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Anna Simon - One of the best experts on this subject based on the ideXlab platform.
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The challenge of autoinflammatory Syndromes: with an emphasis on Hyper-IgD Syndrome
Rheumatology (Oxford England), 2016Co-Authors: Jos W. M. Van Der Meer, Anna SimonAbstract: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.
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Hyper-IgD Syndrome/mevalonate kinase deficiency: what is new?
Seminars in immunopathology, 2015Co-Authors: Catharina M. Mulders-manders, Anna SimonAbstract: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.
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hyper igd Syndrome mevalonate kinase deficiency what is new
Seminars in Immunopathology, 2015Co-Authors: Catharina M Muldersmanders, Anna SimonAbstract: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.
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Mevalonate kinase deficiency nomenclature.
Rheumatology international, 2013Co-Authors: Monique Stoffels, Jos W. M. Van Der Meer, Anna SimonAbstract:In the letter of Celsi et al. [1], the authors suggest dropping the names of Hyper-IgD Syndrome (HIDS) and mevalonate kinase deficiency (MKD) for this hereditary Syndrome. They base their conclusion upon the fact that there is no correlation between serum IgD concentration and disease severity, that not all HIDS patients show elevated IgD, and that they do not believe in a causative association with mevalonate kinase. Through the years, several new names for this disease have been used or suggested. It was first called HIDS because of the observation of elevated IgD serum concentrations in patients [2]. It has also been referred to as Dutch-type periodic fever Syndrome [3], MKD, and even mevalonate-associated periodic Syndrome (MAPS), in analogy with cryopyrin-associated periodic Syndrome (CAPS) and TNF receptor-associated periodic Syndrome (TRAPS) [4]. We agree that indeed the name HIDS may cause confusion for physicians not familiar with this disease. Although a strongly increased IgD concentration gives a good clue for diagnosis if present, it cannot be used as a diagnostic tool. The name ‘‘MKD’’ also has its drawbacks. Deficiencies in mevalonate kinase lead to a continuum of disease phenotypes, with HIDS at the mild end and the more severe mevalonic aciduria at the other end [5, 6]. Recently, the phenotype associated with deficiency in mevalonate kinase was broadened by discovery of cases of disseminated superficial porokeratosis (DSAP) [7], as well as isolated retinitis pigmentosa [8] associated with mevalonate kinase gene mutations. Sometimes, changing the name of a disease may seem a logical step from the pathophysiological point of view. Accordingly, it is now consensus among specialists to use MKD as the overall name, instead of HIDS, although still specifying the type of disease with the designations HIDS (for the phenotype of fever episodes) or mevalonic aciduria (for the more severely affected patients). However, changing a name causes confusion throughout literature, and as such information to clinicians, researchers, as well as for patients becomes complicated and confusing. This is already very much the case for the field of hereditary autoinflammatory Syndromes, making it rather inscrutable for newcomers. This of course is not the purpose of nomenclature. Name changes should be implemented with care, and only when there are solid grounds to do so. We feel that the arguments of the authors of this letter [1] to stop using the name ‘‘MKD’’ are not solid. They mainly base this on in silico SNP data and the suggestion that other novel, previously overlooked genes and mechanisms may play a role in modifying the clinical phenotype. These are merely indications that the pathophysiology of MKD could be more complicated than previously described. This is at present not supported by clinical evidence, and we feel this is not enough reason to reconsider an established concept at this moment. It will actually cause more confusion than anticipated and does not improve understanding at all. These diseases are very rare and not M. Stoffels J. W. M. van der Meer A. Simon (&) Department of Medicine, 463 Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: a.simon@aig.umcn.nl
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Long chain fatty acid (Lcfa) abnormalities in hyper Igd Syndrome (Hids) and familial Mediterranean fever (Fmf): New insight into heritable periodic fevers
Molecular genetics and metabolism, 2013Co-Authors: Anna Simon, Joost P H Drenth, Elizabeth J. Hager, Dietrich Matern, Eric S. Goetzman, K. Michael GibsonAbstract:Abstract Objective To examine essential fatty acids (EFAs) in Hyper-IgD Syndrome (HIDS) and Familial Mediterranean Fever (FMF). Methods EFAs were determined in sera derived from an archival, cross-sectional group of HIDS/FMF patients, stratified for presence and absence of fever. Control populations included healthy afebrile adults, and individuals with non-periodic fever (septic shock). EFAs were quantified using isotope dilution gas chromatography–mass spectrometry and data analyzed employing a Kruskal–Wallis non-parametric ANOVA with Dunn's post-hoc test. Results Sera samples derived from HIDS patients showed significantly decreased C20, C26, phytanic and pristanic acids during febrile crises that normalized in the afebrile state, and a significantly increased afebrile C22_4ω6 level that normalized with fever. Samples derived from FMF patients revealed increased ω-oxidized LCFAs as compared to controls, and the trend was for these same species to be increased in comparison to febrile, but not afebrile, HIDS patients. Individuals with non-periodic fever demonstrated global decreases in C10–C24 fatty acids, both saturated and unsaturated, accompanied by an elevated triene/tetraene ratio. Conclusions Our results suggest that different mechanisms are active in hereditary periodic fever Syndromes that appear unrelated to fever, including depletion of very long chain fatty acids (VLCFAs) in febrile HIDS patients and increased ω-oxidized LCFAs in patients with FMF. These findings underscore new roles for EFAs in the potential production of inflammatory species in patients with hereditary periodic fever.
J.p.h. Drenth - One of the best experts on this subject based on the ideXlab platform.
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Effect of etanercept and anakinra on inflammatory attacks in the Hyper-IgD Syndrome: introducing a vaccination provocation model.
The Netherlands journal of medicine, 2005Co-Authors: Evelien J. Bodar, J.p.h. Drenth, J.w.m. Van Der Meer, J.c.h. Van Der Hilst, Anna SimonAbstract:Hyper-IgD and periodic fever Syndrome (HIDS) is an hereditary autoinflammatory Syndrome, characterised by recurrent inflammatory attacks. Treatment of HIDS is difficult, although simvastatin is beneficial and etanercept might be effective. Studying the treatment of a rare periodic Syndrome is complicated by the varying frequency and severity of symptoms and low prevