B.; Özen, Seza; Topaloglu, Rezan; Abinun, Mario; Kastner, Daniel L.; Aksentijevich, Ivona

    2016-01-01

    Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies. PMID:27559085

  16. Monogenic and polygenic determinants of sarcoma risk: an international genetic study.

    PubMed

    Ballinger, Mandy L; Goode, David L; Ray-Coquard, Isabelle; James, Paul A; Mitchell, Gillian; Niedermayr, Eveline; Puri, Ajay; Schiffman, Joshua D; Dite, Gillian S; Cipponi, Arcadi; Maki, Robert G; Brohl, Andrew S; Myklebost, Ola; Stratford, Eva W; Lorenz, Susanne; Ahn, Sung-Min; Ahn, Jin-Hee; Kim, Jeong Eun; Shanley, Sue; Beshay, Victoria; Randall, Robert Lor; Judson, Ian; Seddon, Beatrice; Campbell, Ian G; Young, Mary-Anne; Sarin, Rajiv; Blay, Jean-Yves; O'Donoghue, Seán I; Thomas, David M

    2016-09-01

    Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24-1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic

  17. Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

    PubMed Central

    Kim, Man Lyang; Chae, Jae Jin; Park, Yong Hwan; De Nardo, Dominic; Stirzaker, Roslynn A.; Ko, Hyun-Ja; Tye, Hazel; Cengia, Louise; DiRago, Ladina; Metcalf, Donald; Roberts, Andrew W.; Kastner, Daniel L.; Lew, Andrew M.; Lyras, Dena; Kile, Benjamin T.; Croker, Ben A.

    2015-01-01

    Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease. PMID:26008898

  18. Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β.

    PubMed

    Kim, Man Lyang; Chae, Jae Jin; Park, Yong Hwan; De Nardo, Dominic; Stirzaker, Roslynn A; Ko, Hyun-Ja; Tye, Hazel; Cengia, Louise; DiRago, Ladina; Metcalf, Donald; Roberts, Andrew W; Kastner, Daniel L; Lew, Andrew M; Lyras, Dena; Kile, Benjamin T; Croker, Ben A; Masters, Seth L

    2015-06-01

    Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.

  19. The search for modifier genes in Huntington disease - Multifactorial aspects of a monogenic disorder.

    PubMed

    Arning, Larissa

    2016-12-01

    It is becoming increasingly evident that the underlying mutation of a single locus is often insufficient for the prediction of the comprehensive phenotype in human Mendelian disorders, implicating that there is no clear distinction between monogenic and complex traits. By definition, monogenic traits show a classic pattern of inheritance and are strongly influenced by variation within a single gene. However, many Mendelian traits that result in genetic disorders can have phenotypes that differ in subtle or profound ways such as severity, onset age and other associated phenotypic characteristics. Among the factors that may explain these differences in disease expression are modifier genes. This review focuses on the role of modifier genes using the example of Huntington Disease (HD), an autosomal dominantly transmitted, progressive neurodegenerative disorder. The advantages and limitations of candidate gene approaches versus genome-wide association studies (GWAS) as well as its implications for diagnostic, prognostic, and therapeutic interventions are discussed.

  20. Parkinson disease: insights in clinical, genetic and pathological features of monogenic disease subtypes.

    PubMed

    Crosiers, David; Theuns, Jessie; Cras, Patrick; Van Broeckhoven, Christine

    2011-10-01

    In the past 15 years, insights in clinical and genetic characteristics of Parkinson disease (PD) have increased substantially. Sequence or copy number variants in at least six genes (SNCA, LRRK2, PARK2, PINK1, DJ-1 and ATP13A2) have been identified to cause monogenic forms of PD. Routine clinical testing for mutations in these genes is feasible and available, but overlapping phenotypes in monogenic and sporadic PD complicate straightforward diagnostic screening. Primarily, a positive familial history and an early onset age should prompt clinicians to consider genetic testing. Based on a literature review on clinical and neuropathological features of PD patients carrying a pathogenic mutation we propose guidelines for genetic diagnostic testing in clinical practice. However, the absence of disease-modifying therapies and the variable penetrance of most known mutations currently limit the usefulness of genetic diagnostic testing for PD in clinical practice.

  1. Leveraging ancestry to improve causal variant identification in exome sequencing for monogenic disorders.

    PubMed

    Brown, Robert; Lee, Hane; Eskin, Ascia; Kichaev, Gleb; Lohmueller, Kirk E; Reversade, Bruno; Nelson, Stanley F; Pasaniuc, Bogdan

    2016-01-01

    Recent breakthroughs in exome-sequencing technology have made possible the identification of many causal variants of monogenic disorders. Although extremely powerful when closely related individuals (eg, child and parents) are simultaneously sequenced, sequencing of a single case is often unsuccessful due to the large number of variants that need to be followed up for functional validation. Many approaches filter out common variants above a given frequency threshold (eg, 1%), and then prioritize the remaining variants according to their functional, structural and conservation properties. Here we present methods that leverage the genetic structure across different populations to improve filtering performance while accounting for the finite sample size of the reference panels. We show that leveraging genetic structure reduces the number of variants that need to be followed up by 16% in simulations and by up to 38% in empirical data of 20 exomes from individuals with monogenic disorders for which the causal variants are known.

  2. Aetiology of colorectal cancer and relevance of monogenic inheritance

    PubMed Central

    Ponz de Leon, M; Benatti, P; Borghi, F; Pedroni, M; Scarselli, A; Di Gregorio, C; Losi, L; Viel, A; Genuardi, M; Abbati, G; Rossi, G; Menigatti, M; Lamberti, I; Ponti, G; Roncucci, L

    2004-01-01

    Background and aims: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. Patients and methods: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. Results: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. Conclusions: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the

  3. The Schnitzler syndrome

    PubMed Central

    2010-01-01

    The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections. In many aspects, the Schnitzler syndrome resembles the genetically determined auto-inflammatory syndromes involving activating mutations of the NLRP3 inflammasome. This latter point and its consequences will be addressed. PMID:21143856

  4. The Schnitzler syndrome.

    PubMed

    Lipsker, Dan

    2010-12-08

    The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections.In many aspects, the Schnitzler syndrome resembles the genetically determined auto-inflammatory syndromes involving activating mutations of the NLRP3 inflammasome. This latter point and its consequences will be addressed.

  5. Genetics of calcium homeostasis in humans: continuum between monogenic diseases and continuous phenotypes.

    PubMed

    Bonny, Olivier; Bochud, Murielle

    2014-09-01

    Extracellular calcium participates in several key physiological functions, such as control of blood coagulation, bone calcification or muscle contraction. Calcium homeostasis in humans is regulated in part by genetic factors, as illustrated by rare monogenic diseases characterized by hypo or hypercalcaemia. Both serum calcium and urinary calcium excretion are heritable continuous traits in humans. Serum calcium levels are tightly regulated by two main hormonal systems, i.e. parathyroid hormone and vitamin D, which are themselves also influenced by genetic factors. Recent technological advances in molecular biology allow for the screening of the human genome at an unprecedented level of detail and using hypothesis-free approaches, such as genome-wide association studies (GWAS). GWAS identified novel loci for calcium-related phenotypes (i.e. serum calcium and 25-OH vitamin D) that shed new light on the biology of calcium in humans. The substantial overlap (i.e. CYP24A1, CASR, GATA3; CYP2R1) between genes involved in rare monogenic diseases and genes located within loci identified in GWAS suggests a genetic and phenotypic continuum between monogenic diseases of calcium homeostasis and slight disturbances of calcium homeostasis in the general population. Future studies using whole-exome and whole-genome sequencing will further advance our understanding of the genetic architecture of calcium homeostasis in humans. These findings will likely provide new insight into the complex mechanisms involved in calcium homeostasis and hopefully lead to novel preventive and therapeutic approaches. Keyword: calcium, monogenic, genome-wide association studies, genetics. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  6. Determinants of Power in Gene-Based Burden Testing for Monogenic Disorders.

    PubMed

    Guo, Michael H; Dauber, Andrew; Lippincott, Margaret F; Chan, Yee-Ming; Salem, Rany M; Hirschhorn, Joel N

    2016-09-01

    Whole-exome sequencing has enabled new approaches for discovering genes associated with monogenic disorders. One such approach is gene-based burden testing, in which the aggregate frequency of "qualifying variants" is compared between case and control subjects for each gene. Despite substantial successes of this approach, the genetic causes for many monogenic disorders remain unknown or only partially known. It is possible that particular genetic architectures lower rates of discovery, but the influence of these factors on power has not been rigorously evaluated. Here, we leverage large-scale exome-sequencing data to create an empirically based simulation framework to evaluate the impact of key parameters (background variation rates, locus heterogeneity, mode of inheritance, penetrance) on power in gene-based burden tests in the context of monogenic disorders. Our results demonstrate that across genes, there is a wide range in sample sizes needed to achieve power due to differences in the background rate of rare variants in each gene. Increasing locus heterogeneity results in rapid increases in sample sizes needed to achieve adequate power, particularly when individual genes contribute to less than 5% of cases under a dominant model. Interestingly, incomplete penetrance as low as 10% had little effect on power due to the low prevalence of monogenic disorders. Our results suggest that moderate incomplete penetrance is not an obstacle in this gene-based burden testing approach but that dominant disorders with high locus heterogeneity will require large sample sizes. Our simulations also provide guidance on sample size needs and inform study design under various genetic architectures.

  7. An Online Monogenic Diabetes Discussion Group: Supporting Families and Fueling New Research

    PubMed Central

    Perrone, Marie E.; Carmody, David; Philipson, Louis H.; Greeley, Siri Atma W

    2016-01-01

    Many online support groups are available for patients with rare disorders, but scant evidence is available on how effectively such groups provide useful information or valuable psychosocial support to their participants. It is also unclear to what extent physicians and researchers may learn more about these disorders by participating in such groups. To formally assess the utility of the Kovler Monogenic Diabetes Registry online discussion group for patients and families affected by KATP channel-related monogenic neonatal diabetes in providing psychosocial and informational support, and in identifying concerns unique to patients with this rare form of diabetes. We qualitatively analyzed all 1,410 messages from the online group that consisted of 64 participants affected by KATP channel monogenic diabetes and 11 researchers. We utilized the Social Behavior Support Code to assign each message to a support category and deductive thematic analysis to identify discussion topics addressed by each message. 44% of messages provided/requested informational support, whereas 31.4% of the messages contained psychosocial/emotional support. The most popular topics of postings to the forums were diabetes treatment (503 messages) and neurodevelopmental concerns (472 messages). Participation in the discussion led researchers to modify survey instruments as well as design new studies focusing on specific topics of concern, such as sleep. We demonstrate that an online support group for a monogenic form of diabetes is an effective informational tool that also provides psychosocial support. Participation by researchers and care providers can inform future research directions and highlight issues of patient concern. PMID:26184072

  8. Allelic Variation, Aneuploidy, and Nongenetic Mechanisms Suppress a Monogenic Trait in Yeast

    PubMed Central

    Sirr, Amy; Cromie, Gareth A.; Jeffery, Eric W.; Gilbert, Teresa L.; Ludlow, Catherine L.; Scott, Adrian C.; Dudley, Aimée M.

    2015-01-01

    Clinically relevant features of monogenic diseases, including severity of symptoms and age of onset, can vary widely in response to environmental differences as well as to the presence of genetic modifiers affecting the trait’s penetrance and expressivity. While a better understanding of modifier loci could lead to treatments for Mendelian diseases, the rarity of individuals harboring both a disease-causing allele and a modifying genotype hinders their study in human populations. We examined the genetic architecture of monogenic trait modifiers using a well-characterized yeast model of the human Mendelian disease classic galactosemia. Yeast strains with loss-of-function mutations in the yeast ortholog (GAL7) of the human disease gene (GALT) fail to grow in the presence of even small amounts of galactose due to accumulation of the same toxic intermediates that poison human cells. To isolate and individually genotype large numbers of the very rare (∼0.1%) galactose-tolerant recombinant progeny from a cross between two gal7Δ parents, we developed a new method, called “FACS-QTL.” FACS-QTL improves upon the currently used approaches of bulk segregant analysis and extreme QTL mapping by requiring less genome engineering and strain manipulation as well as maintaining individual genotype information. Our results identified multiple distinct solutions by which the monogenic trait could be suppressed, including genetic and nongenetic mechanisms as well as frequent aneuploidy. Taken together, our results imply that the modifiers of monogenic traits are likely to be genetically complex and heterogeneous. PMID:25398792

  9. LipidSeq: a next-generation clinical resequencing panel for monogenic dyslipidemias.

    PubMed

    Johansen, Christopher T; Dubé, Joseph B; Loyzer, Melissa N; MacDonald, Austin; Carter, David E; McIntyre, Adam D; Cao, Henian; Wang, Jian; Robinson, John F; Hegele, Robert A

    2014-04-01

    We report the design of a targeted resequencing panel for monogenic dyslipidemias, LipidSeq, for the purpose of replacing Sanger sequencing in the clinical detection of dyslipidemia-causing variants. We also evaluate the performance of the LipidSeq approach versus Sanger sequencing in 84 patients with a range of phenotypes including extreme blood lipid concentrations as well as additional dyslipidemias and related metabolic disorders. The panel performs well, with high concordance (95.2%) in samples with known mutations based on Sanger sequencing and a high detection rate (57.9%) of mutations likely to be causative for disease in samples not previously sequenced. Clinical implementation of LipidSeq has the potential to aid in the molecular diagnosis of patients with monogenic dyslipidemias with a high degree of speed and accuracy and at lower cost than either Sanger sequencing or whole exome sequencing. Furthermore, LipidSeq will help to provide a more focused picture of monogenic and polygenic contributors that underlie dyslipidemia while excluding the discovery of incidental pathogenic clinically actionable variants in nonmetabolism-related genes, such as oncogenes, that would otherwise be identified by a whole exome approach, thus minimizing potential ethical issues.

  10. Genetics 101 for cardiologists: rare genetic variants and monogenic cardiovascular disease.

    PubMed

    Farhan, Sali M K; Hegele, Robert A

    2013-01-01

    Monogenic diseases have a distinctive familial inheritance that follows Mendel's laws, showing patterns like dominant, recessive, or X-linked. There are > 7000 monogenic diseases curated in databases, and together they account for up to 10% of all illnesses encountered in the emergency room or clinic. Despite the rarity of individual monogenic conditions, mapping their causative genes and mutations is important for several reasons. First, knowing the causative gene and mutation could provide actionable information for genetic counselling. Sometimes, knowing the gene and mutation allows for early diagnosis in affected families, which is important if there is an evidence-based intervention. Second, the implication of a mutant gene as being causative for a clinical phenotype provides strong evidence of the importance of the gene product in a cellular or biochemical pathway. Discovery of new molecular pathways in families with rare diseases can serve as the first step toward developing rational therapies to help not only affected families, but also patients with less extreme, nongenetic forms of the same condition. For instance, the study of rare patients with familial hypercholesterolemia helped in developing statin drugs, initially as a treatment for familial hypercholesterolemia but now a widely used therapy to reduce low-density lipoprotein cholesterol and cardiovascular disease risk.

  11. [Monogenic obesity - current status of molecular genetic research and clinical importance].

    PubMed

    Aldhoon-Hainerová, Irena; Včelák, Josef; Zamrazilová, Hana

    2014-01-01

    Obesity and its comorbidities represent one of the major health problems worldwide. A positive energy balance due to inappropriate life-style changes plays a key role in the current obesity epidemic. The influence of genetic factors is also significant - several studies concluded that genes contribute to the development of obesity by 40-70%. Genetic variability predisposes an individual to tendency or resistance to increase body weight in obesogenic environment. Polygenic type of inheritance is responsible in most of obese individuals. However, an intensive research of the past 20 years has led to an identification of several genes causing monogenic forms of obesity. To date, several monogenic genes (leptin, leptin receptor, prohormon convertase 1, proopiomelanocortin, melanocortin 4 receptor, single-minded homolog 1, brain-derived neurotrophic factor, neurotrophic tyrosine kinase receptor type 2) that are either involved in the neuronal differentiation of the paraventricular nucleus or in the leptin-melanocortin pathway are known to cause obesity. Mutation carriers apart from severe early onset obesity manifest with additional phenotypic characteristics as adrenal insufficiency, impaired immunity and impaired fertility. This review provides an overview of molecular-genetic and clinical research in the field of monogenic obesities including therapeutical approaches.

  12. Illumination-invariant pattern recognition using fringe-adjusted joint transform correlator and monogenic signal

    NASA Astrophysics Data System (ADS)

    Sidike, Paheding; Asari, Vijayan K.; Alam, Mohammad S.

    2014-03-01

    The joint transform correlator (JTC) technique has shown attractive performance for real-time pattern recognition applications. Among the various JTC techniques proposed in the literature, the fringe-adjusted JTC (FJTC) yields remarkable promise for object recognition, and it has been shown that the FJTC produces a better correlation output than alternate JTCs under varying illumination conditions of the input scene; however, it has been found that the FJTC is not illumination invariant. Therefore, to alleviate this drawback of the FJTC, an illumination-invariant FJTC, based on combination of the fringe-adjusted filter (FAF) and the monogenic signal, is presented. The performance of the FJTC and the proposed local phase based FJTC technique in unknown input-image with varying illumination is investigated and compared. The proposed detection algorithm makes use of the monogenic signal from a two dimensional object region to extract the local phase information for assisting the FJTC robust to illumination effects. Experimental results show that by utilizing the monogenic phase information enables the FAF-based JTC to produce sharper correlation peaks and higher peak-to-clutter ratio compared to alternate JTCs. The proposed technique may be used as a real-time region-ofinterest identifier in wide-area surveillance for automatic object recognition when the target under very dark or bright condition that beyond human vision.

  13. Insights into the genetic structure of congenital heart disease from human and murine studies on monogenic disorders.

    PubMed

    Prendiville, Terence; Jay, Patrick Y; Pu, William T

    2014-10-01

    Study of monogenic congenital heart disease (CHD) has provided entry points to gain new understanding of heart development and the molecular pathogenesis of CHD. In this review, we discuss monogenic CHD caused by mutations of the cardiac transcription factor genes NKX2-5 and GATA4. Detailed investigation of these genes in mice and humans has expanded our understanding of heart development, shedding light on the complex genetic and environmental factors that influence expression and penetrance of CHD gene mutations.

  14. Autoinflammatory Diseases

    MedlinePlus

    ... Behçet’s Disease Progress and Promise Key Words The Immune System When your body is attacked – perhaps by a virus or other germs – your immune system defends you. It “sees” and kills the germs ...

  15. The infevers autoinflammatory mutation online registry: update with new genes and functions.

    PubMed

    Milhavet, Florian; Cuisset, Laurence; Hoffman, Hal M; Slim, Rima; El-Shanti, Hatem; Aksentijevich, Ivona; Lesage, Suzanne; Waterham, Hans; Wise, Carol; Sarrauste de Menthiere, Cyril; Touitou, Isabelle

    2008-06-01

    Infevers (Internet Fevers; http://fmf.igh.cnrs.fr/ISSAID/infevers), a website dedicated to mutations responsible for hereditary autoinflammatory diseases, was created in 2002 and has continued to evolve. This new version includes eight genes; six were already present: MEFV, MVK, TNFRSF1A, NLRP3, NOD2, PSTPIP1, and two are new, LPIN2 and NLRP7. Currently, Infevers contains over 540 sequence variants. Several new database functions were recently instituted. The website now accepts confidential data and complex alleles. For each gene, a newly created menu offers: 1) a tabular list of the variants that can be sorted by several parameters; 2) a gene graph providing a schematic representation of the variants along the gene; 3) statistical analysis of the data according to the phenotype, alteration type, and location of the mutation in the gene; 4) the cDNA and gDNA sequences of each gene, showing the nucleotide changes along the sequence, with a color-based code highlighting the gene domains, the first ATG, and the termination codon; and 5) a "download" menu making all tables and figures available for the users, which, except for the gene graphs, are all automatically generated and updated upon submission of the variants. Finally, the entire database was curated to comply with the HUGO Gene Nomenclature Committee (HGNC) and HGVS nomenclature guidelines, and wherever necessary, an informative note was provided. Infevers has already proven useful for the scientific community with a mean number of visits per month of 200 in 2002 and 800 in 2007, and its new design will lead to a more comprehensive comparative analysis and interpretation of auto-inflammatory sequence variants.

  16. An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

    PubMed Central

    Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; van Royen-Kerkhoff, Annet; Laxer, Ron; Tedgård, Ulf; Cowen, Edward W.; Pham, Tuyet-Hang; Booty, Matthew; Estes, Jacob D.; Sandler, Netanya G.; Plass, Nicole; Stone, Deborah L.; Turner, Maria L.; Hill, Suvimol; Butman, John A.; Schneider, Rayfel; Babyn, Paul; El-Shanti, Hatem I.; Pope, Elena; Barron, Karyl; Bing, Xinyu; Laurence, Arian; Lee, Chyi-Chia R.; Chapelle, Dawn; Clarke, Gillian I.; Ohson, Kamal; Nicholson, Marc; Gadina, Massimo; Yang, Barbara; Korman, Benjamin D.; Gregersen, Peter K.; van Hagen, P. Martin; Hak, A. Elisabeth; Huizing, Marjan; Rahman, Proton; Douek, Daniel C.; Remmers, Elaine F.; Kastner, Daniel L.; Goldbach-Mansky, Raphaela

    2010-01-01

    Background Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1–receptor antagonist, with prominent involvement of skin and bone. Methods We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1–receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1–pathway genes including IL1RN. Results We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1–family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1β stimulation. Patients treated with anakinra responded rapidly. Conclusions We propose the term deficiency of the interleukin-1–receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1–receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.) PMID:19494218

  17. Epigallocatechin-3-gallate ameliorates both obesity and autoinflammatory arthritis aggravated by obesity by altering the balance among CD4+ T-cell subsets.

    PubMed

    Byun, Jae-Kyeong; Yoon, Bo-Young; Jhun, Joo-Yeon; Oh, Hye-Joa; Kim, Eun-kyoung; Min, Jun-Ki; Cho, Mi-La

    2014-01-01

    Epigallocatechin-3-gallate (EGCG) is the most biologically active catechin in green tea. EGCG has been shown to have therapeutic effects in autoinflammatory diseases and obesity. Obesity is currently regarded-partly-as an inflammatory condition because of the inflammatory cytokines and higher Th1 cell differentiation detected in obese animal models and human cohort studies. In this work, the effects of EGCG on diet-induced obesity (DIO) mice and obese collagen-induced arthritis (CIA) mice were investigated. EGCG reduced the body weight and fat infiltration in liver tissue while improving serum lipid profiles in DIO mice. EGCG also induced a higher Treg/Th17 cell ratio in CD4(+) T-cell differentiation by decreasing the ratio of STAT3/STAT5 expression in DIO mice. EGCG was also effective in obese CIA mice. Reducing Th17 cells and increasing regulatory T (Treg) cells by affecting the STAT protein ratio were important effects of EGCG that might result in improved arthritic scores and levels of several inflammatory indicators. Thus, EGCG has an anti-inflammatory effect by suppressing STAT3 proteins and Th17-cell differentiation. EGCG thus shows promise for treating autoimmune conditions related to STAT3 or Th17 cells, such as metabolic syndrome, inflammatory arthritis, and some neoplastic diseases. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

    PubMed Central

    Zilberman-Rudenko, Jevgenia; Shawver, Linda Monaco; Wessel, Alex W.; Luo, Yongquan; Pelletier, Martin; Tsai, Wanxia Li; Lee, Younglang; Vonortas, Spiridon; Cheng, Laurence; Ashwell, Jonathan D.; Orange, Jordan S.; Siegel, Richard M.; Hanson, Eric P.

    2016-01-01

    Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease. PMID:26802121

  19. When uncommon and common coalesce: adult onset Still's disease associated with breast augmentation as part of autoimmune syndrome induced by adjuvants (ASIA).

    PubMed

    Dagan, A; Kogan, M; Shoenfeld, Y; Segal, G

    2016-06-01

    Adult onset Still's disease (AOSD) is an uncommon, multisystemic, auto-inflammatory disorder, while breast augmentation is a very common cosmetic procedure. We describe a case in which these two coalesce, AOSD, manifested with pleuritis and pericarditis, developed after breast mammoplasty. The pathogenetic, missing link, behind the development of AOSD following mammoplasty, is thought to be the autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA). We reviewed other cases of AOSD associated with breast mammoplasty published to date and the literature regarding AOSD and ASIA syndrome. The review is followed by a short debate of whether silicone implants should be explanted in similar, future cases.

  20. Periodic Fever: A Review on Clinical, Management and Guideline for Iranian Patients - Part II

    PubMed Central

    Ahmadinejad, Zahra; Mansouri, Sedigeh; Ziaee, Vahid; Aghighi, Yahya; Moradinejad, Mohammad-Hassan; Fereshteh-Mehregan, Fatemeh

    2014-01-01

    Periodic fever syndromes are a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. In the first part of this paper, we presented a guideline for approaching patients with periodic fever and reviewed two common disorders with periodic fever in Iranian patients including familial Mediterranean fever (FMF) and periodic fever syndromes except for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). In this part, we review other autoinflammatory disorders including hyper IgD, tumor necrosis factor receptor–associated periodic syndrome (TRAPS), cryopyrin associated periodic syndromes, autoinflammatory bone disorders and some other rare autoinflammatory disorders such as Sweet’s and Blau syndromes. In cryopyrin associated periodic syndromes group, we discussed chronic infantile neurologic cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold autoinflammatory syndrome. Autoinflammatory bone disorders are categorized to monogenic disorders such as pyogenic arthritis, pyoderma ;gangraenosum and acne (PAPA) syndrome, the deficiency of interleukine-1 receptor antagonist (DIRA) and Majeed syndrome and polygenic background or sporadic group such as chronic recurrent multifocal osteomyelitis (CRMO) or synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are classified in sporadic group. Other autoinflammatory syndromes are rare causes of periodic fever in Iranian system registry. PMID:25562014

  1. Periodic Fever: A Review on Clinical, Management and Guideline for Iranian Patients - Part II.

    PubMed

    Ahmadinejad, Zahra; Mansouri, Sedigeh; Ziaee, Vahid; Aghighi, Yahya; Moradinejad, Mohammad-Hassan; Fereshteh-Mehregan, Fatemeh

    2014-06-01

    Periodic fever syndromes are a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. In the first part of this paper, we presented a guideline for approaching patients with periodic fever and reviewed two common disorders with periodic fever in Iranian patients including familial Mediterranean fever (FMF) and periodic fever syndromes except for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). In this part, we review other autoinflammatory disorders including hyper IgD, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrin associated periodic syndromes, autoinflammatory bone disorders and some other rare autoinflammatory disorders such as Sweet's and Blau syndromes. In cryopyrin associated periodic syndromes group, we discussed chronic infantile neurologic cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold autoinflammatory syndrome. Autoinflammatory bone disorders are categorized to monogenic disorders such as pyogenic arthritis, pyoderma ;gangraenosum and acne (PAPA) syndrome, the deficiency of interleukine-1 receptor antagonist (DIRA) and Majeed syndrome and polygenic background or sporadic group such as chronic recurrent multifocal osteomyelitis (CRMO) or synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are classified in sporadic group. Other autoinflammatory syndromes are rare causes of periodic fever in Iranian system registry.

  2. No mutations in the serotonin related TPH1 and HTR1B genes in patients with monogenic sclerosing bone disorders.

    PubMed

    Boudin, Eveline; Jennes, Karen; de Freitas, Fenna; Tegay, David; Mortier, Geert; Van Hul, Wim

    2013-07-01

    Since the identification of LRP5 as the causative gene for the osteoporosis pseudoglioma syndrome (OPPG) as well as the high bone mass (HBM) phenotype, LRP5 and the Wnt/β-catenin signaling have been extensively studied for their role in the differentiation and proliferation of osteoblasts, in the apoptosis of osteoblasts and osteocytes and in the response of bone to mechanical loading. However, more recently the direct effect of LRP5 on osteoblasts and bone formation has been questioned. Gene expression studies showed that mice lacking lrp5 have increased expression of tph1, the rate limiting enzyme for the production of serotonin in the gut. Furthermore mice lacking either tph1 or htr1B, the receptor for serotonin on the osteoblasts, were reported to have an increased bone mass due to increased bone formation. This led to the still controversial hypothesis that LRP5 influences bone formation indirectly by regulating the expression of thp1 and as a consequence influencing the production of serotonin in the gut. Based on these data we decided to evaluate the role of TPH1 and HTR1B in the development of craniotubular hyperostoses, a group of monogenic sclerosing bone dysplasias. We screened the coding regions of both genes in 53 patients lacking a mutation in the known causative genes LRP5, LRP4 and SOST. We could not find disease-causing coding variants in neither of the tested genes and therefore, we cannot provide support for an important function of TPH1 and HTR1B in the pathogenesis of sclerosing bone dysplasias in our tested patient cohort.

  3. What Is the Best NGS Enrichment Method for the Molecular Diagnosis of Monogenic Diabetes and Obesity?

    PubMed Central

    Philippe, Julien; Derhourhi, Mehdi; Durand, Emmanuelle; Vaillant, Emmanuel; Dechaume, Aurélie; Rabearivelo, Iandry; Dhennin, Véronique; Vaxillaire, Martine; De Graeve, Franck; Sand, Olivier; Froguel, Philippe; Bonnefond, Amélie

    2015-01-01

    Molecular diagnosis of monogenic diabetes and obesity is of paramount importance for both the patient and society, as it can result in personalized medicine associated with a better life and it eventually saves health care spending. Genetic clinical laboratories are currently switching from Sanger sequencing to next-generation sequencing (NGS) approaches but choosing the optimal protocols is not easy. Here, we compared the sequencing coverage of 43 genes involved in monogenic forms of diabetes and obesity, and variant detection rates, resulting from four enrichment methods based on the sonication of DNA (Agilent SureSelect, RainDance technologies), or using enzymes for DNA fragmentation (Illumina Nextera, Agilent HaloPlex). We analyzed coding exons and untranslated regions of the 43 genes involved in monogenic diabetes and obesity. We found that none of the methods achieves yet full sequencing of the gene targets. Nonetheless, the RainDance, SureSelect and HaloPlex enrichment methods led to the best sequencing coverage of the targets; while the Nextera method resulted in the poorest sequencing coverage. Although the sequencing coverage was high, we unexpectedly found that the HaloPlex method missed 20% of variants detected by the three other methods and Nextera missed 10%. The question of which NGS technique for genetic diagnosis yields the highest diagnosis rate is frequently discussed in the literature and the response is still unclear. Here, we showed that the RainDance enrichment method as well as SureSelect, which are both based on the sonication of DNA, resulted in a good sequencing quality and variant detection, while the use of enzymes to fragment DNA (HaloPlex or Nextera) might not be the best strategy to get an accurate sequencing. PMID:26599467

  4. What Is the Best NGS Enrichment Method for the Molecular Diagnosis of Monogenic Diabetes and Obesity?

    PubMed

    Philippe, Julien; Derhourhi, Mehdi; Durand, Emmanuelle; Vaillant, Emmanuel; Dechaume, Aurélie; Rabearivelo, Iandry; Dhennin, Véronique; Vaxillaire, Martine; De Graeve, Franck; Sand, Olivier; Froguel, Philippe; Bonnefond, Amélie

    2015-01-01

    Molecular diagnosis of monogenic diabetes and obesity is of paramount importance for both the patient and society, as it can result in personalized medicine associated with a better life and it eventually saves health care spending. Genetic clinical laboratories are currently switching from Sanger sequencing to next-generation sequencing (NGS) approaches but choosing the optimal protocols is not easy. Here, we compared the sequencing coverage of 43 genes involved in monogenic forms of diabetes and obesity, and variant detection rates, resulting from four enrichment methods based on the sonication of DNA (Agilent SureSelect, RainDance technologies), or using enzymes for DNA fragmentation (Illumina Nextera, Agilent HaloPlex). We analyzed coding exons and untranslated regions of the 43 genes involved in monogenic diabetes and obesity. We found that none of the methods achieves yet full sequencing of the gene targets. Nonetheless, the RainDance, SureSelect and HaloPlex enrichment methods led to the best sequencing coverage of the targets; while the Nextera method resulted in the poorest sequencing coverage. Although the sequencing coverage was high, we unexpectedly found that the HaloPlex method missed 20% of variants detected by the three other methods and Nextera missed 10%. The question of which NGS technique for genetic diagnosis yields the highest diagnosis rate is frequently discussed in the literature and the response is still unclear. Here, we showed that the RainDance enrichment method as well as SureSelect, which are both based on the sonication of DNA, resulted in a good sequencing quality and variant detection, while the use of enzymes to fragment DNA (HaloPlex or Nextera) might not be the best strategy to get an accurate sequencing.

  5. Diagnosis of cryopyrin-associated periodic syndrome: challenges, recommendations and emerging concepts.

    PubMed

    Sarrabay, Guillaume; Grandemange, Sylvie; Touitou, Isabelle

    2015-01-01

    Cryopyrin-associated periodic syndrome are rare autosomal dominantly inherited diseases. They include three overlapping phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem autoinflammatory syndrome (NOMID/CINCA). Recurrent fevers, joint pain, and urticarial skin rash are the main clinical features of these conditions. Renal amyloidosis and sensorineural complications may occur. Gain-of-function mutations in NLRP3 gene are responsible for the overactivation of the NLRP3 inflammasome, a multimolecular complex involved in the inflammatory process. Missense mutations are almost always encountered, particularly in exon 3, which encodes the nucleotide-binding domain. Mosaicism is not rare, especially in CINCA/NOMID. Next-generation sequencing will grant access to new insights about NLRP3 implication in oligogenic and multifactorial diseases.

  6. Monogenic Diabetes: What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes

    PubMed Central

    2016-01-01

    To date, more than 30 genes have been linked to monogenic diabetes. Candidate gene and genome-wide association studies have identified > 50 susceptibility loci for common type 1 diabetes (T1D) and approximately 100 susceptibility loci for type 2 diabetes (T2D). About 1–5% of all cases of diabetes result from single-gene mutations and are called monogenic diabetes. Here, we review the pathophysiological basis of the role of monogenic diabetes genes that have also been found to be associated with common T1D and/or T2D. Variants of approximately one-third of monogenic diabetes genes are associated with T2D, but not T1D. Two of the T2D-associated monogenic diabetes genes—potassium inward-rectifying channel, subfamily J, member 11 (KCNJ11), which controls glucose-stimulated insulin secretion in the β-cell; and peroxisome proliferator-activated receptor γ (PPARG), which impacts multiple tissue targets in relation to inflammation and insulin sensitivity—have been developed as major antidiabetic drug targets. Another monogenic diabetes gene, the preproinsulin gene (INS), is unique in that INS mutations can cause hyperinsulinemia, hyperproinsulinemia, neonatal diabetes mellitus, one type of maturity-onset diabetes of the young (MODY10), and autoantibody-negative T1D. Dominant heterozygous INS mutations are the second most common cause of permanent neonatal diabetes. Moreover, INS gene variants are strongly associated with common T1D (type 1a), but inconsistently with T2D. Variants of the monogenic diabetes gene Gli-similar 3 (GLIS3) are associated with both T1D and T2D. GLIS3 is a key transcription factor in insulin production and β-cell differentiation during embryonic development, which perturbation forms the basis of monogenic diabetes as well as its association with T1D. GLIS3 is also required for compensatory β-cell proliferation in adults; impairment of this function predisposes to T2D. Thus, monogenic forms of diabetes are invaluable “human models” that

  7. The SAPHO syndrome and genetics - discoveries in need of replication.

    PubMed

    Wollheim, Frank A

    2013-01-01

    SAPHO and its relative CMRO are uncommon but not rare chronic conditions with unknown etiology. Environmental factors, perhaps related to microorganisms, may be important triggers, but there is no support for a septic nature. The monogenic animal models called cmo and Lupo with autosomal recessive transmission have not been replicated in human diease. Interesting but unconfirmed studies indicate impaired p53 formation, increased IL-10 production and decreased capacity to mount ROS responses in different patients whith SAPHO. There is more evidence supporting an autoinflammatory than an autoimmune pathogenesis of SAPHO. Susceptibility genes on chromosomes 1 and 18 need to be confirmed. More studies in larger numbers of patients are needed to confirm the often anecdotal observations reviewed here. It is hoped that this review may stimulate such work.

  8. A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference

    PubMed Central

    Piram, Maryam; Frenkel, Joost; Gattorno, Marco; Ozen, Seza; Lachmann, Helen J; Goldbach-Mansky, Raphaela; Hentgen, Véronique; Neven, Bénédicte; Stankovic Stojanovic, Katia; Simon, Anna; Kuemmerle-Deschner, Jasmin; Hoffman, Hal; Stojanov, Silvia; Duquesne, Agnès; Pillet, Pascal; Martini, Alberto; Pouchot, Jacques; Koné-Paut, Isabelle

    2012-01-01

    Background The systemic autoinflammatory disorders (SAID) share many clinical manifestations, albeit with variable patterns, intensity and frequency. A common definition of disease activity would be rational and useful in the management of these lifelong diseases. Moreover, standardised disease activity scores are required for the assessment of new therapies in constant development. The aim of this study was to develop preliminary activity scores for familial Mediterranean fever, mevalonate kinase deficiency, tumour necrosis factor receptor-1-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS). Methods The study was conducted using two well-recognised consensus formation methods: the Delphi technique and the nominal group technique. The results from a two-step survey and data from parent/patient interviews were used as preliminary data to develop the agenda for a consensus conference to build a provisional scoring system. Results 24 of 65 experts in SAID from 20 countries answered the web questionnaire and 16 attended the consensus conference. There was consensus agreement to develop separate activity scores for each disease but with a common format based on patient diaries. Fever and disease-specific clinical variables were scored according to their severity. A final score was generated by summing the score of all the variables divided by the number of days over which the diary was completed. Scores varied from 0 to 16 (0–13 in CAPS). These scores were developed for the purpose of clinical studies but could be used in clinical practice. Conclusion Using widely recognised consensus formation techniques, preliminary scores were obtained to measure disease activity in four main SAID. Further prospective validation study of this instrument will follow. PMID:21081528

  9. Severe infectious diseases of childhood as monogenic inborn errors of immunity.

    PubMed

    Casanova, Jean-Laurent

    2015-12-22

    This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

  10. Human induced pluripotent stem cells for monogenic disease modelling and therapy.

    PubMed

    Spitalieri, Paola; Talarico, Valentina Rosa; Murdocca, Michela; Novelli, Giuseppe; Sangiuolo, Federica

    2016-04-26

    Recent and advanced protocols are now available to derive human induced pluripotent stem cells (hiPSCs) from patients affected by genetic diseases. No curative treatments are available for many of these diseases; thus, hiPSCs represent a major impact on patient' health. hiPSCs represent a valid model for the in vitro study of monogenic diseases, together with a better comprehension of the pathogenic mechanisms of the pathology, for both cell and gene therapy protocol applications. Moreover, these pluripotent cells represent a good opportunity to test innovative pharmacological treatments focused on evaluating the efficacy and toxicity of novel drugs. Today, innovative gene therapy protocols, especially gene editing-based, are being developed, allowing the use of these cells not only as in vitro disease models but also as an unlimited source of cells useful for tissue regeneration and regenerative medicine, eluding ethical and immune rejection problems. In this review, we will provide an up-to-date of modelling monogenic disease by using hiPSCs and the ultimate applications of these in vitro models for cell therapy. We consider and summarize some peculiar aspects such as the type of parental cells used for reprogramming, the methods currently used to induce the transcription of the reprogramming factors, and the type of iPSC-derived differentiated cells, relating them to the genetic basis of diseases and to their inheritance model.

  11. Intrusion detection on oil pipeline right of way using monogenic signal representation

    NASA Astrophysics Data System (ADS)

    Nair, Binu M.; Santhaseelan, Varun; Cui, Chen; Asari, Vijayan K.

    2013-05-01

    We present an object detection algorithm to automatically detect and identify possible intrusions such as construction vehicles and equipment on the regions designated as the pipeline right-of-way (ROW) from high resolution aerial imagery. The pipeline industry has buried millions of miles of oil pipelines throughout the country and these regions are under constant threat of unauthorized construction activities. We propose a multi-stage framework which uses a pyramidal template matching scheme in the local phase domain by taking a single high resolution training image to classify a construction vehicle. The proposed detection algorithm makes use of the monogenic signal representation to extract the local phase information. Computing the monogenic signal from a two dimensional object region enables us to separate out the local phase information (structural details) from the local energy (contrast) thereby achieving illumination invariance. The first stage involves the local phase based template matching using only a single high resolution training image in a local region at multiple scales. Then, using the local phase histogram matching, the orientation of the detected region is determined and a voting scheme gives a certain weightage to the resulting clusters. The final stage involves the selection of clusters based on the number of votes attained and using the histogram of oriented phase feature descriptor, the object is located at the correct orientation and scale. The algorithm is successfully tested on four different datasets containing imagery with varying image resolution and object orientation.

  12. Human induced pluripotent stem cells for monogenic disease modelling and therapy

    PubMed Central

    Spitalieri, Paola; Talarico, Valentina Rosa; Murdocca, Michela; Novelli, Giuseppe; Sangiuolo, Federica

    2016-01-01

    Recent and advanced protocols are now available to derive human induced pluripotent stem cells (hiPSCs) from patients affected by genetic diseases. No curative treatments are available for many of these diseases; thus, hiPSCs represent a major impact on patient’ health. hiPSCs represent a valid model for the in vitro study of monogenic diseases, together with a better comprehension of the pathogenic mechanisms of the pathology, for both cell and gene therapy protocol applications. Moreover, these pluripotent cells represent a good opportunity to test innovative pharmacological treatments focused on evaluating the efficacy and toxicity of novel drugs. Today, innovative gene therapy protocols, especially gene editing-based, are being developed, allowing the use of these cells not only as in vitro disease models but also as an unlimited source of cells useful for tissue regeneration and regenerative medicine, eluding ethical and immune rejection problems. In this review, we will provide an up-to-date of modelling monogenic disease by using hiPSCs and the ultimate applications of these in vitro models for cell therapy. We consider and summarize some peculiar aspects such as the type of parental cells used for reprogramming, the methods currently used to induce the transcription of the reprogramming factors, and the type of iPSC-derived differentiated cells, relating them to the genetic basis of diseases and to their inheritance model. PMID:27114745

  13. Severe infectious diseases of childhood as monogenic inborn errors of immunity

    PubMed Central

    Casanova, Jean-Laurent

    2015-01-01

    This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications. PMID:26621750

  14. Long-lasting response to oral therapy in a young male with monogenic diabetes as part of HNF1B-related disease

    PubMed Central

    Lomas, Amparo; Pinés, Pedro J; Lamas, Cristina

    2017-01-01

    Mutations in hepatocyte nuclear factor 1β gene (HNF1B) are responsible for a multisystemic syndrome where monogenic diabetes (classically known as MODY 5) and renal anomalies, mostly cysts, are the most characteristic findings. Urogenital malformations, altered liver function tests, hypomagnesemia or hyperuricemia and gout are also part of the syndrome. Diabetes in these patients usually requires early insulinization. We present the case of a young non-obese male patient with a personal history of renal multicystic dysplasia and a debut of diabetes during adolescence with simple hyperglycemia, negative pancreatic autoimmunity and detectable C-peptide levels. He also presented epididymal and seminal vesicle cysts, hypertransaminasemia, hyperuricemia and low magnesium levels. In the light of these facts we considered the possibility of a HNF1B mutation. The sequencing study of this gene confirmed a heterozygous mutation leading to a truncated and less functional protein. Genetic studies of his relatives were negative; consequently, it was classified as a de novo mutation. In particular, our patient maintained good control of his diabetes on oral antidiabetic agents for a long period of time. He eventually needed insulinization although oral therapy was continued alongside, allowing reduction of prandial insulin requirements. The real prevalence of mutations in HNF1B is probably underestimated owing to a wide phenotypical variability. As endocrinologists, we should consider this possibility in young non-obese diabetic patients with a history of chronic non-diabetic nephropathy, especially in the presence of some of the other characteristic manifestations. Learning points: HNF1B mutations are a rare cause of monogenic diabetes, often being a part of a multisystemic syndrome. The combination of young-onset diabetes and genitourinary anomalies with slowly progressive nephropathy of non-diabetic origin in non-obese subjects should rise the suspicion of such occurrence. A

  15. Long-lasting response to oral therapy in a young male with monogenic diabetes as part of HNF1B-related disease.

    PubMed

    Carrillo, Elena; Lomas, Amparo; Pinés, Pedro J; Lamas, Cristina

    2017-01-01

    Mutations in hepatocyte nuclear factor 1β gene (HNF1B) are responsible for a multisystemic syndrome where monogenic diabetes (classically known as MODY 5) and renal anomalies, mostly cysts, are the most characteristic findings. Urogenital malformations, altered liver function tests, hypomagnesemia or hyperuricemia and gout are also part of the syndrome. Diabetes in these patients usually requires early insulinization. We present the case of a young non-obese male patient with a personal history of renal multicystic dysplasia and a debut of diabetes during adolescence with simple hyperglycemia, negative pancreatic autoimmunity and detectable C-peptide levels. He also presented epididymal and seminal vesicle cysts, hypertransaminasemia, hyperuricemia and low magnesium levels. In the light of these facts we considered the possibility of a HNF1B mutation. The sequencing study of this gene confirmed a heterozygous mutation leading to a truncated and less functional protein. Genetic studies of his relatives were negative; consequently, it was classified as a de novo mutation. In particular, our patient maintained good control of his diabetes on oral antidiabetic agents for a long period of time. He eventually needed insulinization although oral therapy was continued alongside, allowing reduction of prandial insulin requirements. The real prevalence of mutations in HNF1B is probably underestimated owing to a wide phenotypical variability. As endocrinologists, we should consider this possibility in young non-obese diabetic patients with a history of chronic non-diabetic nephropathy, especially in the presence of some of the other characteristic manifestations. HNF1B mutations are a rare cause of monogenic diabetes, often being a part of a multisystemic syndrome.The combination of young-onset diabetes and genitourinary anomalies with slowly progressive nephropathy of non-diabetic origin in non-obese subjects should rise the suspicion of such occurrence. A family history

  16. Genetic testing in nephrotic syndrome--challenges and opportunities.

    PubMed

    Gbadegesin, Rasheed A; Winn, Michelle P; Smoyer, William E

    2013-03-01

    Monogenic nephrotic syndrome (nephrotic syndrome caused by a single gene defect) is responsible for only a small percentage of cases of nephrotic syndrome, but information from studies of the unique cohort of patients with this form of the disease has dramatically improved our understanding of the disease pathogenesis. The use of genetic testing in the management of children and adults with nephrotic syndrome poses unique challenges for clinicians in terms of who to test and how to use the information obtained from testing in the clinical setting. In our view, not enough data exist at present to justify the routine genetic testing of all patients with nephrotic syndrome. Testing is warranted, however, in patients with congenital nephrotic syndrome (onset at 0-3 months), infantile nephrotic syndrome (onset at 3-12 months), a family history of nephrotic syndrome, and those in whom nephrotic syndrome is associated with other congenital malformations. The family and/or the patient should be given complete and unbiased information on the potential benefits and risks associated with therapy, including the reported outcomes of treatment in patients with similar mutations. Based on the data available in the literature so far, intensive immunosuppressive treatment is probably not indicated in monogenic nephrotic syndrome if complete or partial remission has not been achieved within 6 weeks of starting treatment. We advocate that family members of individuals with genetic forms of nephrotic syndrome undergo routine genetic testing prior to living-related kidney transplantation. Prospective, multicentre studies are needed to more completely determine the burden of disease caused by monogenic nephrotic syndrome, and randomized controlled trials are needed to clarify the presence or absence of clinical responses of monogenic nephrotic syndrome to available therapies.

  17. Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

    PubMed Central

    Cassel, Suzanne L.; Janczy, John R.; Bing, Xinyu; Wilson, Shruti P.; Olivier, Alicia K.; Otero, Jesse E.; Iwakura, Yoichiro; Shayakhmetov, Dmitry M.; Bassuk, Alexander G.; Abu-Amer, Yousef; Brogden, Kim A.; Burns, Trudy L.; Sutterwala, Fayyaz S.; Ferguson, Polly J.

    2014-01-01

    Chronic recurrent multifocal osteomyelitis (CRMO) is a human autoinflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL-1RI in cmo mice resulted in a significant reduction in the time to onset of disease as well as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1β, but not IL-1α, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome as well as caspase-1. Neutrophils, but not bone marrow-derived macrophages, from cmo mice secreted increased IL-1β in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome-independent role for IL-1β in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO. PMID:24395802

  18. Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage

    PubMed Central

    Scarpioni, Roberto; Ricardi, Marco; Albertazzi, Vittorio

    2016-01-01

    The release of proinflammatory cytokines during inflammation represents an attempt to respond to injury, but it may produce detrimental effects. The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury; the best-characterized inflammasome is the nod-like receptor protein-3 (NLRP3). Once activated, inflammasome leads to the active form of caspase-1, the enzyme required for the maturation of interleukin-1beta. Additional mechanisms bringing to renal inflammatory, systemic diseases and fibrotic processes were recently reported, via the activation of the inflammasome that consists of NLRP3, apoptosis associated speck-like protein and caspase-1. Several manuscripts seem to identify NLRP3 inflammasome as a possible therapeutic target in the treatment of progressive chronic kidney disease. Serum amyloid A (SAA), as acute-phase protein with also proinflammatory properties, has been shown to induce the secretion of cathepsin B and inflammasome components from human macrophages. SAA is a well recognised potent activator of the NLRP3. Here we will address our description on the involvement of the kidney in autoinflammatory diseases driven mainly by secondary, or reactive, AA amyloidosis with a particular attention on novel therapeutic approach which has to be addressed in suppressing underlying inflammatory disease and reducing the SAA concentration. PMID:26788465

  19. Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years.

    PubMed

    Aksentijevich, Ivona

    2015-07-01

    Autoinflammatory diseases are a genetically heterogeneous group of rheumatologic diseases that are driven by abnormal activation of the innate immune system. Patients present with recurrent episodes of systemic inflammation and a spectrum of organ-specific comorbidities. These diseases are mediated by the overproduction of various inflammatory cytokines, such as IL-1, IL-18, IL-6, TNFα, and type I interferon. Treatments with biologic agents that inhibit these cytokines have been very efficient in most patients. During the past 2 years, remarkable progress has been made in the identification of disease-associated genes owing mostly to new technologies. Next generation sequencing technologies (NGS) have become instrumental in finding single-gene defects in undiagnosed patients with early onset symptoms. NGS has advanced the field of autoinflammation by identifying disease-causing genes that point to pathways not known to regulate cytokine signaling or inflammation. They include a protein that has a role in differentiation of myeloid cells, a ubiquitously expressed enzyme that catalyzes the addition of the CCA terminus to the 3-prime end of tRNA precursors, and an enzyme that catalyzes the oxidation of a broad range of substrates. Lastly, newly described mutations have informed a whole new dimension on genotype-phenotype relationships. Mutations in the same gene can give rise to a range of phenotypes with a common inflammatory component. This suggests greater than anticipated contributions by modifying alleles and environmental factors to disease expressivity.

  20. Does Attention Constrain Developmental Trajectories in Fragile X Syndrome? A 3-Year Prospective Longitudinal Study

    ERIC Educational Resources Information Center

    Cornish, Kim; Cole, Victoria; Longhi, Elena; Karmiloff-Smith, Annette; Scerif, Gaia

    2012-01-01

    Basic attentional processes and their impact on developmental trajectories in fragile X syndrome were assessed in a 3-year prospective study. Although fragile X syndrome is a monogenic X-linked disorder, there is striking variability in outcomes even in young boys with the condition. Attention is a key factor constraining interactions with the…

  1. Does Attention Constrain Developmental Trajectories in Fragile X Syndrome? A 3-Year Prospective Longitudinal Study

    ERIC Educational Resources Information Center

    Cornish, Kim; Cole, Victoria; Longhi, Elena; Karmiloff-Smith, Annette; Scerif, Gaia

    2012-01-01

    Basic attentional processes and their impact on developmental trajectories in fragile X syndrome were assessed in a 3-year prospective study. Although fragile X syndrome is a monogenic X-linked disorder, there is striking variability in outcomes even in young boys with the condition. Attention is a key factor constraining interactions with the…

  2. Disease-modifying genes and monogenic disorders: experience in cystic fibrosis.

    PubMed

    Gallati, Sabina

    2014-01-01

    The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.

  3. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects.

    PubMed

    Grimbacher, Bodo; Warnatz, Klaus; Yong, Patrick F K; Korganow, Anne-Sophie; Peter, Hans-Hartmut

    2016-01-01

    Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity.

  4. Metabolic dysregulation in monogenic disorders and cancer - finding method in madness.

    PubMed

    Erez, Ayelet; DeBerardinis, Ralph J

    2015-07-01

    Cancer is a prime example of a disease process in which carcinogenic and metabolic changes are intertwined to promote cell survival and growth. One approach to unravel this complex relationship is by studying rare, monogenic disorders caused by mutations in genes encoding metabolic enzymes or regulators. There are hundreds of these diseases, most of which manifest in childhood and are collectively termed 'inborn errors of metabolism' (IEMs). Several IEMs demonstrate the consequences of chronic, systemic loss of a particular metabolic activity that can result in malignancy. In this Opinion article, we present a conceptual categorization of IEMs associated with cancer and discuss how assessment of these rare diseases might inform us about the biological foundations of common types of cancer and opportunities for cancer diagnosis and therapy.

  5. Using human-induced pluripotent stem cells to model monogenic metabolic disorders of the liver.

    PubMed

    Ordonez, Maria Paulina; Goldstein, Lawrence S B

    2012-11-01

    A crucial problem in liver disease biology and a major obstacle to the development of new therapies is the inability to conduct mechanistic studies of live human hepatocytes. Liver tissue from patients is difficult to obtain and only reveals the disease aftermath, while animal models lack the significant genetic diversity of humans. Monogenic metabolic disorders of the liver are an ideal platform to explore the complex gene-environment interactions and the role of genetic variation in the onset and progression of liver disease. Human induced pluripotent stem cell (hIPSC) technology provides an unprecedented opportunity to generate live cellular models of disease for therapeutic candidate discovery and cell replacement therapy. In this review, we discuss the potential of hIPSC to increase our understanding of human disease with a focus on the current efforts to model metabolic diseases of the liver and to generate suitable populations of human hepatocytes for cell transplantation.

  6. Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders.

    PubMed

    Stranneheim, H; Wedell, A

    2016-01-01

    Massively parallel DNA sequencing has revolutionized analyses of human genetic variation. From having been out of reach for individual research groups and even more so for clinical diagnostic laboratories until recently, it is now possible to analyse complete human genomes within reasonable time frames and at a reasonable cost using technologies that are becoming increasingly available. This represents a huge advance in our ability to provide correct diagnoses for patients with rare inherited disorders and their families. This paradigm shift is especially dramatic within the area of monogenic disorders. Not only can rapid and safe diagnostics of virtually all known single-gene defects now be established, but novel causes of disease in previously unsolved cases can also be identified, illuminating novel pathways important for normal physiology. This greatly increases the capability not only to improve management of rare disorders, but also to improve understanding of pathogenetic mechanisms relevant for common, complex diseases.

  7. Metabolic differences in ripening of Solanum lycopersicum 'Ailsa Craig' and three monogenic mutants.

    PubMed

    Beisken, Stephan; Earll, Mark; Baxter, Charles; Portwood, David; Ament, Zsuzsanna; Kende, Aniko; Hodgman, Charlie; Seymour, Graham; Smith, Rebecca; Fraser, Paul; Seymour, Mark; Salek, Reza M; Steinbeck, Christoph

    2014-01-01

    Application of mass spectrometry enables the detection of metabolic differences between groups of related organisms. Differences in the metabolic fingerprints of wild-type Solanum lycopersicum and three monogenic mutants, ripening inhibitor (rin), non-ripening (nor) and Colourless non-ripening (Cnr), of tomato are captured with regard to ripening behaviour. A high-resolution tandem mass spectrometry system coupled to liquid chromatography produced a time series of the ripening behaviour at discrete intervals with a focus on changes post-anthesis. Internal standards and quality controls were used to ensure system stability. The raw data of the samples and reference compounds including study protocols have been deposited in the open metabolomics database MetaboLights via the metadata annotation tool Isatab to enable efficient re-use of the datasets, such as in metabolomics cross-study comparisons or data fusion exercises.

  8. How the differential load induced by normal fault scarps controls the distribution of monogenic volcanism

    NASA Astrophysics Data System (ADS)

    Maccaferri, F.; Acocella, V.; Rivalta, E.

    2015-09-01

    Understanding shallow magma transfer and the related vent distribution is crucial for volcanic hazard. Here we investigate how the stress induced by topographic scarps linked to normal faults affects the distribution of monogenic volcanoes at divergent plate boundaries. Our numerical models of dyke propagation below a fault scarp show that the dykes tend to propagate toward and erupt on the footwall side. This effect, increasing with the scarp height, is stronger for dykes propagating underneath the hanging wall side and decreases with the distance from the scarp. A comparison to the East African Rift System, Afar and Iceland shows that (1) the inner rift structure, which shapes the topography, controls shallow dyke propagation; (2) differential loading due to mass redistribution affects magma propagation over a broad scale range (100-105 m). Our results find application to any volcanic field with tectonics- or erosion-induced topographic variations and should be considered in any volcanic hazard assessment.

  9. The diagnostic approach to monogenic very early onset inflammatory bowel disease.

    PubMed

    Uhlig, Holm H; Schwerd, Tobias; Koletzko, Sibylle; Shah, Neil; Kammermeier, Jochen; Elkadri, Abdul; Ouahed, Jodie; Wilson, David C; Travis, Simon P; Turner, Dan; Klein, Christoph; Snapper, Scott B; Muise, Aleixo M

    2014-11-01

    Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

  10. Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson's disease.

    PubMed

    Kertelge, Lena; Brüggemann, Norbert; Schmidt, Alexander; Tadic, Vera; Wisse, Claudia; Dankert, Sylwia; Drude, Laura; van der Vegt, Joyce; Siebner, Hartwig; Pawlack, Heike; Pramstaller, Peter P; Behrens, Maria Isabel; Ramirez, Alfredo; Reichel, Dirk; Buhmann, Carsten; Hagenah, Johann; Klein, Christine; Lohmann, Katja; Kasten, Meike

    2010-11-15

    Olfaction is typically impaired in idiopathic Parkinson's disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth-Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 ± 13.5) compared with all other groups (MC 13.8 ± 11.9, NMC 19.6 ± 13.0, controls 33.8 ± 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 ± 92.7). In MC (122.4 ± 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 ± 38.8) were comparable with controls (97.2 ± 61.1). UPSIT and FM scores were correlated in the control (r = -0.305; P = 0.002) and the IPD group (r = -0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1-associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel.

  11. Familial Chilblain Lupus, a Monogenic Form of Cutaneous Lupus Erythematosus, Maps to Chromosome 3p

    PubMed Central

    Lee-Kirsch, Min Ae; Gong, Maolian; Schulz, Herbert; Rüschendorf, Franz; Stein, Annette; Pfeiffer, Christiane; Ballarini, Annalisa; Gahr, Manfred; Hubner, Norbert; Linné, Maja

    2006-01-01

    Systemic lupus erythematosus is a prototypic autoimmune disease. Apart from rare monogenic deficiencies of complement factors, where lupuslike disease may occur in association with other autoimmune diseases or high susceptibility to bacterial infections, its etiology is multifactorial in nature. Cutaneous findings are a hallmark of the disease and manifest either alone or in association with internal-organ disease. We describe a novel genodermatosis characterized by painful bluish-red inflammatory papular or nodular lesions in acral locations such as fingers, toes, nose, cheeks, and ears. The lesions sometimes appear plaquelike and tend to ulcerate. Manifestation usually begins in early childhood and is precipitated by cold and wet exposure. Apart from arthralgias, there is no evidence for internal-organ disease or an increased susceptibility to infection. Histological findings include a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals show antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins are absent. Thus, the findings are consistent with chilblain lupus, a rare form of cutaneous lupus erythematosus. Investigation of a large German kindred with 18 affected members suggests a highly penetrant trait with autosomal dominant inheritance. By single-nucleotide-polymorphism–based genomewide linkage analysis, the locus was mapped to chromosome 3p. Haplotype analysis defined the locus to a 13.8-cM interval with a LOD score of 5.04. This is the first description of a monogenic form of cutaneous lupus erythematosus. Identification of the gene responsible for familial chilblain lupus may shed light on the pathogenesis of common forms of connective-tissue disease such as systemic lupus erythematosus. PMID:16960810

  12. Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit.

    PubMed

    Radyushkin, K; Hammerschmidt, K; Boretius, S; Varoqueaux, F; El-Kordi, A; Ronnenberg, A; Winter, D; Frahm, J; Fischer, J; Brose, N; Ehrenreich, H

    2009-06-01

    Autism spectrum disorder (ASD) is a frequent neurodevelopmental disorder characterized by variable clinical severity. Core symptoms are qualitatively impaired communication and social behavior, highly restricted interests and repetitive behaviors. Although recent work on genetic mutations in ASD has shed light on the pathophysiology of the disease, classifying it essentially as a synaptopathy, no treatments are available to date. To develop and test novel ASD treatment approaches, validated and informative animal models are required. Of particular interest, in this context are loss-of-function mutations in the postsynaptic cell adhesion protein neuroligin-4 and point mutations in its homologue neuroligin-3 (NL-3) that were found to cause certain forms of monogenic heritable ASD in humans. Here, we show that NL-3-deficient mice display a behavioral phenotype reminiscent of the lead symptoms of ASD: reduced ultrasound vocalization and a lack of social novelty preference. The latter may be related to an olfactory deficiency observed in the NL-3 mutants. Interestingly, such olfactory phenotype is also present in a subgroup of human ASD patients. Tests for learning and memory showed no gross abnormalities in NL-3 mutants. Also, no alterations were found in time spent in social interaction, prepulse inhibition, seizure propensity and sucrose preference. As often seen in adult ASD patients, total brain volume of NL-3 mutant mice was slightly reduced as assessed by magnetic resonance imaging (MRI). Our findings show that the NL-3 knockout mouse represents a useful animal model for understanding pathophysiological events in monogenic heritable ASD and for developing novel treatment strategies in this devastating human disorder.

  13. The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

    PubMed Central

    Uhlig, Holm H.; Schwerd, Tobias; Koletzko, Sibylle; Shah, Neil; Kammermeier, Jochen; Elkadri, Abdul; Ouahed, Jodie; Wilson, David C.; Travis, Simon P.; Turner, Dan; Klein, Christoph; Snapper, Scott B.; Muise, Aleixo M.

    2016-01-01

    Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel diseases (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histologic features of Crohn’s disease, ulcerative colitis or IBD unclassified. Defects in interleukin 10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histologic and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extra-intestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. We provide approaches for identifying patients likely to have these disorders. We discuss classical approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects. PMID:25058236

  14. [Papillary edema in Muckle-Wells syndrome].

    PubMed

    Wirths, G; Grenzebach, U; Eter, N

    2015-09-01

    Papillary edema may occur isolated without functional impairment or secondary related to various syndromes, increased intracerebral pressure or associated with medicinal treatment. The Muckle-Wells syndrome is a rare disease, which among many other symptoms can lead to optic disc swelling and recurrent increase in intracerebral pressure. Besides familial cold-induced autoinflammatory syndrome (FCAS) and neonatal onset multisystem inflammatory disease (NOMID), the Muckle-Wells syndrome also belongs to the cryopyrin-associated periodic syndromes (CAPS). In most cases of CAP syndromes there is an underlying genetic disorder that leads to overproduction of interleukin-1β (IL-1β); therefore, typical symptoms include inflammation reactions, such as repeated skin rash, fatigue, fever, joint pain and conjunctivitis.

  15. Kallmann syndrome

    PubMed Central

    Dodé, Catherine; Hardelin, Jean-Pierre

    2009-01-01

    The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered. PMID:18985070

  16. Rett Syndrome

    PubMed Central

    Smeets, E.E.J.; Pelc, K.; Dan, B.

    2012-01-01

    Rett syndrome is one of the most common causes of complex disability in girls. It is characterized by early neurological regression that severely affects motor, cognitive and communication skills, by autonomic dysfunction and often a seizure disorder. It is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. There are several mouse models either based on conditional knocking out of the Mecp2 gene or on a truncating mutation. We discuss the clinical aspects with special emphasis on the behavioral phenotype and we review current perspectives in clinical management alongside with perspectives in altering gene expression. PMID:22670134

  17. PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk.

    PubMed

    Drobek, Ales; Kralova, Jarmila; Skopcova, Tereza; Kucova, Marketa; Novák, Petr; Angelisová, Pavla; Otahal, Pavel; Alberich-Jorda, Meritxell; Brdicka, Tomas

    2015-10-01

    Mutations in the adaptor protein PSTPIP2 are the cause of the autoinflammatory disease chronic multifocal osteomyelitis in mice. This disease closely resembles the human disorder chronic recurrent multifocal osteomyelitis, characterized by sterile inflammation of the bones and often associated with inflammation in other organs, such as the skin. The most critical process in the disease's development is the enhanced production of IL-1β. This excessive IL-1β is likely produced by neutrophils. In addition, the increased activity of macrophages, osteoclasts, and megakaryocytes has also been described. However, the molecular mechanism of how PSTPIP2 deficiency results in this phenotype is poorly understood. Part of the PSTPIP2 inhibitory function is mediated by protein tyrosine phosphatases from the proline-, glutamic acid-, serine- and threonine-rich (PEST) family, which are known to interact with the central part of this protein, but other regions of PSTPIP2 not required for PEST-family phosphatase binding were also shown to be indispensable for PSTPIP2 function. In this article, we show that PSTPIP2 binds the inhibitory enzymes Csk and SHIP1. The interaction with SHIP1 is of particular importance because it binds to the critical tyrosine residues at the C terminus of PSTPIP2, which is known to be crucial for its PEST-phosphatase-independent inhibitory effects in different cellular systems. We demonstrate that in neutrophils this region is important for the PSTPIP2-mediated suppression of IL-1β processing and that SHIP1 inhibition results in the enhancement of this processing. We also describe deregulated neutrophil response to multiple activators, including silica, Ab aggregates, and LPS, which is suggestive of a rather generalized hypersensitivity of these cells to various external stimulants.

  18. Role of defensins and cathelicidin LL37 in auto-immune and auto-inflammatory diseases.

    PubMed

    Frasca, Loredana; Lande, Roberto

    2012-08-01

    Defensins and cathelicidins are anti-microbial peptides (AMPs) that act as natural antibiotics and are part of the innate immune defence in many species. We consider human defensins and LL37, the only human member of the cathelicidin family. In particular, we refer to the human alpha-defensins called human neutrophil peptides (HNP1 through 4), which are produced by neutrophils, HD5 and HD6, mainly expressed in Paneth cells of intestine, the human beta-defensins HBD1, HBD2 and HBD3, synthesized by epithelial cells and LL37, which is located in granulocytes, but is also produced by epithelial cells of the skin, lungs, and gut. In the last years, the study of AMPs activity and regulation has allowed to understand the important role of these peptides not only in the innate defence mechanisms against bacteria, viruses, fungi, but also in the regulation of immune cell activation and migration. Complementary studies have disclosed a role for AMPs in modulating many physiological processes that involve non-immune cells, such as activation of wound healing, angiogenesis, cartilage remodeling. Due to the pleiotropic tasks of these peptides, many of them are now being discovered to contribute to immune pathology of chronic diseases that affect skin, gut, joints; this is supported by many examples of immune-mediated pathologies in which their expression is disregulated. In this article we review the current literature that suggests a role for human defensins and LL37 in pathogenic mechanisms of several chronic diseases that are considered of auto-immune or auto-inflammatory origin.

  19. Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by next-generation sequencing with linkage analyses.

    PubMed

    Yan, Liying; Huang, Lei; Xu, Liya; Huang, Jin; Ma, Fei; Zhu, Xiaohui; Tang, Yaqiong; Liu, Mingshan; Lian, Ying; Liu, Ping; Li, Rong; Lu, Sijia; Tang, Fuchou; Qiao, Jie; Xie, X Sunney

    2015-12-29

    In vitro fertilization (IVF), preimplantation genetic diagnosis (PGD), and preimplantation genetic screening (PGS) help patients to select embryos free of monogenic diseases and aneuploidy (chromosome abnormality). Next-generation sequencing (NGS) methods, while experiencing a rapid cost reduction, have improved the precision of PGD/PGS. However, the precision of PGD has been limited by the false-positive and false-negative single-nucleotide variations (SNVs), which are not acceptable in IVF and can be circumvented by linkage analyses, such as short tandem repeats or karyomapping. It is noteworthy that existing methods of detecting SNV/copy number variation (CNV) and linkage analysis often require separate procedures for the same embryo. Here we report an NGS-based PGD/PGS procedure that can simultaneously detect a single-gene disorder and aneuploidy and is capable of linkage analysis in a cost-effective way. This method, called "mutated allele revealed by sequencing with aneuploidy and linkage analyses" (MARSALA), involves multiple annealing and looping-based amplification cycles (MALBAC) for single-cell whole-genome amplification. Aneuploidy is determined by CNVs, whereas SNVs associated with the monogenic diseases are detected by PCR amplification of the MALBAC product. The false-positive and -negative SNVs are avoided by an NGS-based linkage analysis. Two healthy babies, free of the monogenic diseases of their parents, were born after such embryo selection. The monogenic diseases originated from a single base mutation on the autosome and the X-chromosome of the disease-carrying father and mother, respectively.

  20. Identification of Buried Objects in GPR Using Amplitude Modulated Signals Extracted from Multiresolution Monogenic Signal Analysis

    PubMed Central

    Qiao, Lihong; Qin, Yao; Ren, Xiaozhen; Wang, Qifu

    2015-01-01

    It is necessary to detect the target reflections in ground penetrating radar (GPR) images, so that surface metal targets can be identified successfully. In order to accurately locate buried metal objects, a novel method called the Multiresolution Monogenic Signal Analysis (MMSA) system is applied in ground penetrating radar (GPR) images. This process includes four steps. First the image is decomposed by the MMSA to extract the amplitude component of the B-scan image. The amplitude component enhances the target reflection and suppresses the direct wave and reflective wave to a large extent. Then we use the region of interest extraction method to locate the genuine target reflections from spurious reflections by calculating the normalized variance of the amplitude component. To find the apexes of the targets, a Hough transform is used in the restricted area. Finally, we estimate the horizontal and vertical position of the target. In terms of buried object detection, the proposed system exhibits promising performance, as shown in the experimental results. PMID:26690146

  1. Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders.

    PubMed

    Qin, Yiren; Gao, Wei-Qiang

    2016-01-01

    Monogenic disorders (MGDs) are caused by a single gene mutation and have a serious impact on human health. At present, there are no effective therapeutic methods for MGDs. Stem cell techniques provide insights into potential treatments for MGDs. With the development of patient-derived stem cells, we can begin to progressively understand the molecular mechanism of MGDs and identify new drugs for MGD treatment. Using powerful genome editing tools, such as zinc finger nucleases, transcriptional activator-like effector nucleases, and the clustered regulatory interspaced short palindromic repeat/Cas9 system, MGD-associated gene mutations can be corrected in MGD stem cells in vitro and then transplanted into MGD animal models to assess their safety and therapeutic effects. Despite the continued challenges surrounding potential pluripotent stem cell tumorigenicity and concerns regarding the genetic modification of stem cells, the extensive clinical application of MGD patient-specific stem cells will be pursued through further advances in basic research in the MGD field. In this review, we will summarize the latest progress in research into the use of patient-derived stem cells for the potential treatment of MGDs and provide predictions regarding the direction of future investigations.

  2. Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery

    PubMed Central

    Görtz, Dieter; Braun, Gerald S.; Maruta, Yuichi; Djudjaj, Sonja; van Roeyen, Claudia R.; Martin, Ina V.; Küster, Andrea; Schmitz-Van de Leur, Hildegard; Scheller, Jürgen; Ostendorf, Tammo; Floege, Jürgen; Müller-Newen, Gerhard

    2015-01-01

    Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases. PMID:26423228

  3. Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.

    PubMed

    Liu, C; Yang, W; Pei, D; Cheng, C; Smith, C; Landier, W; Hageman, L; Chen, Y; Yang, J J; Crews, K R; Kornegay, N; Karol, S E; Wong, F L; Jeha, S; Sandlund, J T; Ribeiro, R C; Rubnitz, J E; Metzger, M L; Pui, C-H; Evans, W E; Bhatia, S; Relling, M V

    2017-03-01

    We performed a genomewide association study (GWAS) of primary erythrocyte thiopurine S-methyltransferase (TPMT) activity in children with leukemia (n = 1,026). Adjusting for age and ancestry, TPMT was the only gene that reached genomewide significance (top hit rs1142345 or 719A>G; P = 8.6 × 10(-61) ). Additional genetic variants (in addition to the three single-nucleotide polymorphisms [SNPs], rs1800462, rs1800460, and rs1142345, defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10(-11) ). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345; P = 6.8 × 10(-5) ), revealing a limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic.

  4. Identification of Buried Objects in GPR Using Amplitude Modulated Signals Extracted from Multiresolution Monogenic Signal Analysis.

    PubMed

    Qiao, Lihong; Qin, Yao; Ren, Xiaozhen; Wang, Qifu

    2015-12-04

    It is necessary to detect the target reflections in ground penetrating radar (GPR) images, so that surface metal targets can be identified successfully. In order to accurately locate buried metal objects, a novel method called the Multiresolution Monogenic Signal Analysis (MMSA) system is applied in ground penetrating radar (GPR) images. This process includes four steps. First the image is decomposed by the MMSA to extract the amplitude component of the B-scan image. The amplitude component enhances the target reflection and suppresses the direct wave and reflective wave to a large extent. Then we use the region of interest extraction method to locate the genuine target reflections from spurious reflections by calculating the normalized variance of the amplitude component. To find the apexes of the targets, a Hough transform is used in the restricted area. Finally, we estimate the horizontal and vertical position of the target. In terms of buried object detection, the proposed system exhibits promising performance, as shown in the experimental results.

  5. Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD.

    PubMed

    Ensari, Arzu; Kelsen, Judith; Russo, Pierre

    2017-07-17

    Childhood enteropathies are a group of diseases causing severe chronic (>2-3 weeks) diarrhoea often starting in the first week of life with the potential for fatal complications for the affected infant. Early identification and accurate classification of childhood enteropathies are, therefore, crucial for making treatment decisions to prevent life-threatening complications. Childhood enteropathies are classified into four groups based on the underlying pathology: (i) conditions related to defective digestion, absorption and transport of nutrients and electrolytes; (ii) disorders related to enterocyte differentiation and polarization; (iii) defects of enteroendocrine cell differentiation; and (iv) disorders associated with defective modulation of intestinal immune response. While the intestinal mucosa is usually normal in enteropathies related to congenital transport or enzyme deficiencies, the intestinal biopsy in other disorders may reveal a wide range of abnormalities varying from normal villous architecture to villous atrophy and/or inflammation, or features specific to the underlying disorder including epithelial abnormalities, lipid vacuolization in the enterocytes, absence of plasma cells, lymphangiectasia, microorganisms, and mucosal eosinophilic or histiocytic infiltration. This review intends to provide an update on small intestinal biopsy findings in childhood enteropathies, the "newcomers", including very early onset monogenic inflammatory bowel disease (IBD), in particular, for the practicing pathologist.

  6. [PFAPA syndrome: study of 10 cases].

    PubMed

    Antón-Martín, Pilar; Ortiz Movilla, Roberto; Álvarez García, Ana; Guillén Martín, Sara; Ruiz Jiménez, Marta; Ramos Amador, José Tomás

    2012-02-04

    «PFAPA syndrome» is an autoinflammatory entity consisting of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Its etiology is unknown although a dysregulation in the control of the autoinflammatory response seems to play a role. Although a genetic origin is suspected, no specific mutation has been determined yet. Corticosteroids are the mainstay of the treatment during the acute attacks. However, in long-term follow-up the role of tonsillectomy is controversial. A retrospective study of the pediatric cases diagnosed with the PFAPA syndrome was performed in our center during the last 4 years. Ten patients were diagnosed with the syndrome who received corticosteroids as the only treatment with improvement and favourable prognosis. PFAPA syndrome is the most common periodic fever disorder described in childhood whose genetic background has not been yet clarified. Our contribution with 10 patients further supports the common existence of this entity and the need to keep it in mind when having recurrent fevers. Copyright © 2011 Elsevier España, S.L. All rights reserved.

  7. Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS).

    PubMed

    Gillespie, Justin; Mathews, Rebeccah; McDermott, Michael F

    2010-01-01

    Cryopyrin-associated periodic syndromes (CAPS) are a subgroup of the hereditary periodic fever syndromes, which are rare autoinflammatory and inherited disorders, characterized by recurrent inflammation and varying degrees of severity. CAPS are thought to be driven by excessive production of interleukin-1β (IL-1β), through over-activation of the inflammasome by gain of function mutations in the gene encoding cryopyrin (NLRP3). This conclusion is supported by the remarkable efficacy of IL-1β blockade in these conditions. Rilonacept (Arcalyst(TM); Regeneron) is the first us Food and Drug Administration-approved treatment for familial cold autoinflammatory syndrome and Muckle-Wells syndrome and the first in a new line of drugs designed for longer-acting IL-1 blockade. Rilonacept has been associated with a decrease in disease activity, high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) in the treatment of CAPS. The clinical safety and efficacy of rilonacept in CAPS and non-CAPS populations will be summarized in this review. Rilonacept is also beneficial for patients who tolerate injections poorly, due to an extended half-life over the unapproved CAPS treatment, anakinra, requiring weekly rather than daily self-administration. Other autoinflammatory disorders may also benefit from rilonacept treatment, with clinical trials in progress for systemic onset juvenile idiopathic arthritis, gout and familial mediterranean fever.

  8. A novel de novo PSTPIP1 mutation in a boy with pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) syndrome.

    PubMed

    Fathalla, Basil M; Al-Wahadneh, Adel M; Al-Mutawa, Mariam; Kambouris, Marios; El-Shanti, Hatem

    2014-01-01

    Autoinflammatory disorders are a group of Mendelian disorders characterized by seemingly unprovoked inflammatory bouts without high-titer autoantibodies or antigen-specific T-cells and are probably due to defects in the innate immunity. We here report on a 4-year-old Arabic boy with the clinical presentation of an autoinflammatory disorder, namely Pyogenic Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome. The presentation includes abscess formation after immunization and recurrent mono-articular acute arthritis in various joints that responded favourably to systemic glucocorticosteroids, albeit without acne or pyoderma gangrenosum. The mutation analysis of the boy identified a novel de novo mutation in PSTPIP1, the gene responsible for PAPA syndrome. We recommend that the diagnosis of PAPA syndrome should be entertained in the differential diagnosis of patients with recurrent sterile pyogenic arthritis prior to the development of pyoderma gangrenosum or acne in order to initiate a timely management of the disorder.

  9. TNF-receptor-associated periodic syndrome (TRAPS): an autosomal dominant multisystem disorder.

    PubMed

    Rezaei, Nima

    2006-11-01

    The TNF-receptor-associated periodic syndrome (TRAPS) is an autosomal dominant auto-inflammatory disorder, characterized by recurrent febrile attacks and localized inflammation. TRAPS is caused by mutations in the gene encoding the TNF Receptor Super Family 1A (TNFRSF1A) on chromosome 12p13. However, the incomplete penetrance and genetic heterogeneity have been reported in this syndrome. Although the ethnic diversity and clinical heterogeneity may propose the role of other genes in the pathogenesis of TRAPS, some low-penetrance TNFRSF1A variants contribute to atypical inflammatory responses in other autoimmune diseases. Furthermore, molecular studies on TRAPS and other auto-inflammatory disorders could be suggested to identify additional genes coding the molecules in the TNF signalling process.

  10. Exploring the differences in evolutionary rates between monogenic and polygenic disease genes in human.

    PubMed

    Podder, Soumita; Ghosh, Tapash C

    2010-04-01

    Comparative analyses on disease and nondisease (ND) genes have greatly facilitated the understanding of human diseases. However, most studies have grouped all the disease genes together and have performed comparative analyses with other ND genes. Thus, the molecular mechanism of disease on which disease genes can be separated into monogenic and polygenic diseases (MDs and PDs) has been ignored in earlier studies. Here, we report a comprehensive study of PD and MD genes with respect to ND genes. Our work shows that MD genes are more conserved than PD genes and that ND genes are themselves more conserved than both classes of disease genes. By separating the ND genes into housekeeping and other genes, it was found that housekeeping genes are the most conserved among all categories of genes, whereas other ND genes show an evolutionary rate intermediate between MD and PD genes. Although PD genes have a higher number of interacting partners than MD and ND genes, the reasons for their higher evolutionary rate require explanation. We provide evidences that the faster evolutionary rate of PD genes is influenced by 1) the predominance of date hubs in protein-protein interaction network, 2) the higher number of disorder residues, 3) the lower expression level, and 4) the involvement with more regulatory processes. Logistic regression analysis suggests that the relative importance of the four individual factors in determining the evolutionary rate variation among the four classes of proteins is in the order of mRNA expression level > presence of party/date hubs > disorder > involvement of proteins in core/regulatory processes.

  11. Bacillus thuringiensis monogenic strains: screening and interactions with insecticides used against rice pests

    PubMed Central

    Pinto, Laura M.N.; Dörr, Natália C.; Ribeiro, Ana Paula A.; de Salles, Silvia M.; de Oliveira, Jaime V.; Menezes, Valmir G.; Fiuza, Lidia M.

    2012-01-01

    The screening of Bacillus thuringiensis (Bt) Cry proteins with high potential to control insect pests has been the goal of numerous research groups. In this study, we evaluated six monogenic Bt strains (Bt dendrolimus HD-37, Bt kurstaki HD-1, Bt kurstaki HD-73, Bt thuringiensis 4412, Bt kurstaki NRD-12 and Bt entomocidus 60.5, which codify the cry1Aa, cry1Ab, cry1Ac, cry1Ba, cry1C, cry2A genes respectively) as potential insecticides for the most important insect pests of irrigated rice: Spodoptera frugiperda, Diatraea saccharalis, Oryzophagus oryzae, Oebalus poecilus and Tibraca limbativentris. We also analyzed their compatibility with chemical insecticides (thiamethoxam, labdacyhalothrin, malathion and fipronil), which are extensively used in rice crops. The bioassay results showed that Bt thuringiensis 4412 and Bt entomocidus 60.5 were the most toxic for the lepidopterans, with a 93% and 82% mortality rate for S. frugiperda and D. saccharalis, respectively. For O. oryzae, the Bt kurstaki NRD-12 (64%) and Bt dendrolimus HD-37 (62%) strains were the most toxic. The Bt dendrolimus HD-37 strain also caused high mortality (82%) to O. poecilus, however the strains assessed to T. limbativentris caused a maximum rate of 5%. The assays for the Bt strains interaction with insecticides revealed the compatibility of the six strains with the four insecticides tested. The results from this study showed the high potential of cry1Aa and cry1Ba genes for genetic engineering of rice plants or the strains to biopesticide formulations. PMID:24031872

  12. Preimplantation Genetic Diagnosis (PGD) for Monogenic Disorders: the Value of Concurrent Aneuploidy Screening.

    PubMed

    Goldman, Kara N; Nazem, Taraneh; Berkeley, Alan; Palter, Steven; Grifo, Jamie A

    2016-12-01

    Pre-implantation genetic diagnosis (PGD) has changed the landscape of clinical genetics by helping families reduce the transmission of monogenic disorders. However, given the high prevalence of embryonic aneuploidy, particularly in patients of advanced reproductive age, unaffected embryos remain at high risk of implantation failure or pregnancy loss due to aneuploidy. 24-chromosome aneuploidy screening has become widely utilized in routine in vitro fertilization (IVF) to pre-select embryos with greater pregnancy potential, but concurrent 24-chromosome aneuploidy screening has not become standard practice in embryos biopsied for PGD. We performed a retrospective cohort study of patients who underwent PGD with or without 24-chromosome aneuploidy screening to explore the value of concurrent screening. Among the PGD + aneuploidy-screened group (n = 355 blastocysts), only 25.6 % of embryos were both Single Gene Disorder (SGD)-negative (or carriers) and euploid; thus the majority of embryos were ineligible for transfer due to the high prevalence of aneuploidy. Despite a young mean age (32.4 ± 5.9y), 49.9 % of Blastocysts were aneuploid. The majority of patients (53.2 %) had ≥1 blastocyst that was Single Gene Disorder (SGD)-unaffected but aneuploid; without screening, these unaffected but aneuploid embryos would likely have been transferred resulting in implantation failure, pregnancy loss, or a pregnancy affected by chromosomal aneuploidy. Despite the transfer of nearly half the number of embryos in the aneuploidy-screened group (1.1 ± 0.3 vs. 1.9 ± 0.6, p < 0.0001), the implantation rate was higher (75 % vs. 53.3 %) and miscarriage rate lower (20 % vs. 40 %) (although not statistically significant). 24-chromosome aneuploidy screening when performed concurrently with PGD provides valuable information for embryo selection, and notably improves single embryo transfer rates.

  13. The "other" vasculitis syndromes and kidney involvement.

    PubMed

    Ozen, Seza

    2010-09-01

    There are a number of vasculitides that are not confined to a specific vessel size, do not have characteristic features, and/or are not secondary to another disease. Most of these vasculitides are rare in childhood. Behçet disease is representative of this group as it involves vessels of any size on both the arterial and venous side. In addition to renal vascular involvement, Behçet disease may involve the kidney through glomerulonephritis, secondary amyloidosis and, rarely, tubulointerstital involvement. Vasculitis secondary to infections, malignancy, and drugs are not common among children. However, vasculitis may be associated with a number of rheumatic diseases in childhood and the auto-inflammatory syndromes (periodic fever syndromes). Auto-inflammatory syndromes are diseases characterized by periodic attacks of clinical and laboratory inflammation. Studies carried out during the past decade have provided valuable information on the mechanism of inflammation and innate immunity in general. This group of vasculitides is associated with secondary amyloidosis of the kidney if not treated. Hypocomplementemic urticarial vasculitis is an interesting vasculitic disease with frequent kidney involvement. Here, we introduce the reader to the wide scope of these diseases; although rare, such diseases represent a challenge to the nephrologist.

  14. Attention across Modalities as a Longitudinal Predictor of Early Outcomes: The Case of Fragile X Syndrome

    ERIC Educational Resources Information Center

    Scerif, Gaia; Longhi, Elena; Cole, Victoria; Karmiloff-Smith, Annette; Cornish, Kim

    2012-01-01

    Background: Fragile X syndrome (FXS) is an early diagnosed monogenic disorder, associated with a striking pattern of cognitive/attentional difficulties and a high risk of poor behavioural outcomes. FXS therefore represents an ideal model disorder to study prospectively the impact of early attention deficits on behaviour. Methods: Thirty-seven boys…

  15. A Comparison of Pragmatic Language in Boys with Autism and Fragile X Syndrome

    ERIC Educational Resources Information Center

    Klusek, Jessica; Martin, Gary E.; Losh, Molly

    2014-01-01

    Purpose: Impaired pragmatic language (i.e., language use for social interaction) is a hallmark feature of both autism spectrum disorder (ASD) and fragile X syndrome (FXS), the most common known monogenic disorder associated with ASD. However, few cross-population comparisons of ASD and FXS have been conducted, and it is unclear whether pragmatic…

  16. A Comparison of Pragmatic Language in Boys with Autism and Fragile X Syndrome

    ERIC Educational Resources Information Center

    Klusek, Jessica; Martin, Gary E.; Losh, Molly

    2014-01-01

    Purpose: Impaired pragmatic language (i.e., language use for social interaction) is a hallmark feature of both autism spectrum disorder (ASD) and fragile X syndrome (FXS), the most common known monogenic disorder associated with ASD. However, few cross-population comparisons of ASD and FXS have been conducted, and it is unclear whether pragmatic…

  17. [Monogenic form of diabetes mellitus due to HNF4α mutation (MODY-1) - the first case in Hungary].

    PubMed

    Jermendy, György; Balogh, István; Gaál, Zsolt

    2016-03-20

    The classification of diabetes mellitus in adolescents and young adults is often difficult. The diagnosis of the monogenic form of diabetes may have substantial influence on quality of life, prognosis and the choice of the appropriate treatment of affected patients. Among MODY (maturity-onset of diabetes in the young) MODY-1 is rarely detected, only 13 families were described in 2000, and 103 different mutations in 173 families were known in 2013 worldwide. The authors present the first Hungarian case of a monogenic form of diabetes due to HNF4α mutation (MODY-1). The diabetes of the index patient No. 1 (42-year-old woman with insulin treated diabetes) was diagnosed as gestational diabetes at age of 20 when she was treated with diet only. Later, insulin treatment has been initiated when marked hyperglycaemia was detected during an episode of acute pneumonia at age of 26. The diabetes of the index patient No. 2 (20-year-old daughter of the index patient No. 1, treated also with insulin) was diagnosed as type 2 diabetes at age of 13 and the patient was treated with diet only. Later the classification was modified to type 1 and insulin therapy was initiated at age of 14. The manifestation of diabetes, the familial occurrence and the low dose insulin requirement were suggestive for monogenic diabetes. Using molecular genetic method a mutation (c.869G>A, p.R290H) of HNF4α gene was found and MODY-1 was diagnosed in both cases. Insulin therapy was switched to treatment with low dose sulfanylurea and an excellent glycaemic control was achieved and sustained at follow-up of 1-year. No further positive cases were found during screening of other family members.

  18. Evaluation of PCR-based preimplantation genetic diagnosis applied to monogenic diseases: a collaborative ESHRE PGD consortium study.

    PubMed

    Dreesen, Jos; Destouni, Aspasia; Kourlaba, Georgia; Degn, Birte; Mette, Wulf Christensen; Carvalho, Filipa; Moutou, Celine; Sengupta, Sioban; Dhanjal, Seema; Renwick, Pamela; Davies, Steven; Kanavakis, Emmanouel; Harton, Gary; Traeger-Synodinos, Joanne

    2014-08-01

    Preimplantation genetic diagnosis (PGD) for monogenic disorders currently involves polymerase chain reaction (PCR)-based methods, which must be robust, sensitive and highly accurate, precluding misdiagnosis. Twelve adverse misdiagnoses reported to the ESHRE PGD-Consortium are likely an underestimate. This retrospective study, involving six PGD centres, assessed the validity of PCR-based PGD through reanalysis of untransferred embryos from monogenic-PGD cycles. Data were collected on the genotype concordance at PGD and follow-up from 940 untransferred embryos, including details on the parameters of PGD cycles: category of monogenic disease, embryo morphology, embryo biopsy and genotype assay strategy. To determine the validity of PCR-based PGD, the sensitivity (Se), specificity (Sp) and diagnostic accuracy were calculated. Stratified analyses were also conducted to assess the influence of the parameters above on the validity of PCR-based PGD. The analysis of overall data showed that 93.7% of embryos had been correctly classified at the time of PGD, with Se of 99.2% and Sp of 80.9%. The stratified analyses found that diagnostic accuracy is statistically significantly higher when PGD is performed on two cells versus one cell (P=0.001). Se was significantly higher when multiplex protocols versus singleplex protocols were applied (P=0.005), as well as for PGD applied on cells from good compared with poor morphology embryos (P=0.032). Morphology, however, did not affect diagnostic accuracy. Multiplex PCR-based methods on one cell, are as robust as those on two cells regarding false negative rate, which is the most important criteria for clinical PGD applications. Overall, this study demonstrates the validity, robustness and high diagnostic value of PCR-based PGD.

  19. Evaluation of PCR-based preimplantation genetic diagnosis applied to monogenic diseases: a collaborative ESHRE PGD consortium study

    PubMed Central

    Dreesen, Jos; Destouni, Aspasia; Kourlaba, Georgia; Degn, Birte; Mette, Wulf Christensen; Carvalho, Filipa; Moutou, Celine; Sengupta, Sioban; Dhanjal, Seema; Renwick, Pamela; Davies, Steven; Kanavakis, Emmanouel; Harton, Gary; Traeger-Synodinos, Joanne

    2014-01-01

    Preimplantation genetic diagnosis (PGD) for monogenic disorders currently involves polymerase chain reaction (PCR)-based methods, which must be robust, sensitive and highly accurate, precluding misdiagnosis. Twelve adverse misdiagnoses reported to the ESHRE PGD-Consortium are likely an underestimate. This retrospective study, involving six PGD centres, assessed the validity of PCR-based PGD through reanalysis of untransferred embryos from monogenic-PGD cycles. Data were collected on the genotype concordance at PGD and follow-up from 940 untransferred embryos, including details on the parameters of PGD cycles: category of monogenic disease, embryo morphology, embryo biopsy and genotype assay strategy. To determine the validity of PCR-based PGD, the sensitivity (Se), specificity (Sp) and diagnostic accuracy were calculated. Stratified analyses were also conducted to assess the influence of the parameters above on the validity of PCR-based PGD. The analysis of overall data showed that 93.7% of embryos had been correctly classified at the time of PGD, with Se of 99.2% and Sp of 80.9%. The stratified analyses found that diagnostic accuracy is statistically significantly higher when PGD is performed on two cells versus one cell (P=0.001). Se was significantly higher when multiplex protocols versus singleplex protocols were applied (P=0.005), as well as for PGD applied on cells from good compared with poor morphology embryos (P=0.032). Morphology, however, did not affect diagnostic accuracy. Multiplex PCR-based methods on one cell, are as robust as those on two cells regarding false negative rate, which is the most important criteria for clinical PGD applications. Overall, this study demonstrates the validity, robustness and high diagnostic value of PCR-based PGD. PMID:24301057

  20. Estimation of cardiac motion in cine-MRI sequences by correlation transform optical flow of monogenic features distance

    NASA Astrophysics Data System (ADS)

    Gao, Bin; Liu, Wanyu; Wang, Liang; Liu, Zhengjun; Croisille, Pierre; Delachartre, Philippe; Clarysse, Patrick

    2016-12-01

    Cine-MRI is widely used for the analysis of cardiac function in clinical routine, because of its high soft tissue contrast and relatively short acquisition time in comparison with other cardiac MRI techniques. The gray level distribution in cardiac cine-MRI is relatively homogenous within the myocardium, and can therefore make motion quantification difficult. To ensure that the motion estimation problem is well posed, more image features have to be considered. This work is inspired by a method previously developed for color image processing. The monogenic signal provides a framework to estimate the local phase, orientation, and amplitude, of an image, three features which locally characterize the 2D intensity profile. The independent monogenic features are combined into a 3D matrix for motion estimation. To improve motion estimation accuracy, we chose the zero-mean normalized cross-correlation as a matching measure, and implemented a bilateral filter for denoising and edge-preservation. The monogenic features distance is used in lieu of the color space distance in the bilateral filter. Results obtained from four realistic simulated sequences outperformed two other state of the art methods even in the presence of noise. The motion estimation errors (end point error) using our proposed method were reduced by about 20% in comparison with those obtained by the other tested methods. The new methodology was evaluated on four clinical sequences from patients presenting with cardiac motion dysfunctions and one healthy volunteer. The derived strain fields were analyzed favorably in their ability to identify myocardial regions with impaired motion.

  1. Estimation of cardiac motion in cine-MRI sequences by correlation transform optical flow of monogenic features distance.

    PubMed

    Gao, Bin; Liu, Wanyu; Wang, Liang; Liu, Zhengjun; Croisille, Pierre; Delachartre, Philippe; Clarysse, Patrick

    2016-12-21

    Cine-MRI is widely used for the analysis of cardiac function in clinical routine, because of its high soft tissue contrast and relatively short acquisition time in comparison with other cardiac MRI techniques. The gray level distribution in cardiac cine-MRI is relatively homogenous within the myocardium, and can therefore make motion quantification difficult. To ensure that the motion estimation problem is well posed, more image features have to be considered. This work is inspired by a method previously developed for color image processing. The monogenic signal provides a framework to estimate the local phase, orientation, and amplitude, of an image, three features which locally characterize the 2D intensity profile. The independent monogenic features are combined into a 3D matrix for motion estimation. To improve motion estimation accuracy, we chose the zero-mean normalized cross-correlation as a matching measure, and implemented a bilateral filter for denoising and edge-preservation. The monogenic features distance is used in lieu of the color space distance in the bilateral filter. Results obtained from four realistic simulated sequences outperformed two other state of the art methods even in the presence of noise. The motion estimation errors (end point error) using our proposed method were reduced by about 20% in comparison with those obtained by the other tested methods. The new methodology was evaluated on four clinical sequences from patients presenting with cardiac motion dysfunctions and one healthy volunteer. The derived strain fields were analyzed favorably in their ability to identify myocardial regions with impaired motion.

  2. Overlap syndrome between Familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome in a lupus patient.

    PubMed

    Nonaka, Fumiaki; Migita, Kiyoshi; Iwasaki, Keisuke; Shimizu, Toshimasa; Kawakami, Atsushi; Yasunami, Michio; Eguchi, Katsumi

    2014-06-01

    Autoinflammatory diseases represent an expanding spectrum of genetic and non-genetic inflammatory diseases characterized by recurrent episodes of fever and systemic inflammation, affecting joints, skin and serosal surfaces. Familial Mediterranean fever (FMF) is the most common autosomal recessive hereditary autoinflammatory disease. Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant hereditary autoinflammatory disease. They share some clinical manifestations such as a periodic fever and skin rash. We present here the association of FMF with TRAPS in a systemic lupus erythematosus (SLE) patient. A 54-year-old SLE patient with recurrent attacks of fever, arthritis, and skin rashes was referred to our hospital. She had been diagnosed with lupus nephritis at 19 years old. Her lupus nephritis was controlled by steroid treatments; however, since childhood she has suffered from recurrent episodes of periodic fever, abdominal pain, arthritis, and erythematous skin rashes. An initial diagnosis of FMF was suspected based on the genetic analysis, showing the compound heterozygous L110P/E148Q mutations in the MEFV gene that is responsible for FMF. Her symptoms responded to colchicine, but the febrile attacks were not completely resolved. Therefore, genetic testing for TRAPS was performed. The results revealed a heterozygous T61I mutation in the TNFRSF1A gene that encodes tumor necrosis factor-α receptor and is responsible for TRAPS. The patient was diagnosed with overlapping FMF and TRAPS, in addition to SLE. This is the first report of SLE associated with both FMF and TRAPS.

  3. Optical projection tomography reveals dynamics of HEV growth after immunization with protein plus CFA and features shared with HEVs in acute autoinflammatory lymphadenopathy.

    PubMed

    Kumar, Varsha; Chyou, Susan; Stein, Jens V; Lu, Theresa T

    2012-01-01

    The vascular-stromal compartment of lymph nodes is important for lymph node function, and high endothelial venules (HEVs) play a critical role in controlling the entry of recirculating lymphocytes. In autoimmune and autoinflammatory diseases, lymph node swelling is often accompanied by apparent HEV expansion and, potentially, targeting HEV expansion could be used therapeutically to limit autoimmunity. In previous studies using mostly flow cytometry analysis, we defined three differentially regulated phases of lymph node vascular-stromal growth: initiation, expansion, and the re-establishment of vascular quiescence and stabilization. In this study, we use optical projection tomography to better understand the morphologic aspects of HEV growth upon immunization with ovalbumin/CFA (OVA/CFA). We find HEV elongation as well as modest arborization during the initiation phase, increased arborization during the expansion phase, and, finally, vessel narrowing during the re-establishment of vascular quiescence and stabilization. We also examine acutely enlarged autoinflammatory lymph nodes induced by regulatory T cell depletion and show that HEVs are expanded and morphologically similar to the expanded HEVs in OVA/CFA-stimulated lymph nodes. These results reinforce the idea of differentially regulated, distinct phases of vascular-stromal growth after immunization and suggest that insights gained from studying immunization-induced lymph node vascular growth may help to understand how the lymph node vascular-stromal compartment could be therapeutically targeted in autoimmune and autoinflammatory diseases.

  4. [Monogenic human obesity: role of the leptin-melanocortin system in the regulation of food intake and body weight in humans].

    PubMed

    González-Jiménez, E; Aguilar Cordero, M J; Padilla López, C A; García García, I

    2012-01-01

    Human obesity is a disorder of multifactorial origin in which genetic and environmental factors are involved. To understand the mechanisms regulating energy intake and fat accumulation in the body, it is important to study the genetic alterations causing monogenic obesity. Most of the genes involved in monogenic obesity are associated with the leptin-melanocortin system; hence the importance of studying this system by analysing natural mutations in mice. Previous studies have described mutations in leptin and its receptor, proopiomelanocortin and prohormone convertase 1 associated with human obesity of monogenic origin. The aim of this study is to provide an updated review of the main characteristics and functioning of the leptin-melanocortin system, and its implications and potentialities in regulating food intake and body weight.

  5. PFAPA syndrome in siblings. Is there a genetic background?

    PubMed

    Antón-Martín, Pilar; Ortiz Movilla, Roberto; Guillén Martín, Sara; Allende, Luis M; Cuesta Rubio, M Teresa; López González, M Fernanda; Ramos Amador, José Tomás

    2011-12-01

    "PFAPA syndrome" is an autoinflammatory entity composed of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. There have been many reports of children with the disease, but only occasionally have been described in siblings, and no specific genetic mutation has been determined yet. Corticosteroids are the mainstay in the treatment of the acute attacks. The role of surgery in long-term follow-up (tonsillectomy with or without adenoidectomy) is controversial. We report two brothers affected with the syndrome, in whom corticosteroids as the only treatment led to an improvement. A genetic work-up was performed, making very unlikely other possible syndromes of recurrent fever. PFAPA syndrome is the most common recurrent periodic fever disorder described in childhood. Its genetic background has not been elucidated yet. Our contribution with two siblings affected with PFAPA syndrome further support the genetic basis for the entity.

  6. Diffuse sclerosing osteomyelitis (DSO) of the mandible in SAPHO syndrome: a novel approach with anti-TNF therapy. Systematic review.

    PubMed

    Marí, Antonio; Morla, Arnaud; Melero, Mireia; Schiavone, Rocio; Rodríguez, Jesus

    2014-12-01

    Diffuse sclerosing osteomyelitis of the mandible is now considered a local manifestation of SAPHO syndrome. This rare condition is thought to be of auto-inflammatory origin. The myriad of treatments shown in the literature, are basically empirical and reflect its unknown origin. We present a clinical case of refractory DSO treated with an anti-TNF drug (etanercept) with complete clinical remission. We advise against radical surgery and an interdisciplinary approach is recommended. A systematic literature review was also conducted.

  7. [Hyperimmunoglobulinemia D and periodic fever syndrome].

    PubMed

    Sakai, Hidemasa; Heike, Toshio

    2011-01-01

    Hyperimmunogloblinemia D and periodic fever syndrome (HIDS) is inherited autoinflammatory syndrome caused by deficiency of the mevalonate kinase (MK), which is involved in metabolism of cholesterol. The disease is characterized as periodic fever from early infancy accompanied by elevated serum C-reactive protein. Since clinical symptoms such as abdominal symptom, skin rash, and arthritis are common to other autoinflammatory disease, the diagnosis of HIDS during clinical work is difficult for the physicians without suspicion of HIDS for infants suffering from fever of unknown origin. Moreover, serum IgD levels are not high during infancy conflicting to the name of the disease, which is often misunderstood in the clinicians. Thus, the diagnosis of HIDS in Japan is bothering, depending on the lack of correct recognition of the disease and on the lack of commercially available examination for the disease. It is important for clinicians, especially pediatricians to update current knowledge about HIDS and to learn the appropriate way to the definitive diagnosis of HIDS, because HIDS patients exist also in Japan and the specific therapies for HIDS would be developed in the near future.

  8. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease.

    PubMed

    Zhou, Qing; Wang, Hongying; Schwartz, Daniella M; Stoffels, Monique; Park, Yong Hwan; Zhang, Yuan; Yang, Dan; Demirkaya, Erkan; Takeuchi, Masaki; Tsai, Wanxia Li; Lyons, Jonathan J; Yu, Xiaomin; Ouyang, Claudia; Chen, Celeste; Chin, David T; Zaal, Kristien; Chandrasekharappa, Settara C; P Hanson, Eric; Yu, Zhen; Mullikin, James C; Hasni, Sarfaraz A; Wertz, Ingrid E; Ombrello, Amanda K; Stone, Deborah L; Hoffmann, Patrycja; Jones, Anne; Barham, Beverly K; Leavis, Helen L; van Royen-Kerkof, Annet; Sibley, Cailin; Batu, Ezgi D; Gül, Ahmet; Siegel, Richard M; Boehm, Manfred; Milner, Joshua D; Ozen, Seza; Gadina, Massimo; Chae, JaeJin; Laxer, Ronald M; Kastner, Daniel L; Aksentijevich, Ivona

    2016-01-01

    Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.

  9. Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression.

    PubMed

    Peeters, Janneke G C; Vervoort, Stephin J; Tan, Sander C; Mijnheer, Gerdien; de Roock, Sytze; Vastert, Sebastiaan J; Nieuwenhuis, Edward E S; van Wijk, Femke; Prakken, Berent J; Creyghton, Menno P; Coffer, Paul J; Mokry, Michal; van Loosdregt, Jorg

    2015-09-29

    The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  10. How Useful Are Monogenic Rodent Models for the Study of Human Non-Alcoholic Fatty Liver Disease?

    PubMed

    Mann, Jake P; Semple, Robert K; Armstrong, Matthew J

    2016-01-01

    Improving understanding of the genetic basis of human non-alcoholic fatty liver disease (NAFLD) has the potential to facilitate risk stratification of affected patients, permit personalized treatment, and inform development of new therapeutic strategies. Animal models have been widely used to interrogate the pathophysiology of, and genetic predisposition to, NAFLD. Nevertheless, considerable interspecies differences in intermediary metabolism potentially limit the extent to which results can be extrapolated to humans. For example, human genome-wide association studies have identified polymorphisms in PNPLA3 and TM6SF2 as the two most prevalent determinants of susceptibility to NAFLD and its inflammatory component (NASH), but animal models of these mutations have had only variable success in recapitulating this link. In this review, we critically appraise selected murine monogenic models of NAFLD, NASH, and hepatocellular carcinoma (HCC) with a focus on how closely they mirror human disease.

  11. How Useful Are Monogenic Rodent Models for the Study of Human Non-Alcoholic Fatty Liver Disease?

    PubMed Central

    Mann, Jake P.; Semple, Robert K.; Armstrong, Matthew J.

    2016-01-01

    Improving understanding of the genetic basis of human non-alcoholic fatty liver disease (NAFLD) has the potential to facilitate risk stratification of affected patients, permit personalized treatment, and inform development of new therapeutic strategies. Animal models have been widely used to interrogate the pathophysiology of, and genetic predisposition to, NAFLD. Nevertheless, considerable interspecies differences in intermediary metabolism potentially limit the extent to which results can be extrapolated to humans. For example, human genome-wide association studies have identified polymorphisms in PNPLA3 and TM6SF2 as the two most prevalent determinants of susceptibility to NAFLD and its inflammatory component (NASH), but animal models of these mutations have had only variable success in recapitulating this link. In this review, we critically appraise selected murine monogenic models of NAFLD, NASH, and hepatocellular carcinoma (HCC) with a focus on how closely they mirror human disease. PMID:27899914

  12. [Periodic fever in children: keep in mind the PFAPA syndrome].

    PubMed

    Hofer, M; Rossetti, G

    2008-02-27

    The autoinflammatory diseases should be considered in the differential diagnosis of recurrent fever in childhood. These diseases are characterized by inflammatory episodes without an evident cause. Some of these diseases, like the Familial Mediterranean Fever, have a genetic origin and need a chronic treatment to avoid severe complications on the long term. PFAPA syndrome is the most frequent cause of recurrent fever and is diagnosed based on unspecific criteria. The treatment is still controversial. One dose of Prednisone is able to interrupt the flare and tonsillectomy may induce a remission in the majority of the cases.

  13. Hyperimmunoglobulinemia D and periodic fever syndrome; treatment with etanercept and follow-up.

    PubMed

    Topaloğlu, Rezan; Ayaz, Nuray Aktay; Waterham, Hans R; Yüce, Aysel; Gumruk, Fatma; Sanal, Ozden

    2008-10-01

    The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) is an autoinflammatory syndrome. It is caused by the mutations of the mevalonate kinase gene. There is no consensus for specific therapy of HIDS, but there are some case reports and studies in regards to its treatment with drugs like colchicine, steroids, nonsteroid anti-inflammatory drugs, simvastatin, anakinra, thalidomide, and etanercept. We are reporting a case evaluated for the complaints of abdominal pain and febrile episodes with massive hepatomegaly, not common finding on physical examination, its treatment with etanercept, and long-term follow-up.

  14. Pyoderma gangrenosum, acne and suppurative hidradenitis syndrome following bowel bypass surgery.

    PubMed

    Marzano, Angelo V; Ishak, Rim S; Colombo, Antonella; Caroli, Francesco; Crosti, Carlo

    2012-01-01

    The clinical triad of pyoderma gangrenosum (PG), acne and suppurative hidradenitis (PASH) has recently been described as a new disease entity within the spectrum of autoinflammatory syndromes, which are an emerging group of inflammatory diseases distinct from autoimmune, allergic and infectious disorders. PASH syndrome is similar to PAPA (pyogenic arthritis, acne and PG), but it differs in lacking the associated arthritis and on a genetic basis. PAPA syndrome is caused by mutations in a gene involved in the regulation of innate immune responses, the PSTPIP1, while no mutations have been detected to date in patients with PASH syndrome. We report a young male patient who developed coexisting disseminated PG, typical suppurative hidradenitis and acneiform eruption on the face, after he had undergone bowel bypass surgery for obesity. The cutaneous manifestations associated with bowel bypass syndrome often mimic PG or other neutrophilic dermatoses, suggesting a pathogenesis related to neutrophil-mediated inflammation for this condition. This is the first report describing PASH syndrome after bariatric surgery, and we propose to include such neutrophilic dermatoses in the list of complications occurring after bowel bypass surgery. Extensive genetic studies may help to clarify the etiopathogenesis of PASH as well as of autoinflammatory diseases in general.

  15. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations.

    PubMed

    Mortimer, Leanne; Moreau, France; MacDonald, Justin A; Chadee, Kris

    2016-10-01

    Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. However, negative regulation of inflammasomes remains poorly understood, as is the signaling cascade that dampens inflammasome activity. We found that rapid NLRP3 inflammasome activation was directly inhibited by protein kinase A (PKA), which was induced by prostaglandin E2 (PGE2) signaling via the PGE2 receptor E-prostanoid 4 (EP4). PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. Mutations in NLRP3-encoding residues adjacent to Ser295 have been linked to the inflammatory disease CAPS (cryopyrin-associated periodic syndromes). NLRP3-S295A phenocopied the human CAPS mutants. These data suggest that negative regulation at Ser295 is critical for restraining the NLRP3 inflammasome and identify a molecular basis for CAPS-associated NLRP3 mutations.

  16. The “other” vasculitis syndromes and kidney involvement

    PubMed Central

    2009-01-01

    There are a number of vasculitides that are not confined to a specific vessel size, do not have characteristic features, and/or are not secondary to another disease. Most of these vasculitides are rare in childhood. Behçet disease is representative of this group as it involves vessels of any size on both the arterial and venous side. In addition to renal vascular involvement, Behçet disease may involve the kidney through glomerulonephritis, secondary amyloidosis and, rarely, tubulointerstital involvement. Vasculitis secondary to infections, malignancy, and drugs are not common among children. However, vasculitis may be associated with a number of rheumatic diseases in childhood and the auto-inflammatory syndromes (periodic fever syndromes). Auto-inflammatory syndromes are diseases characterized by periodic attacks of clinical and laboratory inflammation. Studies carried out during the past decade have provided valuable information on the mechanism of inflammation and innate immunity in general. This group of vasculitides is associated with secondary amyloidosis of the kidney if not treated. Hypocomplementemic urticarial vasculitis is an interesting vasculitic disease with frequent kidney involvement. Here, we introduce the reader to the wide scope of these diseases; although rare, such diseases represent a challenge to the nephrologist. PMID:19898878

  17. Pyogenic Arthritis, Pyoderma Gangrenosum, Acne, Suppurative Hidradenitis (PA-PASH) Syndrome: An Atypical Presentation of a Rare Syndrome

    PubMed Central

    Ursani, Mohammad A.; Appleyard, Joan; Whiteru, Onome

    2016-01-01

    Patient: Male, 44 Final Diagnosis: PAPASH syndrome Symptoms: Recurrent skin ulcers • diarrhea • inflammatory arthritis Medication: Prednisone • anti-tumor necrosis factor Clinical Procedure: N/A Specialty: Rheumatology Objective: Rare disease Background: Pyogenic arthritis, pyoderma gangrenosum (PG), acne, and suppurative hidradenitis (PA-PASH) syndrome has been linked to an auto-inflammatory pathway. We report a case that is an atypical presentation of a rare syndrome, which supports literature suggesting that different phenotypes of PG-related syndromes may be a variation of the same pathogenic spectrum. Interestingly, our patient displayed a positive proteinase-3 antibody (PR-3). The clinical relevance of this is unclear. In recent literature, antineutrophil cytoplasmic autoantibodies (ANCA) positivity has been reported in various inflammatory conditions other than ANCA-associated vasculitis (AAV). Case Report: A 44-year-old African American male with history of pyogenic arthritis, acne, suppurative hidradenitis, and chronic diarrhea presented for evaluation of painful ulcers located on the bilateral lower extremities, bilateral proximal interphalangeal joints, buttocks, and scrotum, and chronic diarrhea. Infectious etiologies for the ulcers were ruled out. Biopsy of an ulcer revealed PG. Colonoscopy revealed inflammation and ulceration with biopsy consistent with ulcerative colitis (UC). After treatment with prednisone, the ulcers healed within 4 weeks, and the chronic diarrhea resolved. Conclusions: Our patient displayed a variation of PA-PASH syndrome and UC. Previously reported cases of similar phenotypes of PG-related syndromes have not presented in this fashion. Furthermore, the literature does not report cases of PG-related syndromes with an elevation in PR-3 antibody. Elevation in PR-3 has been reported in various inflammatory disorders aside from AAV. The relevance of this is currently unclear. It may be possible that the milieus of these various

  18. Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases

    PubMed Central

    Wheeler, Lawrie; Hardcastle, Sarah A; Appleton, Louise H; Addison, Kathryn A; Brugmans, Marieke; Clark, Graeme R; Ward, Kate A; Paggiosi, Margaret; Stone, Mike; Thomas, Joegi; Agarwal, Rohan; Poole, Kenneth ES; McCloskey, Eugene; Fraser, William D; Williams, Eleanor; Bullock, Alex N; Davey Smith, George; Brown, Matthew A; Tobias, Jon H; Duncan, Emma L

    2015-01-01

    ABSTRACT High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52‐kb intronic deletion 3′). Family members were assessed for HBM segregation with identified variants. Three‐dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non‐LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5‐HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST‐LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z‐scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z‐scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only

  19. Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases.

    PubMed

    Gregson, Celia L; Wheeler, Lawrie; Hardcastle, Sarah A; Appleton, Louise H; Addison, Kathryn A; Brugmans, Marieke; Clark, Graeme R; Ward, Kate A; Paggiosi, Margaret; Stone, Mike; Thomas, Joegi; Agarwal, Rohan; Poole, Kenneth E S; McCloskey, Eugene; Fraser, William D; Williams, Eleanor; Bullock, Alex N; Davey Smith, George; Brown, Matthew A; Tobias, Jon H; Duncan, Emma L

    2016-03-01

    High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small

  20. Sickle Cell Disease in the Post Genomic Era: A Monogenic Disease with a Polygenic Phenotype

    PubMed Central

    Driss, A; Asare, KO; Hibbert, JM; Gee, BE; Adamkiewicz, TV; Stiles, JK

    2009-01-01

    More than half a century after the discovery of the molecular basis of Sickle Cell Disease (SCD), the causes of the phenotypic heterogeneity of the disease remain unclear. This heterogeneity manifests with different clinical outcomes such as stroke, vaso-occlusive episodes, acute chest syndrome, avascular necrosis, leg ulcers, priapism and retinopathy. These outcomes cannot be explained by the single mutation in the beta-globin gene alone but may be attributed to genetic modifiers and environmental effects. Recent advances in the post human genome sequence era have opened the door for the identification of novel genetic modifiers in SCD. Studies are showing that phenotypes of SCD seem to be modulated by polymorphisms in genes that are involved in inflammation, cell–cell interaction and modulators of oxidant injury and nitric oxide biology. The discovery of genes implicated in different phenotypes will help understanding of the physiopathology of the disease and aid in establishing targeted cures. However, caution is needed in asserting that genetic modifiers are the cause of all SCD phenotypes, because there are other factors such as genetic background of the population, environmental components, socio-economics and psychology that can play significant roles in the clinical heterogeneity. PMID:20401335

  1. Periodic fever: From Still's disease to Muckle-Wells syndrome.

    PubMed

    Solís Marquínez, Marta Nataya; García Fernández, Edilia; Morís de la Tassa, Joaquín

    2017-06-02

    Muckle-Wells syndrome is a systemic autoinflammatory disease included in the group of hereditary periodic febrile syndromes. We report the case of a patient with this rare disease to call the attention to the singularity of this condition, its low incidence, its atypical presentation and the subsequent delay in the diagnosis, which is reached when late and devastating consequences have taken place. In this case, the first-line therapy, anti-interleukin 1 (IL-1), failed to control the disease. Nevertheless, the IL-6 inhibitor, tocilizumab, proved effective, achieving the total remission of nephrotic syndrome associated with AA secondary amyloidosis, changing the bleak prognosis of this disease. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  2. Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review.

    PubMed

    Smith, Elisabeth J; Allantaz, Florence; Bennett, Lynda; Zhang, Dongping; Gao, Xiaochong; Wood, Geryl; Kastner, Daniel L; Punaro, Marilynn; Aksentijevich, Ivona; Pascual, Virginia; Wise, Carol A

    2010-11-01

    PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne) is an autosomal dominant, hereditary auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. These mutations produce a hyper-phosphorylated PSTPIP1 protein and alter its participation in activation of the "inflammasome" involved in interleukin-1 (IL-1β) production. Overproduction of IL-1β is a clear molecular feature of PAPA syndrome. Ongoing research is implicating other biochemical pathways that may be relevant to the distinct pyogenic inflammation of the skin and joints characteristic of this disease. This review summarizes the recent and rapidly accumulating knowledge on these molecular aspects of PAPA syndrome and related disorders.

  3. Mutations in PSMB8 Cause CANDLE Syndrome with Evidence of Genetic and Phenotypic Heterogeneity

    PubMed Central

    Liu, Yin; Ramot, Yuval; Torrelo, Antonio; Paller, Amy S.; Si, Nuo; Babay, Sofia; Kim, Peter W.; Sheikh, Afzal; Lee, Chyi-Chia Richard; Chen, Yongqing; Vera, Angel; Zhang, Xue; Goldbach-Mansky, Raphaela; Zlotogorski, Abraham

    2011-01-01

    Objective Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is an autoinflammatory syndrome recently described in children. We investigated the clinical phenotype, genetic cause and the immune dysregulation in nine CANDLE patients. Methods Genomic DNA from all patients was screened for PSMB8 (Proteasome subunit beta type-8) mutations. Serum cytokine levels were measured from four patients. Skin biopsies were evaluated immunohistochemically and blood microarray profile (n=4) and stat-1 phosphorylation (n=3) were assessed. Results One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A) suggesting a protein truncation, four patients were homozygous and two were heterozygous for a previously reported missense mutation (c.224C>T), and one patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the four patients with the same mutation, only two share the same haplotype indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high IP-10 (Interferon gamma-induced protein 10) levels. Levels of MCP-1, IL-6, and IL-1Ra were moderately elevated. Microarray profiles and monocyte stat-1 activation suggested a unique interferon (IFN) signaling signature, unlike in other autoinflammatory disorders. Conclusion CANDLE is caused by mutations in PSMB8, a gene recently reported to cause JMP syndrome (joint contractures, muscle atrophy and panniculitis induced lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target. PMID:21953331

  4. [The sick building syndrome as a part of 'ASIA' (autoimmune/auto-inflammatory syndrome induced by adjuvants)].

    PubMed

    Maoz-Segal, Ramit; Agmon-Levin, Nancy; Israeli, Eitan; Shoenfeld, Yehuda

    2015-02-01

    The entity 'sick building syndrome' is poorly defined and comprises of a set of symptoms resulting from environmental exposure to a work or a living environment. The symptoms are mainly "allergic"-like and include nasal, eye, and mucous membrane irritation, dry skin as well as respiratory symptoms and general symptoms such as fatigue, lethargy, headaches and fever. The Autoimmune [Auto-inflammatory] Syndrome Induced by Adjuvants (ASIA) is a wider term which describes the role of various environmental factors in the pathogenesis of immune mediated diseases. Factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were found in association with defined and non-defined immune mediated diseases. The sick building syndrome and ASIA share a similar complex of signs and symptoms and probably the same immunological mechanisms which further support a common denominator.

  5. Generation of Human Induced Pluripotent Stem Cells from Extraembryonic Tissues of Fetuses Affected by Monogenic Diseases.

    PubMed

    Spitalieri, Paola; Talarico, Rosa V; Botta, Annalisa; Murdocca, Michela; D'Apice, Maria Rosaria; Orlandi, Augusto; Giardina, Emiliano; Santoro, Massimo; Brancati, Francesco; Novelli, Giuseppe; Sangiuolo, Federica

    2015-08-01

    The generation of human induced pluripotent stem cells (hiPSCs) derived from an autologous extraembryonic fetal source is an innovative personalized regenerative technology that can transform own-self cells into embryonic stem-like ones. These cells are regarded as a promising candidate for cell-based therapy, as well as an ideal target for disease modeling and drug discovery. Thus, hiPSCs enable researchers to undertake studies for treating diseases or for future applications of in utero therapy. We used a polycistronic lentiviral vector (hSTEMCCA-loxP) encoding OCT4, SOX2, KLF4, and cMYC genes and containing loxP sites, excisible by Cre recombinase, to reprogram patient-specific fetal cells derived from prenatal diagnosis for several genetic disorders, such as myotonic dystrophy type 1 (DM1), β-thalassemia (β-Thal), lymphedema-distichiasis syndrome (LDS), spinal muscular atrophy (SMA), cystic fibrosis (CF), as well as from wild-type (WT) fetal cells. Because cell types tested to create hiPSCs influence both the reprogramming process efficiency and the kinetics, we used chorionic villus (CV) and amniotic fluid (AF) cells, demonstrating how they represent an ideal cell resource for a more efficient generation of hiPSCs. The successful reprogramming of both CV and AF cells into hiPSCs was confirmed by specific morphological, molecular, and immunocytochemical markers and also by their teratogenic potential when inoculated in vivo. We further demonstrated the stability of reprogrammed cells over 10 and more passages and their capability to differentiate into the three embryonic germ layers, as well as into neural cells. These data suggest that hiPSCs-CV/AF can be considered a valid cellular model to accomplish pathogenesis studies and therapeutic applications.

  6. The genetics of Tourette syndrome.

    PubMed

    Deng, Hao; Gao, Kai; Jankovic, Joseph

    2012-03-13

    Tourette syndrome is a complex neurological disorder that usually becomes evident between 4 and 18 years of age. The disorder is characterized by chronic motor and phonic tics, often with a variety of behavioural comorbidities; in particular, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and impulse control disorder. The cause of Tourette syndrome is poorly understood. Although environmental factors are proposed to have a role, genetic factors are thought to be the primary contributors to the pathogenesis of this disorder. However, identification of the causative gene mutations or risk alleles has proved to be difficult. Early studies on the genetics of Tourette syndrome focused on multigenerational lineages and suggested Mendelian inheritance, but subsequent segregation analyses point to a more-complex inheritance pattern. A monogenic inheritance model has been proposed following the identification of rare genetic mutations associated with the Tourette syndrome phenotype. Although no specific mutations have found to directly cause Tourette syndrome, genetic findings may enable identification of the affected pathways, and could lead to the development of new treatment strategies. In this Review, we provide an overview of the genetics of Tourette syndrome and highlight how this knowledge has improved our understanding of the possible pathogenic mechanisms of this neurological disorder.

  7. Statistical Guidance for Experimental Design and Data Analysis of Mutation Detection in Rare Monogenic Mendelian Diseases by Exome Sequencing

    PubMed Central

    Zhi, Degui; Chen, Rui

    2012-01-01

    Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work. PMID:22348076

  8. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes.

    PubMed

    Torsvik, Janniche; Johansson, Stefan; Johansen, Anders; Ek, Jakob; Minton, Jayne; Raeder, Helge; Ellard, Sian; Hattersley, Andrew; Pedersen, Oluf; Hansen, Torben; Molven, Anders; Njølstad, Pål R

    2010-01-01

    We have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase (CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. These deletions were found in the first and fourth repeats of a variable number of tandem repeats (VNTR), which has proven challenging to sequence due to high GC-content and considerable length variation. We have therefore developed a screening method consisting of a multiplex PCR followed by fragment analysis. The method detected putative disease-causing insertions and deletions in the proximal repeats of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely to be a rare cause of monogenic diabetes.

  9. RareVariantVis: new tool for visualization of causative variants in rare monogenic disorders using whole genome sequencing data.

    PubMed

    Stokowy, Tomasz; Garbulowski, Mateusz; Fiskerstrand, Torunn; Holdhus, Rita; Labun, Kornel; Sztromwasser, Pawel; Gilissen, Christian; Hoischen, Alexander; Houge, Gunnar; Petersen, Kjell; Jonassen, Inge; Steen, Vidar M

    2016-10-01

    The search for causative genetic variants in rare diseases of presumed monogenic inheritance has been boosted by the implementation of whole exome (WES) and whole genome (WGS) sequencing. In many cases, WGS seems to be superior to WES, but the analysis and visualization of the vast amounts of data is demanding. To aid this challenge, we have developed a new tool-RareVariantVis-for analysis of genome sequence data (including non-coding regions) for both germ line and somatic variants. It visualizes variants along their respective chromosomes, providing information about exact chromosomal position, zygosity and frequency, with point-and-click information regarding dbSNP IDs, gene association and variant inheritance. Rare variants as well as de novo variants can be flagged in different colors. We show the performance of the RareVariantVis tool in the Genome in a Bottle WGS data set. https://www.bioconductor.org/packages/3.3/bioc/html/RareVariantVis.html tomasz.stokowy@k2.uib.no Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Hyper-IgD and periodic fever syndrome (HIDS) due to compound heterozygosity for G336S and V377I in a 44-year-old patient with a 27-year history of fever.

    PubMed

    Schlabe, Stefan; Schwarze-Zander, Carolynne; Lohse, Peter; Rockstroh, Jürgen Kurt

    2016-11-29

    Hereditary autoinflammatory syndromes are a rare, but notable cause of fever of unknown origin. During the last few years, the knowledge of the genetic background has significantly increased. Here, we report a novel pathogenic mutation in the MVK gene as the cause of fever in a 44-year-old male patient with a history of fever over a period of 27 years.

  11. Single-Nucleotide Mutations in FMR1 Reveal Novel Functions and Regulatory Mechanisms of the Fragile X Syndrome Protein FMRP

    PubMed Central

    Suhl, Joshua A.; Warren, Stephen T.

    2015-01-01

    Fragile X syndrome is a monogenic disorder and a common cause of intellectual disability. Despite nearly 25 years of research on FMR1, the gene underlying the syndrome, very few pathological mutations other than the typical CGG-repeat expansion have been reported. This is in contrast to other X-linked, monogenic, intellectual disability disorders, such as Rett syndrome, where many point mutations have been validated as causative of the disorder. As technology has improved and significantly driven down the cost of sequencing, allowing for whole genes to be sequenced with relative ease, in-depth sequencing studies on FMR1 have recently been performed. These studies have led to the identification of novel variants in FMR1, where some of which have been functionally evaluated and are likely pathogenic. In this review, we discuss recently identified FMR1 variants, the ways these novel variants cause dysfunction, and how they reveal new regulatory mechanisms and functionalities of the gene. PMID:26819560

  12. Pyogenic Arthritis, Pyoderma Gangrenosum, Acne, Suppurative Hidradenitis (PA-PASH) Syndrome: An Atypical Presentation of a Rare Syndrome.

    PubMed

    Ursani, Mohammad A; Appleyard, Joan; Whiteru, Onome

    2016-08-17

    BACKGROUND Pyogenic arthritis, pyoderma gangrenosum (PG), acne, and suppurative hidradenitis (PA-PASH) syndrome has been linked to an auto-inflammatory pathway. We report a case that is an atypical presentation of a rare syndrome, which supports literature suggesting that different phenotypes of PG-related syndromes may be a variation of the same pathogenic spectrum. Interestingly, our patient displayed a positive proteinase-3 antibody (PR-3). The clinical relevance of this is unclear. In recent literature, antineutrophil cytoplasmic autoantibodies (ANCA) positivity has been reported in various inflammatory conditions other than ANCA-associated vasculitis (AAV). CASE REPORT A 44-year-old African American male with history of pyogenic arthritis, acne, suppurative hidradenitis, and chronic diarrhea presented for evaluation of painful ulcers located on the bilateral lower extremities, bilateral proximal interphalangeal joints, buttocks, and scrotum, and chronic diarrhea. Infectious etiologies for the ulcers were ruled out. Biopsy of an ulcer revealed PG. Colonoscopy revealed inflammation and ulceration with biopsy consistent with ulcerative colitis (UC). After treatment with prednisone, the ulcers healed within 4 weeks, and the chronic diarrhea resolved. CONCLUSIONS Our patient displayed a variation of PA-PASH syndrome and UC. Previously reported cases of similar phenotypes of PG-related syndromes have not presented in this fashion. Furthermore, the literature does not report cases of PG-related syndromes with an elevation in PR-3 antibody. Elevation in PR-3 has been reported in various inflammatory disorders aside from AAV. The relevance of this is currently unclear. It may be possible that the milieus of these various auto-inflammatory disorders may share pathogenic commonalities.

  13. Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation.

    PubMed

    Marzano, A V; Borghi, A; Meroni, P L; Cugno, M

    2016-11-01

    Pyoderma gangrenosum is a rare inflammatory neutrophilic dermatosis manifesting as painful ulcers with violaceous, undermined borders on the lower extremities. It may occur in the context of classic syndromes like PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis), as well as in a recently described entity named PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). Pyoderma gangrenosum has recently been included within the spectrum of autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. In PAPA syndrome, different mutations involving the PSTPIP1 gene, via an increased binding affinity to pyrin, induce the assembly of inflammasomes. These are molecular platforms involved in the activation of caspase 1, a protease that cleaves inactive prointerleukin (pro-IL)-1β to its active isoform IL-1β. The overproduction of IL-1β triggers the release of a number of proinflammatory cytokines and chemokines, which are responsible for the recruitment and activation of neutrophils, leading to neutrophil-mediated inflammation. In SAPHO syndrome, the activation of the PSTPIP2 inflammasome has been suggested to play a role in inducing the dysfunction of the innate immune system. Patients with PASH have recently been reported to present alterations of genes involved in well-known autoinflammatory diseases, such as PSTPIP1, MEFV, NOD2 and NLRP3. Pyoderma gangrenosum and its syndromic forms can be regarded as a single clinicopathological spectrum in the context of autoinflammation.

  14. Markedly elevated CD64 expressions on neutrophils and monocytes are useful for diagnosis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome during flares.

    PubMed

    Yamazaki, Takashi; Hokibara, Sho; Shigemura, Tomonari; Kobayashi, Norimoto; Honda, Kimiko; Umeda, Yoh; Agematsu, Kazunaga

    2014-05-01

    Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most commonly encountered autoinflammatory disease in children, but its pathogenesis and diagnostic biomarkers are unknown. In this study, we examined the utility of CD64, a member of the Fcγ receptors, expressions on neutrophils and monocytes in diagnosing patients with PFAPA, along with other autoinflammatory diseases exhibiting periodic fever, and bacterial infections. Although CD64 was expressed at a similar level in the attack-free period of PFAPA and in controls, CD64 expressions on both neutrophils and monocytes were dramatically increased during attacks. Serum IFN-γ also increased in some PFAPA patients during flares, suggesting the involvement of T cell activation. Our findings demonstrate that remarkable CD64 expression during PFAPA flares serves as a potential biomarker for the diagnosis. We also suspect that IFN-γ, possibly from retention of activated T cells in peripheral tissues, increases CD64 synthesis in such cases.

  15. From bench to bedside and back again: translational research in autoinflammation.

    PubMed

    Holzinger, Dirk; Kessel, Christoph; Omenetti, Alessia; Gattorno, Marco

    2015-10-01

    Translational research approaches brought major changes to the understanding and treatment options of autoinflammatory diseases. Patients with common complex multifactorial diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), and particularly those with rare monogenic autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) or TNF receptor-associated periodic syndrome (TRAPS), benefited from a deeper understanding of the pathophysiological mechanisms and new treatment options emerging from preclinical studies. The study of IL-1 and IL-6 in this context led to novel therapies by forward translation. Conversely, effective treatment of sJIA and TRAPS with IL-1 blockade stimulated reverse translational efforts to study the pathophysiology of these cytokines in autoinflammatory diseases. These translational efforts led to the discovery of biomarkers such as S100 proteins, IL-18 or serum amyloid A, which are components of the inflammatory process, support diagnosis and allow for monitoring of disease activity, helping to predict patient outcomes. The ongoing characterization of autoinflammatory diseases in individual patients has led to classification into heterogeneous subgroups. Further characterization of relevant subgroups and the design of tailored treatment regimens, as well as the identification of new therapeutic targets and treatment options, are the major future challenges in the field of autoinflammatory diseases, particularly for paediatric rheumatologists.

  16. Novel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report.

    PubMed

    Radhakrishna, Suhas M; Grimm, Amy; Broderick, Lori

    2017-04-20

    Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is the second most common heritable autoinflammatory disease, typically presenting in pre-school aged children with fever episodes lasting 1-3 weeks. Systemic symptoms can include rash, myalgia, ocular inflammation, and serositis. Here we report an unusual presentation of TRAPS in a 7 month old girl who presented with only persistent fever. She was initially diagnosed with incomplete Kawasaki Disease and received IVIG and infliximab; however, her fevers quickly recurred. Subsequent testing revealed a urinary tract infection, but she did not improve despite appropriate therapy. As fever continued, she developed significant abdominal distension with imaging concerning for appendicitis, followed by hyperthermia and hemodynamic instability. Given her protracted clinical course and maternal history of a poorly defined inflammatory condition, an autoinflammatory disease was considered. Therapy with anakinra was initiated, resulting in rapid resolution of fever and normalization of inflammatory markers. She was found to have a previously unreported mutation, Thr90Pro, in the TNFRSF1A gene associated with TRAPS. This novel mutation was also confirmed in the patient's mother and maternal uncle. This report reviews a severe case of TRAPS in infancy associated with a novel mutation, Thr90Pro, in the TNFRSF1A gene, and emphasizes that autoinflammatory disease should be considered in the differential of infants with fever of unknown origin.

  17. Cochlear implantation in a child with CINCA syndrome who also has wide vestibular aqueducts.

    PubMed

    Bates, J E H M; Bruce, I A; Henderson, L; Melling, C; Green, K M J

    2012-08-01

    Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a severe auto-inflammatory disease, due to mutation of the CIAS1 gene. CINCA syndrome should be considered the most severe of a spectrum of three disorders all due to mutation of the CIAS1 gene. CINCA syndrome produces a triad of symptoms of neonatal onset: maculopapular urticarial rash, chronic meningitis, and chronic non-inflammatory arthropathy with recurrent fever. CINCA syndrome is also associated with sensory organ damage, especially progressive hearing loss and loss of vision. In this case report, we present the first case of cochlear implantation in a 13-year-old child with CINCA syndrome. Cochlear implantation was successful at rehabilitating the hearing loss with the child able to continue mainstream education, with her academic performance and speech discrimination both showing marked improvement. Anakinra (an interleukin 1 receptor antagonist) is now in widespread use to treat CINCA syndrome and is known to rapidly reverse the inflammatory features of CINCA syndrome. However, current evidence suggests that anakinra has limited effectiveness in reversing the sensorineural hearing loss seen in CINCA syndrome. We therefore propose that cochlear implantation is a viable treatment option in this rare yet severe auto-inflammatory disease, if the patient has failed to respond to anakinra. Owing to the unknown pathogenesis of the progressive hearing loss seen in CINCA syndrome and the limited effectiveness of anakinra in reversing the progressive hearing loss, we suggest that cochlear implantation is the modality of choice in rehabilitating severe-to-profound hearing loss not responsive to anakinra.

  18. [An approach to the patients with cryopyrin-associated periodic syndrome (CAPS) : a new biologic response modifier, canakinumab].

    PubMed

    Yokota, Shumpei; Kikuchi, Masako; Nozawa, Tomo; Kizawa, Toshiatsu; Kanetaka, Taichi; Miyamae, Takako; Mori, Masa-aki; Nishikomori, Ryohta; Takata, Hidetoshi; Heike, Toshio; Hara, Toshiro; Imagawa, Tomoyuki

    2012-01-01

    Cryopyrin-associated periodic syndrome (CAPS) comprises a group of rare, but severe, autoinflammatory syndrome, and includes 3 distinct conditions, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (MONID). These syndromes are characterized by urticarial-like rash, periodic fever, central nervous system inflammation, an arthropathy, and the risk of amyloidosis. About 20% die by age 20 years in the most severe cases. The disease is associated with mutations in the NLRP3 gene that encodes for the protein cryopyrin, a component of the inflammasome complex that regulates the production and secretion of IL-1β. Canakinumab is a human IgG monoclonal antibody targeting IL-1β. The clinical trials of canakinumab for patients with CAPS in both western countries and Japan were well-tolerated in most patients, and provided significant advantages over existing competitive therapies. Although no serious adverse effects have been reported, the frequencies of common infectious diseases including nasopharyngitis, upper respiratory tract infections, and gastroenteritis were reported presumably due to the blockade of proinflammatory cytokine, IL-1β. For us pediatrician, it will be important to be more careful for infectious diseases to provide the maximum safety of canakinumab for these patients.

  19. Monogenic mutations differentially impact the quantity and quality of T follicular helper cells in human primary immunodeficiencies

    PubMed Central

    Ma, Cindy S; Wong, Natalie; Rao, Geetha; Avery, Danielle T; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada, Satoshi; Stoddard, Jennifer L; Deenick, Elissa K; Pelham, Simon J; Payne, Katherine; Boisson-Dupuis, Stéphanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D; Kilic, Sara Sebnem; Baghdadi, Jamila El; Nonoyama, Shigeaki; Minegishi, Yoshiyuki; Mahdaviani, Seyed Alireza; Mansouri, Davood; Bousfiha, Aziz; Blincoe, Annaliesse K; French, Martyn A; Hsu, Peter; Campbell, Dianne E.; Stormon, Michael O; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M; Fulcher, David A; Cook, Matthew C; Phan, Tri G; Stepensky, Polina; Boztug, Kaan; Kansu, Aydan; Ikincioğullari, Aydan; Baumann, Ulrich; Beier, Rita; Roscioli, Tony; Ziegler, John B; Gray, Paul; Picard, Capucine; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M; Casanova, Jean-Laurent; Uzel, Gulbu; Tangye, Stuart G

    2016-01-01

    Background T follicular helper (Tfh) cells underpin T-cell dependent humoral immunity and the success of most vaccines. Tfh cells also contribute to human immune disorders such as autoimmunity, immunodeficiency and malignancy. Understanding the molecular requirements for the generation and function of Tfh cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunological abnormalities. Objective To determine the signaling pathways and cellular interactions required for the development and function of Tfh cells in humans. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating Tfh (cTfh) cell subsets, memory B cells and serum Ig levels were quantified and functionally assessed in healthy controls as well as patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS or BTK. Results Loss-of function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS or BTK reduced cTfh frequencies. STAT3, IL21/R LOF and STAT1 gain-of function mutations skewed cTfh differentiation towards a phenotype characterized by over-expression of IFNγ and programmed death -1 (PD-1). IFNγ inhibited cTfh function in vitro and in vivo, corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1 and IL12RB1 LOF mutations. Conclusion Specific mutations impact the quantity and quality of cTfh cells, highlighting the need to assess Tfh cells in patients by multiple criteria, including phenotype and function. Furthermore, IFNγ functions in vivo to restrain Tfh-induced B cell differentiation. These findings shed new light on Tfh biology and the integrated signaling pathways required for their generation, maintenance and effector function, and explain compromised humoral immunity in some PIDs. PMID:26162572

  20. A preliminary study of the whole-genome expression profile of sporadic and monogenic early-onset Alzheimer's disease.

    PubMed

    Antonell, Anna; Lladó, Albert; Altirriba, Jordi; Botta-Orfila, Teresa; Balasa, Mircea; Fernández, Manel; Ferrer, Isidre; Sánchez-Valle, Raquel; Molinuevo, José Luis

    2013-07-01

    Alzheimer's disease (AD) is the most common neurodegenerative dementia. Approximately 10% of cases present at an age of onset before 65 years old, which in turn can be monogenic familial AD (FAD) or sporadic early-onset AD (sEOAD). Mutations in PSEN1, PSEN2, and APP genes have been linked with FAD. The aim of our study is to describe the brain whole-genome RNA expression profile of the posterior cingulate area in sEOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). Fourteen patients (7 sEOAD and 7 FAD-PSEN1) and 7 neurologically healthy control subjects were selected and whole-genome expression was measured using Affymetrix Human Gene 1.1 microarrays. We identified statistically significant expression changes in sEOAD and FAD-PSEN1 brains with respect to control subjects (3183 and 3350 differentially expressed genes [DEG] respectively, false discovery rate-corrected p < 0.05). Of them, 1916 DEG were common between the 2 comparisons. We did not identify DEG between sEOAD and FAD-PSEN1. Microarray data were validated through real-time quantitative polymerase chain reaction. In silico analysis of DEG revealed an alteration in biological pathways related to intracellular signaling pathways (particularly calcium signaling), neuroactive ligand-receptor interactions, axon guidance, and long-term potentiation in both groups of patients. In conclusion, the altered biological final pathways in sEOAD and FAD-PSEN1 are mainly related with cell signaling cascades, synaptic plasticity, and learning and memory processes. We hypothesize that these 2 groups of early-onset AD with distinct etiologies and likely different could present a neurodegenerative process with potential different pathways that might converge in a common and similar final stage of the disease.

  1. Genotyping of β-globin gene mutations in single lymphocytes: a preliminary study for preimplantation genetic diagnosis of monogenic disorders.

    PubMed

    Durmaz, Burak; Ozkinay, Ferda; Onay, Huseyin; Karaca, Emin; Aydinok, Yesim; Tavmergen, Erol; Vrettou, Christina; Traeger-Synodinos, Jan; Kanavakis, Emmanuel

    2012-01-01

    Hemoglobinopathies, especially β-thalassemia (β-thal), represent an important health burden in Mediterranean countries like Turkey. Some couples prefer the option of preimplantation genetic diagnosis (PGD). However, clinical application of PGD, especially for the monogenic disorders is technically demanding. To ensure reliable results, protocols need to be robust and well standardized. Ideally PGD-PCR (polymerase chain reaction) protocols should be based on multiplex and fluorescent PCR for analysis of the disease-causing mutation(s) along with linked markers across the disease-associated locus. In this study, we aimed to constitute a protocol in single cells involving first round multiplex PCR with primers to amplify the region of the β-globin gene containing the most common mutations. Two microsatellites linked to the β-globin gene cluster (D11S4891, D11S2362) and two unlinked (D13S314, GABRB3) microsatellite markers, were used to rule out allele dropout (ADO) and contamination; followed by nested real-time PCR for genotyping the β-globin mutations. We also investigated the allele frequencies and heterozygote rates of these microsatellites in the Turkish population that have not been reported to date. This protocol was tested in 100 single lymphocytes from heterozygotes with known β-globin mutations. Amplification failure was detected in one lymphocyte (1%) and ADO was observed in two lymphocytes (2%). No contamination was detected. All results were concordant with the genotypes of the patients. Overall, this protocol was demonstrated to be sensitive, accurate, reliable and rapid for the detection of β-globin mutations in single cells and shows potential for the clinical application of PGD for hemoglobinopathies in the Turkish population.

  2. Structure-function studies of HNF1A (MODY3) gene mutations in South Indian patients with monogenic diabetes.

    PubMed

    Balamurugan, K; Bjørkhaug, L; Mahajan, S; Kanthimathi, S; Njølstad, P R; Srinivasan, N; Mohan, V; Radha, V

    2016-12-01

    Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of diabetes characterized by onset of diabetes below 25 years of age, autosomal dominant mode of inheritance and primary defect in insulin secretion. Mutations in the gene (HNF1A) encoding transcription factor hepatocyte nuclear factor 1A (HNF-1A) results in one of the most common forms of MODY (MODY3). HNF-1A is mainly enriched in pancreatic β-cells and hepatocytes and important for organ development and normal pancreatic function. We here report on the functional interrogation of eight missense HNF1A mutations associated with MODY3 in South Indian subjects, and the contributing effect of common variant (S487N) within HNF1A. Of the eight mutations, three mutations (p.R171G, p.G245R and p.R263H), in particular, affected HNF-1A function in transfected HeLa cells by reducing both transcriptional activity and nuclear localization, possibly due to disruption of the integrity of the three dimensional structure. The common variant p.S487N contributed further to the loss-of-function of p.R271Q (p.R271Q+p.S487N double mutant), in vitro, on both activity and localization. Our data on the first functional study of HNF1A mutations in South India subjects confers that the defect of the HNF-1A mutant proteins are responsible for MODY3 diabetes in these patients.

  3. [Hyperimmunoglobulinemia D and periodic fever syndrome].

    PubMed

    Agbo-kpati, K-P; Condor, R; Hollenberg, H; Chalvon Demersay, A; Cuisset, L; Quartier, P

    2014-07-01

    We report the cases of two sisters born of parents who were first-degree cousins, who started recurrent fever with lymph node and digestive tract involvement at the age of 2 years. There was no mutation of the familial Mediterranean fever gene and a diagnosis of partial mevalonate kinase (MVK) deficiency was made. However, immunoglobulin (Ig) D and A levels were normal. Elevated mevalonic acid in the patients' urine during an episode and MVK gene analysis provided the diagnosis. Clinical remission was obtained under anti-TNF-alpha treatment with etanercept. These observations and those of several previously reported patients, particularly in French and Dutch series, illustrate the importance of considering the diagnosis in a child with early-onset auto-inflammatory syndrome even in the absence of hyper-IgD or -IgA.

  4. Collagen-induced arthritis and related animal models: how much of their pathogenesis is auto-immune, how much is auto-inflammatory?

    PubMed

    Billiau, Alfons; Matthys, Patrick

    2011-01-01

    In this review, we discuss our studies on the pathogenesis of collagen-induced arthritis (CIA) and related mouse models for rheumatoid arthritis. Of note, these models invariably rely on the use of complete Freund's adjuvant (CFA). Our analysis has focused on explaining the dichotomous - either protective or disease-promoting - role of endogenous IFN-γ. Induction of a myelopoietic burst by CFA was identified as an important and underestimated factor in mediating the role of IFN-γ and other cytokines (IL-6, IL-17, GCP-2, RANK-L). Myelopoiesis provides an excess in precursors for joint-infiltrating neutrophils and osteoclasts. We postulate that classical CIA is primarily an auto-inflammatory disease, in part because of a strong innate immune response to the adjuvant. Superimposed on this, collagen-specific auto-immunity reinforces inflammatory reactivity in joints.

  5. Super-refractory status epilepticus and febrile infection-related epilepsy syndrome treated with anakinra

    PubMed Central

    Kenney-Jung, Daniel L.; Kahoud, Robert J.; Vezzani, Annamaria; LaFrance-Corey, Reghann G.; Ho, Mai-Lan; Muskardin, Theresa Wampler; Gleich, Stephen J.; Wirrell, Elaine C.; Howe, Charles L.; Payne, Eric T.

    2017-01-01

    Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well-tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. PMID:27770579

  6. [Schnitzlers SyndromeDifferential diagnostics, an overview of therapeutic options and description of 5 cases treated with anakinra].

    PubMed

    Adam, Zdeněk; Šedivá, Anna; Koukalová, Renata; Řehák, Zdeněk; Petrášová, Hana; Szturz, Petr; Adamová, Zdenka; Vetešníková, Eva; Pour, Luděk; Krejčí, Marta; Sandecká, Viera; Pourová, Eva; Čermáková, Zdeňka; Ševčíková, Sabina; Král, Zdeněk; Mayer, Jiří

    2016-01-01

    Schnitzlers syndrome is an acquired auto-inflammatory disease of still unclear origin. The Strasbourg criteria were adopted (non-infectious fever, chronic urticaria, changes in the bone structure, leukocytosis and higher values of inflammatory markers - CRP and presence of monoclonal immunoglobulin mostly of type IgM, very rarely of IgG) to establish this diagnosis. The first-choice therapy for this disease is the blocking of interleukin-1 effects. In practice, the interleukin-1 receptor antagonist, anakinra, is the most commonly used. Currently reports also appear of the use of other medicines blocking the effect of interleukin-1, namely canakinumab and rilonacept. We have been treating 5 patients with anakinra (108, 72, 33, 32 and 1 months) on a long-term basis. In all the patients, we commenced administration of anakinra in a dose of 100 mg once a day. As a result of 100 mg being administered once a day, all symptoms went away completely in 4 patients, while they receded by about 75 % in 1 patient, without disappearing completely. This patient needs an increased dose of 2 ampoules per day on the days of spontaneously intensified medical ailments. After one year of treatment it turned out for one of the four patients whose symptoms had completely disappeared when administered the 100mg daily dose, that he only needed the respective dose of anakinra at 48-hour intervals. However this patient does not tolerate further extension of the intervals between dose administrations. We have not recorded any adverse effects of anakinra in the course of the treatment, and no decline in the efficiency of anakinra has been observed: it acts as effectively now as it did at the beginning of the treatment. The text discusses the differential diagnostics of the Schnitzler syndrome.Key words: anakinra - auto-inflammatory diseases - canakinumab - fever of unknown origin - FUO - interleukin 1 - cryopyrin-associated autoinflammatory syndrome (CAPS) - monoclonal gammopathy - rilonacept

  7. Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome.

    PubMed

    Pucino, Valentina; Lucherini, Orso Maria; Perna, Francesco; Obici, Laura; Merlini, Giampaolo; Cattalini, Marco; La Torre, Francesco; Maggio, Maria Cristina; Lepore, Maria Teresa; Magnotti, Flora; Galgani, Mario; Galeazzi, Mauro; Marone, Gianni; De Rosa, Veronica; Talarico, Rosaria; Cantarini, Luca; Matarese, Giuseppe

    2016-05-01

    TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4(+)CD25(-) and regulatory CD4(+)CD25(+) T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR-associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR-associated periodic syndrome involving both CD4(+) conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.

  8. Neutrophilic dermatoses as systemic diseases.

    PubMed

    Prat, Lola; Bouaziz, Jean-David; Wallach, Daniel; Vignon-Pennamen, Marie-Dominique; Bagot, Martine

    2014-01-01

    Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal polymorphonuclear leukocytes. The main clinical forms of ND include Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and their atypical or transitional forms. ND are often idiopathic, but they may be associated with myeloid hematologic malignancies (Sweet syndrome), inflammatory bowel disease or rheumatoid arthritis (pyoderma gangrenosum), and monoclonal gammopathies (erythema elevatum diutinum, subcorneal pustular dermatosis). The possible infiltration of internal organs with neutrophils during the setting of ND underlies the concept of a neutrophilic systemic disease. ND may be seen as a polygenic autoinflammatory syndrome due to their frequent association with other autoinflammatory disorders (monogenic or polygenic) and the recent published efficacy of interleukin-1 blocking therapies in their management. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Infections and vaccines in the etiology of antiphospholipid syndrome.

    PubMed

    Cruz-Tapias, Paola; Blank, Miri; Anaya, Juan-Manuel; Shoenfeld, Yehuda

    2012-07-01

    To present scientific evidence supporting the infectious origin for the antiphospholipid syndrome (APS) by molecular mimicry between pathogens, infection and vaccination with β2-glycoprotein I (β2-GPI) molecule. APS is characterized by the presence of pathogenic autoantibodies against β2-GPI. The infection etiology of APS was well established. Likewise, a link between vaccination such as tetanus toxoid may trigger antibodies targeting tetanus toxoid and β2-GPI, due to molecular mimicry between the two molecules. During the years, the pathogenic potential of anti-tetanus toxoid antibodies cross reactive with β2-GPI were found to be pathogenic in animal models, inducing experimental APS. Accumulated evidence supports that the presence of anti-β2-GPI antibodies is associated with a history of infections and the main mechanism to explain this correlation is molecular mimicry. The relationship between tetanus toxoid vaccination and APS reveals a novel view on the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA).

  10. BDNF in fragile X syndrome.

    PubMed

    Castrén, Maija L; Castrén, Eero

    2014-01-01

    Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity. However, numerous alterations are found during the early development in FXS, including abnormal differentiation of neural progenitors and impaired migration of newly born neurons. Several aspects of FMRP function are modulated by brain-derived neurotrophic factor (BDNF) signaling. Here, we review the evidence of the role for BDNF in the developing and adult FXS brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  11. [MVK gene abnormality and new approach to treatment of hyper IgD syndrome and periodic fever syndrome].

    PubMed

    Naruto, Takuya

    2007-04-01

    Hyper IgD and periodic fever syndrome (HIDS; OMIM 260920) is one of the hereditary autoinflammatory syndromes characterized by recurrent episodes of fever and inflammation.. HIDS is an autosomal recessive disorder characterized by recurrent fever attacks in early childhood. HIDS caused by mevalonate kinase (MK) mutations, also that is the gene of mevalonic aciduria (OMIM 251170). During febrile episodes, urinary mevalonate concentrations were found to be significantly elevated in patients. Diagnosis of HIDS was retrieving gene or measurement of the enzyme activity in peripheral blood lymphocyte in general. This of HIDS is an activity decline of MK, and a complete deficiency of MK becomes a mevalonic aciduria with a nervous symptom. The relation between the fever and inflammation of mevalonate or isoprenoid products are uncertain. The therapy attempt with statins, which is inhibited the next enzyme after HMG-CoA reductase, or inhibit the proinflammatory cytokines.

  12. Single Gene and Syndromic Causes of Obesity: Illustrative Examples.

    PubMed

    Butler, Merlin G

    2016-01-01

    Obesity is a significant health problem in westernized societies, particularly in the United States where it has reached epidemic proportions in both adults and children. The prevalence of childhood obesity has doubled in the past 30 years. The causation is complex with multiple sources, including an obesity promoting environment with plentiful highly dense food sources and overall decreased physical activity noted for much of the general population, but genetic factors clearly play a role. Advances in genetic technology using candidate gene approaches, genome-wide association studies, structural and expression microarrays, and next generation sequencing have led to the discovery of hundreds of genes recognized as contributing to obesity. Polygenic and monogenic causes of obesity are now recognized including dozens of examples of syndromic obesity with Prader-Willi syndrome, as a classical example and recognized as the most common known cause of life-threatening obesity. Genetic factors playing a role in the causation of obesity will be discussed along with the growing evidence of single genes and the continuum between monogenic and polygenic obesity. The clinical and genetic aspects of four classical but rare obesity-related syndromes (ie, Prader-Willi, Alström, fragile X, and Albright hereditary osteodystrophy) will be described and illustrated in this review of single gene and syndromic causes of obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

    PubMed

    Ma, Cindy S; Wong, Natalie; Rao, Geetha; Avery, Danielle T; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada, Satoshi; Stoddard, Jennifer L; Deenick, Elissa K; Pelham, Simon J; Payne, Kathryn; Boisson-Dupuis, Stéphanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D; Kilic, Sara Sebnem; El Baghdadi, Jamila; Nonoyama, Shigeaki; Minegishi, Yoshiyuki; Mahdaviani, Seyed Alireza; Mansouri, Davood; Bousfiha, Aziz; Blincoe, Annaliesse K; French, Martyn A; Hsu, Peter; Campbell, Dianne E; Stormon, Michael O; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M; Fulcher, David A; Cook, Matthew C; Phan, Tri Giang; Stepensky, Polina; Boztug, Kaan; Kansu, Aydan; İkincioğullari, Aydan; Baumann, Ulrich; Beier, Rita; Roscioli, Tony; Ziegler, John B; Gray, Paul; Picard, Capucine; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M; Casanova, Jean-Laurent; Uzel, Gulbu; Tangye, Stuart G

    2015-10-01

    Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised

  14. Monogenic human skin disorders.

    PubMed

    Lemke, Johannes R; Kernland-Lang, Kristin; Hörtnagel, Konstanze; Itin, Peter

    2014-01-01

    Human genodermatoses represent a broad and partly confusing spectrum of countless rare diseases with confluent and overlapping phenotypes often impeding a precise diagnosis in an affected individual. High-throughput sequencing techniques have expedited the identification of novel genes and have dramatically simplified the establishment of genetic diagnoses in such heterogeneous disorders. The precise genetic diagnosis of a skin disorder is crucial for the appropriate counselling of patients and their relatives regarding the course of the disease, prognosis and recurrence risks. Understanding the underlying pathophysiology is a prerequisite to understanding the disease and developing specific, targeted or individualized therapeutic approaches. We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We hope this may represent a useful tool in guiding dermatologists towards genetic diagnoses, providing patients with individual knowledge on the respective disorder and applying novel research findings to clinical practice.

  15. Auto inflammatory syndromes: Diagnosis and treatment.

    PubMed

    Stankovic, Katia; Grateau, Gilles

    2007-12-01

    Hereditary recurrent fevers are rare genetic diseases characterized by apparently spontaneous attacks of inflammation. They include familial Mediterranean fever (FMF); tumor necrosis factor (TNF) receptor periodic syndrome (TRAPS); hyperimmunoglobulinemia D syndrome (HIDS); and hereditary periodic fevers related to mutations in the CIAS1 (cold induced autoinflammatory syndrome 1) gene, such as Muckle-Wells syndrome, familial cold urticaria, and CINCA/NOMID (chronic infantile neurological cutaneous and articular/neonatal-onset multisystemic inflammatory disease). Musculoskeletal manifestations are common. They may occur as features of the acute inflammatory attacks or persist for longer periods. Among them, the most common include arthritis of the large and medium-sized joints in FMF and CINCA, arthralgia in HIDS, and myalgia or pseudo-fasciitis in TRAPS. The outcome is usually favorable, although joint destruction may develop in CINCA or at the hip in FMF. The recurrent bouts of fever and accompanying clinical manifestations suggest the diagnosis, which can be confirmed by genetic testing. Among differential diagnoses, infection should be considered routinely. The treatment of the inflammatory attacks is nonspecific. New pathophysiological insights have led to the development of promising maintenance treatments designed to reduce the number and severity of the inflammatory attacks and to diminish the risk of secondary amyloidosis.

  16. [Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome].

    PubMed

    Kusuhara, Koichi

    2011-01-01

    Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is a non-hereditary autoinflammatory disease, characterized by relatively regular recurrence of febrile episodes of 3-6 days duration, accompanied by aphthous stomatitis, pharyngitis/tonsillitis, and/or cervical adenititis. It is considered to be the most common periodic fever syndrome in Japan. Although no responsible gene is identified, some genetic factors may confer the predisposition toward this disorder. Important differential diagnosis includes hereditary periodic syndromes and cyclic neutropenia. Although its etiology is still to be elucidated, a recent study suggested an environmentally triggered activation of complement and IL-1β/IL-18 during PFAPA syndrome flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. This study also demonstrated the possibility that IP-10/CXCL10 might serve as a potential biomarker to differentiate PFAPA syndrome from other periodic fever syndromes. Therapeutic strategy for PFAPA syndrome has not been well established. Recent advances in the understating of etiology and pathophysiology might lead to re-evaluation of recent therapeutic options and/or development of new treatment.

  17. Demographic, clinical and therapeutic findings in a monocentric cohort of adult patients with suspected PFAPA syndrome.

    PubMed

    Vitale, Antonio; Orlando, Ida; Lopalco, Giuseppe; Emmi, Giacomo; Cattalini, Marco; Frediani, Bruno; Galeazzi, Mauro; Iannone, Florenzo; Rigante, Donato; Cantarini, Luca

    2016-01-01

    Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a non-Mendelian autoinflammatory disorder until now considered to be specifically limited to paediatric age. Recently, an increasing number of reports seems to suggest that PFAPA syndrome, diagnosed by the Marshall criteria revised by Thomas et al., can also affect adults. The Marshall/Thomas criteria have been applied to 989 adult patients presenting for recurrent fever episodes: all patients enrolled were reviewed for demographic, clinical, and therapeutic data. Infectious, neoplastic, autoimmune and other autoinflammatory diseases were ruled out. We identified 30 adult patients (19 males, 11 females) with a suspected PFAPA syndrome: their mean age at disease onset was 33.75±14.01 years, mean age at diagnosis 39.1±14.39 years, and mean body temperature peak 39.5±0.7°C. In addition, the mean frequency of febrile episodes was 11.58±8.97 per year. More precisely, patients complained of pharyngitis (77%), cervical adenitis (73%), asthenia (63%), arthralgia (67%), oral aphthosis (50%), myalgia (54%), cephalalgia (43%), abdominal pain (27%), nausea/vomiting (17%), periorbital pain (17%), and arthritis (10%). Six out of 30 (20%) patients had suffered from PFAPA syndrome also during childhood, and the disease had reappeared in adulthood. We provide the largest monocentric cohort of patients diagnosed with a suspected PFAPA syndrome in adulthood confirming that this syndrome can occur also during adulthood; moreover, due to the medical history of our patients and based on our experience, PFAPA syndrome might relapse during adulthood after a temporary remission reached in the course of paediatric age.

  18. A systematic review of genetic syndromes with obesity.

    PubMed

    Kaur, Y; de Souza, R J; Gibson, W T; Meyre, D

    2017-03-27

    Syndromic monogenic obesity typically follows Mendelian patterns of inheritance and involves the co-presentation of other characteristics, such as mental retardation, dysmorphic features and organ-specific abnormalities. Previous reviews on obesity have reported 20 to 30 syndromes but no systematic review has yet been conducted on syndromic obesity. We searched seven databases using terms such as 'obesity', 'syndrome' and 'gene' to conduct a systematic review of literature on syndromic obesity. Our literature search identified 13,719 references. After abstract and full-text review, 119 relevant papers were eligible, and 42 papers were identified through additional searches. Our analysis of these 161 papers found that 79 obesity syndromes have been reported in literature. Of the 79 syndromes, 19 have been fully genetically elucidated, 11 have been partially elucidated, 27 have been mapped to a chromosomal region and for the remaining 22, neither the gene(s) nor the chromosomal location(s) have yet been identified. Interestingly, 54.4% of the syndromes have not been assigned a name, whereas 13.9% have more than one name. We report on organizational inconsistencies (e.g. naming discrepancies and syndrome classification) and provide suggestions for improvements. Overall, this review illustrates the need for increased clinical and genetic research on syndromes with obesity.

  19. Hyper-IgE Syndromes and the Lung.

    PubMed

    Freeman, Alexandra F; Olivier, Kenneth N

    2016-09-01

    Elevated serum IgE has many etiologies including parasitic infection, allergy and asthma, malignancy, and immune dysregulation. The hyper-IgE syndromes caused by mutations in STAT3, DOCK8, and PGM3 are monogenic primary immunodeficiencies associated with high IgE, eczema, and recurrent infections. These primary immunodeficiencies are associated with recurrent pneumonias leading to bronchiectasis; however, each has unique features and genetic diagnosis is essential in guiding therapy, discussing family planning, and defining prognosis. This article discusses the clinical features of these primary immunodeficiencies with a particular focus on the pulmonary manifestations and discussion of the genetics, pathogenesis, and approaches to therapy.

  20. Patterns of Allergic Sensitization in High IgE Syndromes.

    PubMed

    Lawrence, Monica G

    2015-12-01

    Dramatic elevations in the serum IgE level are seen both in polygenic allergic diseases such as atopic dermatitis and food allergy, and in a growing list of monogenic primary immune deficiencies (PIDs). Although the IgE produced in patients with PID has generally been considered to be driven by dysregulated IL-4 production and thus lack antigen specificity, in fact allergen-specific IgE can be detected by skin and serum testing in many of these patients. However, perhaps not surprisingly given the distinct immunologic pathways involved, the patterns of allergic disease and atopic sensitization vary widely between syndromes, leading to strikingly different clinical phenotypes.

  1. Autoimmune hepatitis type 2 arising in PFAPA syndrome: coincidences or possible correlations?

    PubMed

    Della Corte, Claudia; Ranucci, Giusy; Tufano, Maria; Alessio, Maria; Iorio, Raffaele

    2010-03-01

    PFAPA syndrome is a chronic disease classified in the group of autoinflammatory syndromes characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis in young children. The etiology of this disorder is still unknown, but a primary dysfunction of the innate immune system seems to be involved. According to Marshall criteria, it is not possible to diagnose PFAPA in the presence of autoimmune diseases. We present here the case report of an 8-month girl with PFAPA who developed autoimmune hepatitis type 2 at the age of 18 months. We suppose that the dysregulation in innate immunity that is typical of patients with PFAPA could trigger autoimmune disorders such as autoimmune hepatitis in susceptible subjects. The possible relationships between immune-system dysfunction peculiar to this syndrome and autoimmune hepatitis are discussed.

  2. Dramatic improvement of pyoderma gangrenosum with infliximab in a patient with PAPA syndrome.

    PubMed

    Stichweh, Dorothee S; Punaro, Marilynn; Pascual, Virginia

    2005-01-01

    Infliximab, a chimeric antitumor necrosis factor alpha monoclonal antibody (anti-TNF alpha), has been recently shown to have a beneficial effect on pyoderma gangrenosum associated with inflammatory bowel disease. Patients with the syndromic triad of pyogenic sterile arthritis, pyoderma gangrenosum, and acne, an autoinflammatory process caused by mutations in the CD2 binding protein-1 (CD2BP1) gene, can have severe pyoderma gangrenosum. We describe a 14-year-old patient with this syndrome who was unresponsive to multiple therapies. A dramatic improvement in his pyoderma gangrenosum was observed after one infusion of infliximab, and a second infusion led to its resolution. Our observation extends the therapeutic use of infliximab to this component of PAPA syndrome.

  3. Hyperimmunoglobulinaemia D syndrome: a rare cause of prolonged fever and treatment with anti-interleukin 1 agent.

    PubMed

    Aygun, Deniz; Sahin, Sezgin; Cokugras, Haluk; Kasapcopur, Ozgur

    2016-05-17

    Hyperimmunoglobulinaemia D syndrome (HIDS) is an autosomal recessive, autoinflammatory disease that is characterised with intermittent febrile episodes, cervical lymphadenopathy, rashes, arthritis and gastrointestinal symptoms associated with synovial or serosal inflammation. HIDS is caused by mutations in the gene encoding mevalonate kinase enzyme. The febrile attacks usually start in early childhood and triggered by stress or vaccinations. We report a case of 16-month-old boy who had episodes of recurrent fever accompanied by maculopapular rash and lymphadenopathy. He was diagnosed as HIDS and he had heterozygote mutation of mevalonate kinase gene. 2016 BMJ Publishing Group Ltd.

  4. Methodological challenges in monitoring new treatments for rare diseases: lessons from the cryopyrin-associated periodic syndrome registry

    PubMed Central

    2013-01-01

    Background The Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare hereditary autoinflammatory diseases and encompass Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal Onset Multisystem Inflammatory Disease (NOMID). Canakinumab is a monoclonal antibody directed against IL-1 beta and approved for CAPS patients but requires post-approval monitoring due to low and short exposures during the licensing process. Creative approaches to observational methodology are needed, harnessing novel registry strategies to ensure Health Care Provider reporting and patient monitoring. Methods A web-based registry was set up to collect information on long-term safety and effectiveness of canakinumab for CAPS. Results Starting in November 2009, this registry enrolled 241 patients in 43 centers and 13 countries by December 31, 2012. One-third of the enrolled population was aged < 18; the overall population is evenly divided by gender. Enrolment is ongoing for children. Conclusions Innovative therapies in orphan diseases require post-approval structures to enable in depth understanding of safety and natural history of disease. The rarity and distribution of such diseases and unpredictability of treatment require innovative methods for enrolment and follow-up. Broad international practice-based recruitment and web-based data collection are practical. PMID:24016338

  5. Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

    PubMed

    Bierzynska, Agnieszka; McCarthy, Hugh J; Soderquest, Katrina; Sen, Ethan S; Colby, Elizabeth; Ding, Wen Y; Nabhan, Marwa M; Kerecuk, Larissa; Hegde, Shivram; Hughes, David; Marks, Stephen; Feather, Sally; Jones, Caroline; Webb, Nicholas J A; Ognjanovic, Milos; Christian, Martin; Gilbert, Rodney D; Sinha, Manish D; Lord, Graham M; Simpson, Michael; Koziell, Ania B; Welsh, Gavin I; Saleem, Moin A

    2017-04-01

    Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.

  6. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists.

    PubMed

    Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L; Nelson, Tanya N; Richer, Julie; Sadikovic, Bekim; Skidmore, David L; Stockley, Tracy; Taylor, Sherry; van Karnebeek, Clara; Zawati, Ma'n H; Lauzon, Julie; Armour, Christine M

    2015-07-01

    The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should

  7. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

    PubMed Central

    Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L; Nelson, Tanya N; Richer, Julie; Sadikovic, Bekim; Skidmore, David L; Stockley, Tracy; Taylor, Sherry; van Karnebeek, Clara; Zawati, Ma'n H; Lauzon, Julie; Armour, Christine M

    2015-01-01

    Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes

  8. Genome-wide association studies of obesity and metabolic syndrome.

    PubMed

    Fall, Tove; Ingelsson, Erik

    2014-01-25

    Until just a few years ago, the genetic determinants of obesity and metabolic syndrome were largely unknown, with the exception of a few forms of monogenic extreme obesity. Since genome-wide association studies (GWAS) became available, large advances have been made. The first single nucleotide polymorphism robustly associated with increased body mass index (BMI) was in 2007 mapped to a gene with for the time unknown function. This gene, now known as fat mass and obesity associated (FTO) has been repeatedly replicated in several ethnicities and is affecting obesity by regulating appetite. Since the first report from a GWAS of obesity, an increasing number of markers have been shown to be associated with BMI, other measures of obesity or fat distribution and metabolic syndrome. This systematic review of obesity GWAS will summarize genome-wide significant findings for obesity and metabolic syndrome and briefly give a few suggestions of what is to be expected in the next few years.

  9. Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism.

    PubMed

    El-Kordi, Ahmed; Winkler, Daniela; Hammerschmidt, Kurt; Kästner, Anne; Krueger, Dilja; Ronnenberg, Anja; Ritter, Caroline; Jatho, Jasmin; Radyushkin, Konstantin; Bourgeron, Thomas; Fischer, Julia; Brose, Nils; Ehrenreich, Hannelore

    2013-08-15

    Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a 'synapse disorder'. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X). We previously described autism-like behaviors in male Nlgn4 null mutant mice, including reduced social interaction and ultrasonic communication. Here, we extend the phenotypical characterization of Nlgn4 null mutant mice to both genders and add a series of additional autism-relevant behavioral readouts. We now report similar social interaction and ultrasonic communication deficits in females as in males. Furthermore, aggression, nest-building parameters, as well as self-grooming and circling as indicators of repetitive behaviors/stereotypies were explored in both genders. The construction of a gender-specific autism severity composite score for Nlgn4 mutant mice markedly diminishes population/sample heterogeneity typically obtained for single tests, resulting in p values of <0.00001 and a genotype predictability of 100% for male and of >83% for female mice. Taken together, these data underscore the similarity of phenotypical consequences of Nlgn4/NLGN4X loss-of-function in mouse and man, and emphasize the high relevance of Nlgn4 null mutant mice as an ASD model with both construct and face validity.

  10. Cerebrospinal fluid neopterin and cryopyrin-associated periodic syndrome.

    PubMed

    Serrano, Mercedes; Ormazábal, Aida; Antón, Jordi; Aróstegui, Juan I; García-Cazorla, Angels

    2009-12-01

    Cryopyrin-associated periodic syndrome is a category of autoinflammatory disorders caused by mutations of the NLRP3 gene, with chronic infantile neurologic cutaneous and articular syndrome being the severest clinical phenotype. Various pterins have been reported as mediating immunologic functions in the central nervous system, but to date studies of pterin cerebrospinal fluid (CSF) values and cryopyrin-associated periodic syndrome have been lacking. A 2-year-old child was affected with a severe atypical form of cryopyrin-associated periodic syndrome, suspected based on the analysis of neopterin in CSF. He initially presented isolated neurologic manifestations mimicking a neuroregressive disorder. Blood and CSF analyses did not present any routine inflammatory markers, but CSF neopterin was elevated. Later, the patient developed arthritis and recurrent episodes of fever, and the cryopyrin-associated periodic syndrome diagnosis was confirmed by genetic studies. Neopterin was the most altered indicator over the time. Child neurologists should be on the alert when unexplained neurologic signs appear, giving consideration to the possibility of inflammatory or immune-mediated diseases. The present case demonstrates the clinical utility of measurement of CSF neopterin levels in screening for these immune-mediated diseases, especially when neurologic symptoms are associated with normal results on routine CSF tests.

  11. Muckle-Wells syndrome: a treatable cause of congenital sensorineural hearing loss.

    PubMed

    Stew, B T; Fishpool, S J C; Owens, D; Quine, S

    2013-01-01

    Muckle-Wells syndrome (MWS) is a rare autosomal dominant condition with variable expression. It is a subset of auto-inflammatory diseases characterised by recurrent inflammatory crises and is associated with chronic recurrent urticaria, sensorineural deafness, periodic arthritis and secondary amyloidosis. The diagnosis of MWS is a clinical one with sufferers classically presenting in childhood with a moderate fever and non-pruiginous urticaria. We describe a case of a six-year-old girl who was successfully diagnosed and treated with Anakinra. Muckle and Wells originally described this syndrome in 1962; however, only recently was it discovered to be genetically linked to chromosome 1q44 and subsequently to missense mutations in the CIAS1/NALP3/PYPAF1 gene. Since then, treatment has evolved and it remains one of few treatable causes of congenital profound sensorineural hearing loss.

  12. Monogenec Arrhythmic Syndromes: From Molecular and Genetic Aspects to Bedside

    PubMed Central

    E.Z., Golukhova; O.I., Gromova; R.A., Shomahov; N.I., Bulaeva; L.A., Bockeria

    2016-01-01

    The abrupt cessation of effective cardiac function that is generally due to heart rhythm disorders can cause sudden and unexpected death at any age and is referred to as a syndrome called “sudden cardiac death” (SCD). Annually, about 400,000 cases of SCD occur in the United States alone. Less than 5% of the resuscitation techniques are effective. The prevalence of SCD in a population rises with age according to the prevalence of coronary artery disease, which is the most common cause of sudden cardiac arrest. However, there is a peak in SCD incidence for the age below 5 years, which is equal to 17 cases per 100,000 of the population. This peak is due to congenital monogenic arrhythmic canalopathies. Despite their relative rarity, these cases are obviously the most tragic. The immediate causes, or mechanisms, of SCD are comprehensive. Generally, it is arrhythmic death due to ventricular tachyarrythmias – sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Bradyarrhythmias and pulseless electrical activity account for no more than 40% of all registered cardiac arrests, and they are more often the outcome of the abovementioned arrhythmias. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, the fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of the heart rhythm (for example, the long QT syndrome). This review presents an overview of the molecular and genetic basis of SCD in the long QT syndrome, Brugada syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and idiopathic ventricular fibrillation, and arrhythmogenic right ventricular dysplasia, and sudden cardiac death prevention strategies by modern techniques (including implantable cardioverter-defibrillator) PMID:27437140

  13. Genetics of obesity and overgrowth syndromes.

    PubMed

    Sabin, Matthew A; Werther, George A; Kiess, Wieland

    2011-02-01

    Childhood overweight and obesity is highly prevalent within society. In the majority of individuals, weight gain is the result of exposure to an 'obesogenic' environment, superimposed on a background of genetic susceptibility brought about by evolutionary adaptation. These individuals tend to be tall in childhood with a normal final adult height, as opposed to those who have an underlying monogenic cause where short stature is more common (although not universal). Identifying genetic causes of weight gain, or tall stature and overgrowth, within this setting can be extremely problematic and yet it is imperative that clinicians remain alert, as identification of a genetic diagnosis has major implications for the individual, family and potential offspring. Alongside this, the recognition of new genetic mutations in this area is furthering our knowledge on the important mechanisms that regulate childhood growth and body composition. This review describes the genetic syndromes associated with obesity and overgrowth.

  14. Blau syndrome, clinical and genetic aspects.

    PubMed

    Sfriso, Paolo; Caso, Francesco; Tognon, Sofia; Galozzi, Paola; Gava, Alessandra; Punzi, Leonardo

    2012-11-01

    Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous recurrent uveitis, dermatitis and symmetric arthritis. The gene responsible for BS has been identified in the caspase recruitment domain gene CARD15/NOD2. In the majority of patients, the disease is characterized by early onset, usually before 3-4years of age. The manifestations at disease onset are usually represented by articular and cutaneous involvement signs, generally followed later by ocular manifestations which are often the most relevant morbidity of BS. In some cases the presence of fever is also observed; atypical cases of BS have been reported with cardiovascular, neurological, renal, intestinal and other organ involvement. The rarity and the variations in the severity and evolution of its expressions do not permit sufficient data about optimal treatment for patients with BS. The first step of therapy is represented by the use of corticosteroids and successively, in case of unsatisfactory response, by additional treatment with immunosuppressive agents. The results with biologic anti-cytokine agents, such as anti-TNFα and anti-IL1β, are different, particularly with regard to ocular morbidity. Clinical and genetic aspects of the familial and the sporadic form of BS will be discussed and focused on. A description of a case study of an Italian family is also included.

  15. [Uncommon acne-associated syndromes and their significance in understanding the pathogenesis of acne].

    PubMed

    Hong, J-B; Prucha, H; Melnik, B; Ziai, M; Ring, J; Chen, W

    2013-04-01

    Acne is an intriguing model for the study of interactions between hormones, innate immunity, inflammation and wound healing (scarring). The manifestations and involvement of acne in different systemic diseases and some rare syndromes demonstrate its multifaceted nature. Synovitis-Acne-Pustulosis-Hyperostosis-Osteitis (SAPHO) and Pyogenic Arthritis-Pyoderma gangrenosum-Acne (PAPA) syndromes, both regarded as autoinflammatory diseases, highlight the attributes of inflammation in acne. While SAPHO syndrome can be used to explore the pathogenic role of Propionibacterium acnes in acne, PAPA syndrome and Apert syndrome can help understand the genetic influence on acne. The genetic defects in the gain-of-function of FGFR2 mutations in Apert syndrome and acne nevus of Munro lend further support to the hypothesis that the interaction of forkhead box class O (FoxOs)-mediated transcriptional regulation with androgen receptor transactivation and insulin/insulin like growth factor-1(IGF-1)-signaling is crucial in acne pathogenesis. Novel biologics, such as tumor necrosis factor (TNF) blockers and IL-1 inhibitors, appear promising in opposing the inflammation associated with SAPHO and PAPA syndromes, but it remains to seen if they can also improve severe acne particularly in the long term.

  16. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

    PubMed Central

    Nelson-Williams, Carol; Stiegler, Amy L; Loring, Erin; Choi, Murim; Overton, John; Meffre, Eric; Khokha, Mustafa K; Huttner, Anita J; West, Brian; Podoltsev, Nikolai A; Boggon, Titus J; Kazmierczak, Barbara I; Lifton, Richard P

    2014-01-01

    Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs), whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multi-protein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever, and inflammatory cell death (pyroptosis)1,2. Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features3. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal/near-fatal episodes of autoinflammation caused by a de novo gain-of-function mutation (p.V341A) in the HD1 domain of NLRC4 that co-segregates with disease. Mutant NLRC4 causes constitutive Interleukin-1 family cytokine production and macrophage cell death. Infected patient macrophages are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings describe and reveal the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. PMID:25217960

  17. PFAPA syndrome and Behçet's disease: a comparison of two medical entities based on the clinical interviews performed by three different specialists.

    PubMed

    Cantarini, Luca; Vitale, Antonio; Bersani, Giulia; Nieves, Laura Martin; Cattalini, Marco; Lopalco, Giuseppe; Caso, Francesco; Costa, Luisa; Iannone, Florenzo; Lapadula, Giovanni; Galeazzi, Mauro; Ceribelli, Angela; Brunetta, Enrico; Selmi, Carlo; Rigante, Donato

    2016-02-01

    The pediatric syndrome characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and adult Behçet's disease share some clinical manifestations and are both polygenic autoinflammatory disorders with interleukin-1β showing to play a pivotal role. However, the diagnosis is mostly clinical and we hypothesize that specific criteria may be addressed differently by different physicians. To determine the diagnostic variability, we compared the answers of 80 patients with a definite diagnosis of Behçet's disease (age 42.1 ± 13.7 years) obtained by separate telephone interviews conducted by a rheumatologist, a pediatrician, and an internist working largely in the field of autoinflammatory disorders. Questions were related to the age of symptom onset, the occurrence of recurrent fevers during childhood, and the association with oral aphthosis, cervical adenitis and/or pharyngitis, previous treatments, possible growth impairment, the time lapse between PFAPA-like symptoms and the onset of Behçet's disease, and the occurrence of Behçet-related manifestation during childhood. The rheumatologist identified 30 % of patients with Behçet's disease fulfilling PFAPA syndrome diagnostic criteria, compared to the pediatrician and the internist identifying 10 and 7.5 %, respectively. Most of the patients suffered from recurrent oral aphthosis in childhood also without fever (50, 39, and 48 % with each interviewer), yet no patient fulfilled the Behçet's disease diagnostic criteria. Our data suggest that physician awareness and expertise are central to the diagnosis of autoinflammatory disorders through an accurate collection of the medical history.

  18. [Syndromes 2. Pfeiffer syndrome].

    PubMed

    Freihofer, H P

    1998-07-01

    Acrocephalosyndactylias are syndromes characterized by abnormalities of the head (craniosynostosis), the face (hypertelorism, retromaxillism), hands and feet (cutaneous or bony syndactyly). Inheritance is autosomal dominant, but spontaneous cases are described also. The group is divided into several syndromes with varying penetrance and expressivity. As an example of an acrocephalosyndactylia is the Pfeiffer syndrome presented.

  19. Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling.

    PubMed

    Potter, Christopher S; Wang, Zhe; Silva, Kathleen A; Kennedy, Victoria E; Stearns, Timothy M; Burzenski, Lisa; Shultz, Leonard D; Hogenesch, Harm; Sundberg, John P

    2014-01-01

    SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(-/-) mice, which lack mature B and T cells, were crossed with Sharpin(-/-) mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(-/-) mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(-/-) mice. Double homozygous Sharpin(-/-) , Il4ra(-/-) mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(-/-) , Il4ra(-/-) double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(-/-) , Il4ra(-/-) mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(-/-) mice and this was maintained in Sharpin(-/-) , Il4ra(-/-) mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling

  20. Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling

    PubMed Central

    Potter, Christopher S.; Wang, Zhe; Silva, Kathleen A.; Kennedy, Victoria E.; Stearns, Timothy M.; Burzenski, Lisa; Shultz, Leonard D.; HogenEsch, Harm; Sundberg, John P.

    2014-01-01

    SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1−/− mice, which lack mature B and T cells, were crossed with Sharpin−/− mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra−/− mice, unresponsive to both IL4 and IL13, were crossed with Sharpin−/− mice. Double homozygous Sharpin−/−, Il4ra−/− mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin−/−, Il4ra−/− double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin−/−, Il4ra−/− mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin−/− mice and this was maintained in Sharpin−/−, Il4ra−/− mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and

  1. Identifying Glucokinase Monogenic Diabetes in a Multiethnic Gestational Diabetes Mellitus Cohort: New Pregnancy Screening Criteria and Utility of HbA1c.

    PubMed

    Rudland, Victoria L; Hinchcliffe, Marcus; Pinner, Jason; Cole, Stuart; Mercorella, Belinda; Molyneaux, Lynda; Constantino, Maria; Yue, Dennis K; Ross, Glynis P; Wong, Jencia

    2016-01-01

    Glucokinase monogenic diabetes (GCK-maturity-onset diabetes of the young [MODY]) should be differentiated from gestational diabetes mellitus (GDM) because management differs. New pregnancy-specific screening criteria (NSC) have been proposed to identify women who warrant GCK genetic testing. We tested NSC and HbA1c in a multiethnic GDM cohort and examined projected referrals for GCK testing. Using a GDM database, 63 of 776 women had a postpartum oral glucose tolerance test suggestive of GCK-MODY. Of these 63 women, 31 agreed to undergo GCK testing. NSC accuracy and HbA1c were examined. Projected referrals were calculated by applying the NSC to a larger GDM database (n = 4,415). Four of 31 women were confirmed as having GCK-MODY (prevalence ∼0.5-1/100 with GDM). The NSC identified all Anglo-Celtic women but did not identify one Indian woman. The NSC will refer 6.1% of GDM cases for GCK testing, with more Asian/Indian women referred despite lower disease prevalence. Antepartum HbA1c was not higher in those with GCK-MODY. The NSC performed well in Anglo-Celtic women. Ethnic-specific criteria should be explored. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  2. Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls.

    PubMed

    Nordang, Gry B N; Busk, Øyvind L; Tveten, Kristian; Hanevik, Hans Ivar; Fell, Anne Kristin M; Hjelmesæth, Jøran; Holla, Øystein L; Hertel, Jens K

    2017-05-01

    Rare sequence variants in at least five genes are known to cause monogenic obesity. In this study we aimed to investigate the prevalence of, and characterize, rare coding and splice site variants in LEP, LEPR, MC4R, PCSK1 and POMC in patients with morbid obesity and normal weight controls. Targeted next-generation sequencing of all exons in LEP, LEPR, MC4R, PCSK1 and POMC was performed in 485 patients with morbid obesity and 327 normal weight population-based controls from Norway. In total 151 variants were detected. Twenty-eight (18.5%) of these were rare, coding or splice variants and five (3.3%) were novel. All individuals, except one control, were heterozygous for the 28 variants, and the distribution of the rare variants showed a significantly higher carrier frequency among cases than controls (9.9% vs. 4.9%, p=0.011). Four variants in MC4R were classified as pathogenic or likely pathogenic. Four cases (0.8%) of monogenic obesity were detected, all due to MC4R variants previously linked to monogenic obesity. Significant differences in carrier frequencies among patients with morbid obesity and normal weight controls suggest an association between heterozygous rare coding variants in these five genes and morbid obesity. However, additional studies in larger cohorts and functional testing of the novel variants identified are required to confirm the findings. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis

    PubMed Central

    2014-01-01

    Background Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. Methods To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Results Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/−) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Conclusions Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/− mice mirror some, but not all, of the perturbed molecular pathways in the brain. PMID:24564913

  4. Macrophage activation syndrome triggered by coeliac disease: a unique case report.

    PubMed

    Palman, J; May, J; Pilkington, C

    2016-12-09

    Macrophage activation syndrome is described as a "clinical syndrome of hyperinflammation resulting in an uncontrolled and ineffective immune response" in the context of an autoinflammatory or rheumatic disease. Current associations of macrophage activation syndrome with autoimmune disease most notably include a host of rheumatological conditions and inflammatory bowel disease. Epidemiological studies have shown that macrophage activation syndrome is precipitated by autoimmune disease more commonly than previously thought. Diagnosing the precipitating factor is essential for effective treatment and prognosis. We report a case of a six year old girl with coeliac disease diagnosed after two episodes of secondary haemophagocytic lymphohistiocytosis. Her condition only responded to treatment once the patient was placed on a gluten free diet. Further immunological testing confirmed anti-transglutaminase and anti-endomysial antibodies, however histological biopsy was deemed inappropriate due to the severity of her condition. She has remained stable with no further episodes of macrophage activation syndrome since commencing a gluten free diet. This case report is the first literature that links macrophage activation syndrome to coeliac disease and highlights the challenge of diagnosing coeliac disease with unusual features such as associated prolonged fever. Clinicians should have a low threshold for screening children with other autoimmune diseases for coeliac disease.

  5. Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey

    PubMed Central

    2010-01-01

    Objective To analyze the prevalence of diagnosed and suspected autoinflammatory diseases in Eastern and Central European (ECE) countries, with a particular interest on the diagnostic facilities in these countries. Methods Two different strategies were used to collect data on patients with periodic fever syndromes from ECE countries- the Eurofever survey and collection of data with the structured questionnaire. Results Data from 35 centers in 14 ECE countries were collected. All together there were 11 patients reported with genetically confirmed familial Mediterranean fever (FMF), 14 with mevalonate-kinase deficiency (MKD), 11 with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and 4 with chronic infantile neurological cutaneous and articular syndrome (CINCA). Significantly higher numbers were reported for suspected cases which were not genetically tested. All together there were 49 suspected FMF patients reported, 24 MKD, 16 TRAPS, 7 CINCA and 2 suspected Muckle-Wells syndrome (MWS) patients. Conclusions The number of genetically confirmed patients with periodic fever syndromes in ECE countries is very low. In order to identify more patients in the future, it is important to organize educational programs for increasing the knowledge on these diseases and to establish a network for genetic testing of periodic fever syndromes in ECE countries. PMID:21539753

  6. Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers.

    PubMed

    Cantarini, Luca; Vitale, Antonio; Bartolomei, Beatrice; Galeazzi, Mauro; Rigante, Donato

    2012-01-01

    The pathophysiology of PFAPA syndrome, mainly characterised by regularly recurring periodic fevers associated with aphthous stomatitis, pharyngitis and/or lymphadenitis, and mostly occurring in the paediatric setting, resembles an acquired autoinflammatory disease. The description of PFAPA syndrome in adult patients is largely increasing. To recognise PFAPA syndrome in a group of adult patients evaluated for recurrent fevers in our Rheumatology Unit. To apply current diagnostic criteria for PFAPA syndrome in a group of 359 adults with unexplained recurrent fevers monitored in our Unit between January 2007 and June 2011. We have found 17 out of 359 patients fulfilling the diagnosis of PFAPA syndrome: these patients (10 males, 7 females) were Caucasian with a mean age of 33.3±9.5 years, had recurrent febrile episodes begun at a mean age of 25.9±8.3 years and a mean number of episodes of 8.3±5.2 per year with a mean duration of 5.5±1.8 days. In particular, 7/17 patients had the 3 cardinal signs, the other 10 had a combination of 2 signs. Corticosteroids were given in 14/17 patients; tonsillectomy was performed in 9/17 patients: corticosteroid responsiveness and tonsillectomy efficacy were observed respectively in 11 and 2 patients. Our case highlights the importance of considering PFAPA syndrome in adults presenting with unexplained recurrent fevers and symptoms commonly encountered in general medical practice.

  7. Different presentations in patients with tumor necrosis factor receptor-associated periodic syndrome mutations: report of two cases.

    PubMed

    Celebi-Tayfur, Aslı; Bilginer, Yelda; Finetti, Martina; Gattorno, Marco; Ozen, Seza

    2013-01-01

    Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene encoding the 55-kDa receptor for tumor necrosis factor (TNF)-α. It is characterized by recurrent prolonged episodes of fever accompanied by abdominal pain, pleuritis, migratory skin rashes, fasciitis, headache, conjunctivitis, and periorbital edema. We report two children, one with a severe mutation in the TNFRSF1A gene causing the typical phenotype. The second patient had a homozygous R92Q-type mutation and displayed a periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome-like phenotype. In the eastern Mediterranean region, TRAPS is probably underdiagnosed because of the overwhelming frequency of familial Mediterranean fever (FMF). However, TRAPS should be sought for in patients with atypical symptoms for FMF.

  8. Alport syndrome: impact of digenic inheritance in patients management.

    PubMed

    Fallerini, C; Baldassarri, M; Trevisson, E; Morbidoni, V; La Manna, A; Lazzarin, R; Pasini, A; Barbano, G; Pinciaroli, A R; Garosi, G; Frullanti, E; Pinto, A M; Mencarelli, M A; Mari, F; Renieri, A; Ariani, F

    2016-11-08

    Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members.

  9. Does attention constrain developmental trajectories in fragile x syndrome? A 3-year prospective longitudinal study.

    PubMed

    Cornish, Kim; Cole, Victoria; Longhi, Elena; Karmiloff-Smith, Annette; Scerif, Gaia

    2012-03-01

    Basic attentional processes and their impact on developmental trajectories in fragile X syndrome were assessed in a 3-year prospective study. Although fragile X syndrome is a monogenic X-linked disorder, there is striking variability in outcomes even in young boys with the condition. Attention is a key factor constraining interactions with the environment, so it is a perfect candidate to predict trajectories in cognitive and behavioral outcomes. In this study, 48 boys with fragile X syndrome were assessed 3 times over 24 months. Although nonverbal IQ declined, there were significant improvements in nonverbal growth scores and in cognitive attention. In contrast, behavioral difficulties (i.e., autistic symptomatology, hyperactivity-inattention) remained stable over this time frame. Attentional markers in the visual and auditory modalities predicted intellectual abilities and classroom behavior, whereas auditory markers alone predicted autistic symptomatology.

  10. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic Diabetes in Pregnancy cohort.

    PubMed

    Chakera, Ali J; Spyer, Gill; Vincent, Nicola; Ellard, Sian; Hattersley, Andrew T; Dunne, Fidelma P

    2014-01-01

    Identifying glucokinase monogenic diabetes (GCK-MODY) in pregnancy is important, as management is different from management for other forms of gestational diabetes mellitus (GDM) and there is no increased maternal risk of type 2 diabetes. We calculated the population prevalence of GCK-MODY in pregnancy and determined the clinical characteristics that differentiate pregnant women with GCK-MODY from those with GDM. We calculated the population prevalence of GCK-MODY in pregnancy by testing a subset of patients from the population-based Atlantic Diabetes in Pregnancy (Atlantic DIP) study (n = 5,500). We sequenced for GCK mutations in 247 women with a fasting glucose ≥5.1 mmol/L and 109 randomly selected control subjects with normal fasting glucose. Using data from the cases found and 40 previously identified GCK-MODY pregnancies, we analyzed whether clinical criteria could be used to differentiate GCK-MODY from GDM. Four women with fasting glucose ≥5.1 mmol/L were diagnosed with GCK-MODY. No cases were identified with normal fasting glucose. The population prevalence of GCK-MODY is 1.1 in 1,000 (95% CI 0.3-2.9 in 1,000) and prevalence in GDM is 0.9% (95% CI 0.3-2.3). Fasting glucose and BMI significantly differentiate GCK-MODY from GDM (P < 0.0001). Combined criteria of BMI <25 kg/m(2) and fasting glucose ≥5.5 mmol/L has a sensitivity 68%, specificity 96%, and number needed to test of 2.7 women with GDM to find one case of GCK-MODY. Our large population cohort of pregnant women tested estimates the population prevalence of GCK-MODY of 1.1 in 1,000. We have shown routine clinical criteria that can identify which women should be tested for GCK-MODY in pregnancy.

  11. Clinical genetic testing of periodic fever syndromes.

    PubMed

    Marcuzzi, Annalisa; Piscianz, Elisa; Kleiner, Giulio; Tommasini, Alberto; Severini, Giovanni Maria; Monasta, Lorenzo; Crovella, Sergio

    2013-01-01

    Periodic fever syndromes (PFSs) are a wide group of autoinflammatory diseases. Due to some clinical overlap between different PFSs, differential diagnosis can be a difficult challenge. Nowadays, there are no universally agreed recommendations for most PFSs, and near half of patients may remain without a genetic diagnosis even after performing multiple-gene analyses. Molecular analysis of periodic fevers' causative genes can improve patient quality of life by providing early and accurate diagnosis and allowing the administration of appropriate treatment. In this paper we focus our discussion on effective usefulness of genetic diagnosis of PFSs. The aim of this paper is to establish how much can the diagnostic system improve, in order to increase the success of PFS diagnosis. The mayor expectation in the near future will be addressed to the so-called next generation sequencing approach. Although the application of bioinformatics to high-throughput genetic analysis could allow the identification of complex genotypes, the complexity of this definition will hardly result in a clear contribution for the physician. In our opinion, however, to obtain the best from this new development a rule should always be kept well in mind: use genetics only to answer specific clinical questions.

  12. Clinical Genetic Testing of Periodic Fever Syndromes

    PubMed Central

    Marcuzzi, Annalisa; Piscianz, Elisa; Kleiner, Giulio; Tommasini, Alberto; Severini, Giovanni Maria; Monasta, Lorenzo; Crovella, Sergio

    2013-01-01

    Periodic fever syndromes (PFSs) are a wide group of autoinflammatory diseases. Due to some clinical overlap between different PFSs, differential diagnosis can be a difficult challenge. Nowadays, there are no universally agreed recommendations for most PFSs, and near half of patients may remain without a genetic diagnosis even after performing multiple-gene analyses. Molecular analysis of periodic fevers' causative genes can improve patient quality of life by providing early and accurate diagnosis and allowing the administration of appropriate treatment. In this paper we focus our discussion on effective usefulness of genetic diagnosis of PFSs. The aim of this paper is to establish how much can the diagnostic system improve, in order to increase the success of PFS diagnosis. The mayor expectation in the near future will be addressed to the so-called next generation sequencing approach. Although the application of bioinformatics to high-throughput genetic analysis could allow the identification of complex genotypes, the complexity of this definition will hardly result in a clear contribution for the physician. In our opinion, however, to obtain the best from this new development a rule should always be kept well in mind: use genetics only to answer specific clinical questions. PMID:23484126

  13. Anti-interleukin 6 receptor therapy for hyper-IgD syndrome.

    PubMed

    Musters, Anne; Tak, Paul Peter; Baeten, Dominique L P; Tas, Sander W

    2015-10-29

    Hyper-IgD syndrome (HIDS) is a rare, severe hereditary autoinflammatory disease characterised by periodic fevers, elevated serum IgD levels and a wide range of symptoms. Although a few randomised controlled trials have been performed in this disorder, there are no straightforward treatment protocols and none of the potential therapies are registered for this indication. We report a case of a young woman with severe HIDS who failed numerous therapies. Eventually, rational treatment with a monoclonal anti-interleukin 6 receptor antibody was initiated. This therapy resulted in an impressive clinical improvement and reduction in the number of hospital admissions per year. This case report underlines the difficulty of finding a suitable treatment for rare, severe inflammatory diseases. Furthermore, we show that treating patients with targeted therapies may result in clinical benefit for the patient, as well as simultaneously teach us more about the pathophysiology of these rare, relatively understudied diseases.

  14. Identification of a homozygous PSTPIP1 mutation in a patient with a PAPA-like syndrome responding to canakinumab treatment.

    PubMed

    Geusau, Alexandra; Mothes-Luksch, Nadine; Nahavandi, Hesam; Pickl, Winfried F; Wise, Carol A; Pourpak, Zahra; Ponweiser, Elisabeth; Eckhart, Leopold; Sunder-Plassmann, Raute

    2013-02-01

    Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (OMIM 604416) is a rare autosomal dominant inherited autoinflammatory syndrome characterized by pyogenic sterile arthritis and less frequently accompanied by pyoderma gangrenosum and acne. It is associated with dominant missense mutations in the proline-serine-threonine phosphatase-interacting protein 1 gene (PSTPIP1) located on chromosome 15. The patient was diagnosed as having features of a PAPA-like syndrome in which cutaneous manifestations, such as pyoderma gangrenosum and acne fulminans, predominated. Sequencing of the PSTPIP1 gene was performed in the patient and his extended family. The patient's DNA analysis revealed a homozygous nucleotide exchange c.773G>C in the PSTPIP1 gene, leading to the substitution of glycine 258 by alanine (p.Gly258Ala), a previously reported heterozygous polymorphism. Heterozygous changes were identified in both of the patient's parents and in 7 other family members, all of whom were asymptomatic. The patient was treated with canakinumab, a human anti-interleukin 1β monoclonal antibody, which led to rapid remission of the symptoms. To our knowledge, this is the first reported case of the resolution of dermatological symptoms associated with a PAPA-like syndrome using canakinumab treatment. Further study of the p.Gly258Ala variant is warranted to determine whether this mutation has a role in causing an apparently recessive cutaneous syndrome resembling PAPA syndrome.

  15. Williams syndrome

    MedlinePlus

    ... with Williams syndrome may show: A flattened nasal bridge with small upturned nose Long ridges in the ... Alternative Names Williams-Beuren syndrome Images Low nasal bridge References Morris CA. Williams syndrome. In: Pagon RA, ...

  16. Marfan Syndrome

    MedlinePlus

    Marfan syndrome is a disorder that affects connective tissue. Connective tissues are proteins that support skin, bones, blood ... fibrillin. A problem with the fibrillin gene causes Marfan syndrome. Marfan syndrome can be mild to severe, and ...

  17. Sjogren's Syndrome

    MedlinePlus

    Sjogren's syndrome Overview By Mayo Clinic Staff Sjogren's (SHOW-grins) syndrome is a disorder of your immune system ... disorders, such as rheumatoid arthritis and lupus. In Sjogren's syndrome, the mucous membranes and moisture-secreting glands of ...

  18. Mapping genetic modifiers of survival in a mouse model of Dravet syndrome

    PubMed Central

    Miller, Alison R.; Hawkins, Nicole A.; McCollom, Clint E.; Kearney, Jennifer A.

    2014-01-01

    Epilepsy is a common neurological disorder affecting approximately 1% of the population. Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes. More than 800 mutations in the voltage-gated sodium channel SCN1A have been reported in patients with generalized epilepsy with febrile seizures plus and Dravet syndrome. Heterozygous loss-of-function mutations in SCN1A result in Dravet syndrome, a severe infant-onset epileptic encephalopathy characterized by intractable seizures, developmental delays and increased mortality. A common feature of monogenic epilepsies is variable expressivity among individuals with the same mutation, suggesting that genetic modifiers may influence clinical severity. Mice with heterozygous deletion of Scn1a (Scn1a+/−) model a number of Dravet syndrome features, including spontaneous seizures and premature lethality. Phenotype severity in Scn1a+/− mice is strongly dependent on strain background. On the 129S6/SvEvTac strain Scn1a+/− mice exhibit no overt phenotype, while on the (C57BL/6J × 129S6/SvEvTac)F1 strain Scn1a+/− mice exhibit spontaneous seizures and early lethality. To systematically identify loci that influence premature lethality in Scn1a+/− mice, we performed genome scans on reciprocal backcrosses. QTL mapping revealed modifier loci on mouse chromosomes 5, 7, 8 and 11. RNA-seq analysis of strain-dependent gene expression, regulation and coding sequence variation provided a list of potential functional candidate genes at each locus. Identification of modifier genes that influence survival in Scn1a+/− mice will improve our understanding of the pathophysiology of Dravet syndrome and may suggest novel therapeutic strategies for improved treatment of human patients. PMID:24152123

  19. Rett Syndrome: Crossing the Threshold to Clinical Translation

    PubMed Central

    Katz, David M.; Bird, Adrian; Coenraads, Monica; Gray, Steven J.; Menon, Debashish U.; Philpot, Benjamin D.; Tarquinio, Daniel C.

    2016-01-01

    Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders. PMID:26830113

  20. Rett Syndrome: Crossing the Threshold to Clinical Translation.

    PubMed

    Katz, David M; Bird, Adrian; Coenraads, Monica; Gray, Steven J; Menon, Debashish U; Philpot, Benjamin D; Tarquinio, Daniel C

    2016-02-01

    Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders.

  1. Cushing's Syndrome

    MedlinePlus

    ... example, polycystic ovary syndrome can cause menstrual disturbances, weight gain beginning in adolescence, excess hair growth, and impaired insulin action and diabetes. Metabolic syndrome-a combination of ...

  2. PAPA, PASH and PAPASH Syndromes: Pathophysiology, Presentation and Treatment.

    PubMed

    Cugno, Massimo; Borghi, Alessandro; Marzano, Angelo V

    2017-08-01

    Pyoderma gangrenosum (PG) is a neutrophilic dermatosis usually manifesting as skin ulcers with undermined erythematous-violaceous borders. It may be isolated, associated with systemic conditions or occurring in the context of autoinflammatory syndromes such as PAPA (pyogenic arthritis, PG and acne), PASH (PG, acne and suppurative hidradenitis) or PAPASH (pyogenic arthritis, acne, PG and suppurative hidradenitis). From a physiopathological point of view, all these conditions share common mechanisms consisting of over-activation of the innate immune system leading to increased production of the interleukin (IL)-1 family and 'sterile' neutrophil-rich cutaneous inflammation. From a genetic point of view, a number of mutations affecting the proteins of the inflammasome complex (the molecular platform responsible for triggering autoinflammation) or the proteins that regulate inflammasome function have been described in these disorders. As these debilitating entities are all associated with the over-expression of IL-1 and tumour necrosis factor (TNF)-α, biological drugs specifically targeting these cytokines are currently the most effective treatments but, given the emerging role of IL-17 in the pathogenesis of these syndromes, IL-17 antagonists may represent the future management of these conditions.

  3. The most common genetic syndromes and associated anomalies in Latvian patients with cleft lip with or without palate.

    PubMed

    Lace, Baiba; Barkane, Biruta; Akota, Ilze

    2006-01-01

    1 over 700 newborns every year is born with cleft lip with/or without palate, in 30% of cases there is a certain genetic mechanism underlying development of disease: chromosomal anomalies, monogenic diseases, exposure to teratogens or in utero disruptive mechanisms. The objective of our study is to describe the most common genetic syndromes and associated anomalies in patients with CL/CP in Latvia. Study material was medical records obtained from Riga Cleft Lip and Palate Centre Registry in a time period of 1980 till 2005. There was analyzed information about patients with identified genetic syndromes and associated anomalies. In a time period from 1980 till 2005, the following genetic syndromes were identified: Van der Woude, Fetal alcohol syndrome, Holzgreve syndrome, Marfan syndrome, Myotonic dystrophy, Klippel-Feil syndrome, Patau syndrome, Potter sequence and Pierre Robin sequence. 16% of CL/CP patients have recognized genetic syndromes or associated anomalies, including profound, severe and moderate mental retardation. Number is lower than expected, but still correlates with date presented in other populations. Long term follow-up of multidisciplinary specialists which includes cardiologists, clinical-geneticists and paediatricians, is needed for CL/CP patients with associated anomalies in order to identify timely side diseases and complications. Grant: Baltic-Taiwan joint research project "Identification of genes involved in craniofacial morphogenesis and susceptibility to orofacial clefting in a human genome scan 2004-2006".

  4. KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

    PubMed Central

    Gee, Heon Yung; Zhang, Fujian; Ashraf, Shazia; Kohl, Stefan; Sadowski, Carolin E.; Vega-Warner, Virginia; Zhou, Weibin; Lovric, Svjetlana; Fang, Humphrey; Nettleton, Margaret; Zhu, Jun-yi; Hoefele, Julia; Weber, Lutz T.; Podracka, Ludmila; Boor, Andrej; Fehrenbach, Henry; Innis, Jeffrey W.; Washburn, Joseph; Levy, Shawn; Lifton, Richard P.; Otto, Edgar A.; Han, Zhe; Hildebrandt, Friedhelm

    2015-01-01

    Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTP-bound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling. PMID:25961457

  5. Evolving Frontiers in the Treatment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis (PFAPA) Syndrome.

    PubMed

    Rigante, Donato; Gentileschi, Stefano; Vitale, Antonio; Tarantino, Giusyda; Cantarini, Luca

    2017-07-01

    Fevers recurring at a nearly predictable rate every 3-8 weeks are the signature symptom of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome, an acquired autoinflammatory disorder which recurs in association with at least one sign among aphthous stomatitis, pharyngitis, and/or cervical lymph node enlargement without clinical signs related to upper respiratory airways or other localized infections. The disease usually has a rather benign course, although it might relapse during adulthood after a spontaneous or treatment-induced resolution in childhood. The number of treatment choices currently available for PFAPA syndrome has grown in recent years, but data from clinical trials dedicated to this disorder are limited to small cohorts of patients or single case reports. The response of PFAPA patients to a single dose of corticosteroids is usually striking, while little data exist for treatment with cimetidine and colchicine. Preliminary interesting results have been published with regard to vitamin D supplementation in PFAPA syndrome, while inhibition of interleukin-1 might represent an intriguing treatment for PFAPA patients who have not responded to standard therapies. Tonsillectomy has been proven curative in many studies related to PFAPA syndrome, although the evidence of its efficacy is not widely shared by different specialists, including pediatricians, rheumatologists and otorhynolaryngologists.

  6. Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period.

    PubMed

    Stoevesandt, Johanna; Morbach, Henner; Martin, Tammy M; Zierhut, Manfred; Girschick, Hermann; Hamm, Henning

    2010-01-01

    Blau syndrome is a dominantly inherited, chronic autoinflammatory disorder characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis with onset below 4 years of age. It is caused by activating mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene, previously referred to as CARD15 gene. Noncaseating granulomas in affected tissues are the pathologic hallmark of the condition. We report the lifelong severe disease course in a 14-year-old Caucasian boy with sporadic Blau syndrome. Unusually, granulomatous dermatitis started in the first week of life. Whereas skin involvement faded away spontaneously in subsequent years, polyarthritis and anterior uveitis appeared in the second and third year of life respectively. Mutational analysis of the NOD2 gene revealed a missense mutation (R334W) previously detected in other Blau syndrome pedigrees. With this report, we would like to stress the rare possibility of Blau syndrome in generalized papular rashes of infancy and the importance of histopathologic study for clarification. The finding of early-onset widespread granulomatous dermatitis should prompt eye and joint examination in regular intervals and entail mutational analysis of the NOD2 gene.

  7. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome)

    PubMed Central

    Ferguson, P; Chen, S; Tayeh, M; Ochoa, L; Leal, S; Pelet, A; Munnich, A; Lyonnet, S; Majeed, H; El-Shanti, H

    2005-01-01

    Background: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. Methods: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. Results: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. Conclusions: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis. PMID:15994876

  8. Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

    PubMed Central

    Casper, Catharina; Kalliolia, Eirini; Warner, Thomas T

    2013-01-01

    The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias. PMID:23814535

  9. A new infant case of Nakajo-Nishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations.

    PubMed

    Kunimoto, Kayo; Kimura, Ayako; Uede, Koji; Okuda, Masumi; Aoyagi, Noriyuki; Furukawa, Fukumi; Kanazawa, Nobuo

    2013-01-01

    Nakajo-Nishimura syndrome (NNS) is a very rare hereditary autoinflammatory disorder that generally has its onset in infancy with pernio-like rashes and gradually develops into partial lipodystrophy. A distinct homozygous PSMB8 mutation encoding an immunoproteasome subunit has recently been identified as its genetic cause. Here, we report a new case of a patient with NNS who developed exudative erythemas on his face and extremities at 2 months of age, along with high fever, elevated serum hepatic aminotransferase levels and hepatosplenomegaly. Massive infiltration of inflammatory cells was observed histologically in the dermis and subcutis without apparent leukocytoclastic vasculitis. These symptoms improved with oral corticosteroids but recurred periodically, and a thin angular face with long clubbed fingers gradually developed. Identification of the PSMB8 mutation finalized the diagnosis of NNS at 5 years of age. Understanding a variety of clinicopathological features at the developmental stages is necessary to make an early diagnosis of NNS.

  10. Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).

    PubMed

    Demidowich, Andrew P; Freeman, Alexandra F; Kuhns, Douglas B; Aksentijevich, Ivona; Gallin, John I; Turner, Maria L; Kastner, Daniel L; Holland, Steven M

    2012-06-01

    To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment. This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome. Copyright © 2012 by the American College of Rheumatology.

  11. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS)

    PubMed Central

    2011-01-01

    Introduction Cryopyrin-associated periodic syndrome (CAPS) represents a spectrum of three auto-inflammatory syndromes, familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA) with etiology linked to mutations in the NLRP3 gene resulting in elevated interleukin-1β (IL-1β) release. CAPS is a rare hereditary auto-inflammatory disease, which may start early in childhood and requires a life-long treatment. Canakinumab, a fully human anti-IL-1β antibody, produces sustained selective inhibition of IL-1β. This study was conducted to assess the efficacy, safety, and pharmacokinetics of canakinumab in the treatment of pediatric CAPS patients. Methods Seven pediatric patients (five children and two adolescents) with CAPS were enrolled in a phase II, open-label study of canakinumab in patients with CAPS. Canakinumab was administered at a dose of 2 mg/kg subcutaneously (s.c.) (for patients with body weight ≤ 40 kg) or 150 mg s.c. (for patients with body weight > 40 kg) with re-dosing upon each relapse. The primary efficacy variable was time to relapse following achievement of a complete response (defined as a global assessment of no or minimal disease activity and no or minimal rash and values for serum C-reactive protein (CRP) and/or serum amyloid A (SAA) within the normal range, < 10 mg/L). Results All patients achieved a complete response within seven days after the first dose of canakinumab and responses were reinduced on retreatment following relapse. Improvements in symptoms were evident within 24 hours after the first dose, according to physician assessments. The estimated median time to relapse was 49 days (95% CI 29 to 68) in children who received a dose of 2 mg/kg. Canakinumab was well tolerated. One serious adverse event, vertigo, was reported, but resolved during treatment. Conclusions Canakinumab, 2 mg/kg or

  12. Microdeletions involving chromosomes 12 and 22 associated with syndromic Duane retraction syndrome.

    PubMed

    Abu-Amero, Khaled K; Kondkar, Altaf A; Oystreck, Darren T; Khan, Arif O; Bosley, Thomas M

    2014-09-01

    Duane retraction syndrome (DRS) is the most common of the congenital cranial dysinnervation disorders (CCDDs). CCDDs can be monogenic or chromosomal in origin. Identification of the genetic cause(s) in patients and families with DRS facilitates definitive diagnosis and provides insights into these developmental errors. This study described a young girl with DRS on the left and several additional developmental abnormalities. Clinical examination including neuroimaging, sequencing of candidate genes associated with DRS, and array comparative genomic hybridization (array CGH) were performed. The proband had unilateral DRS type 3 on the left with somewhat low-set ears, mild motor delay with normal intelligence, and an asymmetric neck without a palpable right sternocleidomastoid muscle. Spine X-rays revealed a Klippel-Feil syndrome (KFS) and an MRI showed a webbed neck. She also had spina bifida at C8-T1 and a submucosal cleft palate. The parents of the proband were related with no other family member affected similarly. Sequencing of SALL4, CHN1, HOXA1, and TUBB3 did not show any mutation. Array CGH revealed de novo deletions of 21 Kb on chromosome 12q24.31 and 11 Kb on chromosome 22q13.31, each encompassing only one gene, ring finger protein 34, E3 ubiquitin protein ligase (RNF34) and peroxisome proliferator-activated receptor alpha (PPARA) respectively. This patient presents an unusual phenotype associated with a unique combination of two chromosomal microdeletions.

  13. Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (pfapa) syndrome in children.

    PubMed

    Semianchuk, Vira B

    Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome refers to a group of primary immunodeficiencies, namely autoinflammatory diseases. Most pediatricians and otolaryngologists do not suspect PFAPA syndrome when treating recurrent pharyngitis (according to Ukrainian classification - tonsillitis) and stomatitis. Therefore, patients with a given syndrome receive unnecessary treatment (antibiotic therapy or antiviral drugs) and the diagnosis is made late. The aim of the research was to provide pediatricians, family physicians and otolaryngologists with information on the importance of early diagnosis of PFAPA syndrome. The analysis of the prevalence and diagnosis of PFAPA syndrome in Ukraine and worldwide has been made as well as a late diagnosis of PFAPA syndrome in a child living in Ivano-Frankivsk, Ukraine has been described (case report). The Сase report 7-year-old boy, who grows and develops normally. The symptoms of pharyngitis including high body temperature (>40 º С), sore throat and white spots on the tonsils appeared for the first time at the age of two years. The boy received antibacterial drugs about 10 times a year. During a four-year period of recurrent episodes of the disease antimicrobial susceptibility testing to determine susceptibility of the oropharyngeal flora to the antibiotics were continuously performed, different blood tests for herpes viruses, Epstein-Barr virus infection and cytomegalovirus in particular were made using the enzyme immunoassay (EIA) and polymerase chain reaction (PCR) in addition to long-term treatment. An example of late diagnosing PFAPA syndrome (four years after the onset of first symptoms) resulting in regular examinations, medical manoeuvres, outpatient and inpatient treatment, use of antibiotic therapy including intravenous injections on a monthly basis has been studied.

  14. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome.

    PubMed

    Rand-Hendriksen, Svend; Tjeldhorn, Lena; Lundby, Rigmor; Semb, Svein Ove; Offstad, Jon; Andersen, Kai; Geiran, Odd; Paus, Benedicte

    2007-09-01

    In monogenic disorders, correlation between genotype and phenotype is a premise for predicting prognosis in affected patients. Predictive genetic testing may enable prophylaxis and promote clinical follow-up. Although Marfan syndrome (MFS) is known as a monogenic disorder, according to the present diagnostic criteria a mutation in the gene FBN1 is not sufficient for the diagnosis, which also depends on the presence of a number of clinical, radiological, and other findings. The fact that MFS patient cohorts only infrequently have been examined for all relevant phenotypic manifestations may have contributed to inconsistent reports of genotype-phenotype correlations. In the Norwegian Study of Marfan syndrome, all participants were examined for all findings contained in the Ghent nosology by the same investigators. Mutation identification was carried out by robot-assisted direct sequencing of the entire FBN1 coding sequence and MLPA analysis. A total of 46 mutations were identified in 44 unrelated patients, all fulfilling Ghent criteria. Although no statistically significant correlation could be obtained, the data indicate associations between missense or splice site mutations and ocular manifestations. While mutations in TGF-domains were associated with the fulfillment of few major criteria, severe affection was indicated in two cases with C-terminal mutations. Intrafamilial phenotypic variation among carriers of the same mutation, suggesting the influence of epigenetic facors, complicates genetic counseling. The usefulness of predictive genetic testing in FBN1 mutations requires further investigation. Copyright 2007 Wiley-Liss, Inc.

  15. Fragile X syndrome: From protein function to therapy.

    PubMed

    Bagni, Claudia; Oostra, Ben A

    2013-11-01

    Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism. The FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The disease is a result of lack of expression of the fragile X mental retardation protein leading to severe symptoms, including intellectual disability, hyperactivity, and autistic-like behavior. The FMR1 protein (FMRP) has a number of functions. The translational dysregulation of a subset of mRNAs targeted by FMRP is probably the major contribution to FXS. FMRP is also involved in mRNA transport to synapses where protein synthesis occurs. For some FMRP-bound mRNAs, FMRP is a direct modulator of mRNA stability either by sustaining or preventing mRNA decay. Increased knowledge about the role of FMRP has led to the identification of potential treatments for fragile X syndrome that were often tested first in the different animal models. This review gives an overview about the present knowledge of the function of FMRP and the therapeutic strategies in mouse and man.

  16. Alström Syndrome: Mutation spectrum of ALMS1

    PubMed Central

    Marshall, Jan D.; Muller, Jean; Collin, Gayle B.; Milan, Gabriella; Kingsmore, Stephen F.; Dinwiddie, Darrell; Farrow, Emily G.; Miller, Neil A.; Favaretto, Francesca; Maffei, Pietro; Dollfus, Hélène; Vettor, Roberto; Naggert, Jürgen K.

    2015-01-01

    Alström Syndrome, a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multi-system involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of Alström Syndrome. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with Alström Syndrome, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date. PMID:25846608

  17. Etanercept-Induced Myelopathy in a Pediatric Case of Blau Syndrome

    PubMed Central

    Caracseghi, Fabiola; Izquierdo-Blasco, Jaume; Sanchez-Montanez, Angel; Melendo-Perez, Susana; Roig-Quilis, Manuel; Modesto, Consuelo

    2011-01-01

    Blau syndrome is a rare autoinflammatory disorder within the group of pediatric granulomatous diseases. Mutations in nucleotide-binding oligomerization domain 2 (NOD2/CARD15) are responsible for this condition, which has an autosomal dominant pattern of inheritance and variable expressivity. The clinical picture includes arthritis, uveitis, skin rash, and granulomatous inflammation. Central nervous system involvement is seldom reported, although some isolated cases of seizures, neurosensorial hearing loss, and transient cranial nerve palsy have been described. Treatment consists of nonsteroidal anti-inflammatory drugs, corticosteroids, and immunosuppressive agents, among which anti-tumor-necrosis-factor-alpha (TNF-α) biologic agents, such as etanercept, play an important role. Among the major adverse effects of TNF-α inhibitors, demyelinating disease, multiple sclerosis, and acute transverse myelitis have been reported in adults. We describe a case of pediatric Blau syndrome affected by etanercept-induced myelopathy, manifesting as a clinical syndrome of transverse myelitis. The patient experienced rapid recovery after etanercept was discontinued. To our knowledge, this is the first such case reported in the literature and, possibly, the one with the latest onset, following 8 years of treatment. We discuss the etiopathogenic mechanisms of this reaction and possible explanations for the imaging findings. PMID:22937436

  18. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet Syndrome treatment

    PubMed Central

    Baraban, Scott C.; Dinday, Matthew T.; Hortopan, Gabriela A.

    2013-01-01

    Dravet syndrome (DS) is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Nav1.1 (SCN1A), a voltage-gated sodium channel. Here we characterise zebrafish Nav1.1 (scn1Lab) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviors. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (~3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviors and electrographic seizures. This approach represents a new direction in modeling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder. PMID:24002024

  19. Metabolic syndrome

    MedlinePlus

    Insulin resistance syndrome; Syndrome X ... middle and upper parts of the body (central obesity ). This body type may be described as "apple-shaped." Insulin resistance. Insulin is a hormone produced in the pancreas. ...

  20. Marfan Syndrome

    MedlinePlus

    ... Like for Kids With Marfan Syndrome? en español Síndrome de Marfan Evan couldn't wait for school ... for Marfan syndrome runs in families, getting passed down to children from parents who have the disease. ...

  1. Dumping Syndrome

    MedlinePlus

    ... Syndrome Related Topics Section Navigation Digestive Diseases Abdominal Adhesions Acid Reflux (GER & GERD) in Adults Definition & Facts ... Eating, Diet, & Nutrition Clinical Trials Cyclic Vomiting Syndrome Dental Enamel Defects and Celiac Disease Dermatitis Herpetiformis Dermatitis ...

  2. Aicardi Syndrome

    MedlinePlus

    ... Girls with Aicardi syndrome have varying degrees of intellectual disability and developmental delay. Many girls also have developmental ... Girls with Aicardi syndrome have varying degrees of intellectual disability and developmental delay. Many girls also have developmental ...

  3. Malabsorption Syndromes

    MedlinePlus

    ... the foods you eat. If you have a malabsorption syndrome, your small intestine cannot absorb nutrients from foods. Causes of malabsorption syndromes include Celiac disease Lactose intolerance Short bowel ...

  4. Rett Syndrome

    MedlinePlus

    Rett syndrome is a rare genetic disease that causes developmental and nervous system problems, mostly in girls. It's related to autism spectrum disorder. Babies with Rett syndrome seem to grow and develop normally at first. ...

  5. Horner syndrome

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000708.htm Horner syndrome To use the sharing features on this page, please enable JavaScript. Horner syndrome is a rare condition that affects the nerves ...

  6. Marfan Syndrome

    MedlinePlus

    ... Like for Kids With Marfan Syndrome? en español Síndrome de Marfan Evan couldn't wait for school ... for Marfan syndrome runs in families, getting passed down to children from parents who have the disease. ...

  7. Down Syndrome

    MedlinePlus

    ... cells is caused by abnormal cell division after fertilization. Translocation Down syndrome. Down syndrome can also occur ... one option available for couples undergoing in vitro fertilization who are at increased risk of passing along ...

  8. LEOPARD syndrome

    MedlinePlus

    LEOPARD syndrome is a very rare inherited disorder in which there are problems with the skin, face, ... LEOPARD syndrome is inherited as an autosomal dominant trait. This means the person only needs the abnormal ...

  9. Myelodysplastic Syndromes

    MedlinePlus

    ... help with blood clotting. If you have a myelodysplastic syndrome, the stem cells do not mature into healthy ... can lead to infection, anemia, or easy bleeding. Myelodysplastic syndromes often do not cause early symptoms and are ...

  10. Klinefelter Syndrome

    MedlinePlus

    ... testicles, which can lead to lower production of testosterone. The syndrome may also cause reduced muscle mass, ... caused by Klinefelter syndrome are related to low testosterone (hypogonadism). Testosterone replacement therapy reduces the risk of ...

  11. Alport syndrome

    MedlinePlus

    ... Autosomal dominant Alport syndrome (ADAS) -- This is the rarest type. Males and females have equally severe disease. Symptoms KIDNEYS With all types of Alport syndrome the kidneys are affected. The tiny blood vessels in the glomeruli of the kidneys are ...

  12. Turner Syndrome

    MedlinePlus

    ... at increased risk of developing weak, brittle bones (osteoporosis). Pregnancy complications. Most women with Turner syndrome are infertile. ... loss, eye problems, high blood pressure, diabetes and osteoporosis. Periodic ... Pregnancy and fertility treatment Few women with Turner syndrome ...

  13. Marfan syndrome

    MedlinePlus

    Marfan syndrome is a disorder of connective tissue. This is the tissue that strengthens the body's structures. Disorders ... Marfan syndrome is caused by defects in a gene called fibrillin-1. Fibrillin-1 plays an important role ...

  14. Apert Syndrome.

    PubMed

    Datta, Saikat; Saha, Sandip; Kar, Arnab; Mondal, Souvonik; Basu, Syamantak

    2014-09-01

    Apert syndrome is one of the craniosynostosis syndromes which, due to its association with other skeletal anomalies, is also known as acrocephalosyndactyly. It is a rare congenital anomaly which stands out from other craniosynostosis due to its characteristic skeletal presentations.

  15. Turcot Syndrome

    MedlinePlus

    ... types of brain tumors in Turcot syndrome are: Glioblastoma . This type of brain tumor is a very ... to generation in a family. In families with glioblastoma and other features of Lynch syndrome, mutations (alterations) ...

  16. Proteus Syndrome

    MedlinePlus

    ... Donate Cash Donation Life Insurance Gift Matching Gift Stock Gift Sunshine Society Contact Privacy Policy Proteus Syndrome ... approved by the Proteus Syndrome Foundation Assessment and management of the orthopedic and other complications of Proteus ...

  17. Edwards' syndrome.

    PubMed

    Crawford, Doreen; Dearmun, Annette

    2016-12-08

    Edwards' syndrome is a serious genetic condition that affects fetal cellular functions, tissue development and organogenesis. Most infants with the syndrome are female, but there is no race predominance.

  18. Turner Syndrome

    MedlinePlus

    Turner syndrome is a genetic disorder that affects a girl's development. The cause is a missing or incomplete ... t work properly. Other physical features typical of Turner syndrome are Short, "webbed" neck with folds of skin ...

  19. Craniofacial Syndrome Descriptions

    MedlinePlus

    ... Dysplasia Goldenhar/Hemifacial Moebius syndrome Pfeiffer syndrome Pierre Robin Sequence Treacher Collins syndrome Other syndromes Wonder News & ... absence of the radial limb. Pfeiffer syndrome Pierre Robin Sequence Saethre-Chotzen Saethre-Chotzen syndrome is a ...

  20. Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome.

    PubMed

    Boland, Michael J; Nazor, Kristopher L; Tran, Ha T; Szücs, Attila; Lynch, Candace L; Paredes, Ryder; Tassone, Flora; Sanna, Pietro Paolo; Hagerman, Randi J; Loring, Jeanne F

    2017-03-01

    New research suggests that common pathways are altered in many neurodevelopmental disorders including autism spectrum disorder; however, little is known about early molecular events that contribute to the pathology of these diseases. The study of monogenic, neurodevelopmental disorders with a high incidence of autistic behaviours, such as fragile X syndrome, has the potential to identify genes and pathways that are dysregulated in autism spectrum disorder as well as fragile X syndrome. In vitro generation of human disease-relevant cell types provides the ability to investigate aspects of disease that are impossible to study in patients or animal models. Differentiation of human pluripotent stem cells recapitulates development of the neocortex, an area affected in both fragile X syndrome and autism spectrum disorder. We have generated induced human pluripotent stem cells from several individuals clinically diagnosed with fragile X syndrome and autism spectrum disorder. When differentiated to dorsal forebrain cell fates, our fragile X syndrome human pluripotent stem cell lines exhibited reproducible aberrant neurogenic phenotypes. Using global gene expression and DNA methylation profiling, we have analysed the early stages of neurogenesis in fragile X syndrome human pluripotent stem cells. We discovered aberrant DNA methylation patterns at specific genomic regions in fragile X syndrome cells, and identified dysregulated gene- and network-level correlates of fragile X syndrome that are associated with developmental signalling, cell migration, and neuronal maturation. Integration of our gene expression and epigenetic analysis identified altered epigenetic-mediated transcriptional regulation of a distinct set of genes in fragile X syndrome. These fragile X syndrome-aberrant networks are significantly enriched for genes associated with autism spectrum disorder, giving support to the idea that underlying similarities exist among these neurodevelopmental diseases.

  1. Velocardiofacial Syndrome

    ERIC Educational Resources Information Center

    Gothelf, Doron; Frisch, Amos; Michaelovsky, Elena; Weizman, Abraham; Shprintzen, Robert J.

    2009-01-01

    Velocardiofacial syndrome (VCFS), also known as DiGeorge, conotruncal anomaly face, and Cayler syndromes, is caused by a microdeletion in the long arm of Chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the…

  2. Velocardiofacial Syndrome

    ERIC Educational Resources Information Center

    Gothelf, Doron; Frisch, Amos; Michaelovsky, Elena; Weizman, Abraham; Shprintzen, Robert J.

    2009-01-01

    Velocardiofacial syndrome (VCFS), also known as DiGeorge, conotruncal anomaly face, and Cayler syndromes, is caused by a microdeletion in the long arm of Chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the…

  3. Fraser syndrome.

    PubMed

    Kalpana Kumari, M K; Kamath, Sulata; Mysorekar, Vijaya V; Nandini, G

    2008-01-01

    Fraser syndrome or cryptophthalmos is a rare autosomal recessive disorder characterized by major features such as cryptophthalmos, syndactyly and abnormal genitalia. The diagnosis of this syndrome can be made on clinical examination and perinatal autopsy. We present the autopsy findings of a rare case of Fraser syndrome in a male infant.

  4. SPAG7 is a candidate gene for the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome.

    PubMed

    Bens, S; Zichner, T; Stütz, A M; Caliebe, A; Wagener, R; Hoff, K; Korbel, J O; von Bismarck, P; Siebert, R

    2014-01-01

    Periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome is an auto-inflammatory disease for which a genetic basis has been postulated. Nevertheless, in contrast to the other periodic fever syndromes, no candidate genes have yet been identified. By cloning, following long insert size paired-end sequencing, of a de novo chromosomal translocation t(10;17)(q11.2;p13) in a patient with typical PFAPA syndrome lacking mutations in genes associated with other periodic fever syndromes we identified SPAG7 as a candidate gene for PFAPA. SPAG7 protein is expressed in tissues affected by PFAPA and has been functionally linked to antiviral and inflammatory responses. Haploinsufficiency of SPAG7 due to a microdeletion at the translocation breakpoint leading to loss of exons 2-7 from one allele was associated with PFAPA in the index. Sequence analyses of SPAG7 in additional patients with PFAPA point to genetic heterogeneity or alternative mechanisms of SPAG7 deregulation, such as somatic or epigenetic changes.

  5. MEFV Variants in Patients with PFAPA Syndrome in Japan.

    PubMed

    Taniuchi, Shoichiro; Nishikomori, Ryuta; Iharada, Anna; Tuji, Shoji; Heike, Toshio; Kaneko, Kazunari

    2013-01-01

    The pathogenesis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome is unknown as yet. In order to understand whether genes implicated in other auto-inflammatory diseases might be involved in the pathogenesis of PFAPA, all variants in the genes causing familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and Hyper IgD syndrome were analyzed in children with PFAPA. All variants in MEFV, TNFRSF1A, and MVK were analyzed in 20 patients with PFAPA. PFAPA were diagnosed by previous published criteria. The findings of all analyses in PFAPA patients were compared with those of unaffected normal subjects (n=62). In the 13 children of 20 with PFAPA, the heterozygous variants of MEFV (5 patients: E148Q-L110P, 2 patients: E148Q, 1 patient: E148Q-L110P/E148Q, 1 patient: E148Q-P369S-R408Q-E84K, 1 patient: E148Q-L110P-P369S-A408G, 1 patient: R202Q, 1 patient: P115R) were found. No variants belonging to TNFRSF1A or MVK were detected in children with PFAPA. The frequency of the E148Q-L110P variants in children with PFAPA was significantly higher than that observed in unaffected normal subjects (7/20 versus 8/62). The duration of the episodes of illness in PFAPA children with MEFV variants was shorter than that of patients without variants. Genes involved in the development and progression of MEFV may affect the incidence and the phenotype of PFAPA in children.

  6. Aging and Immunopathology in Primary Sjögren's Syndrome.

    PubMed

    Bouma, Hjalmar R; Bootsma, Hendrika; van Nimwegen, Jolien F; Haacke, Erlin A; Spijkervet, Fred K; Vissink, Arjan; Kroese, Frans G M

    2015-01-01

    Sicca complaints (sensation of dry mouth and/or eyes) are present in about a quarter of the individuals above the age of 65 years old and are mainly due to medication. However, physiological changes that occur during aging might also lead to a diminished glandular function. These age-related changes are, at least in part, to be the consequence of decreased androgen levels. In addition to these physiological effects that occur during normal aging, sicca complaints can also be caused by Sjögren's syndrome (SS): a systemic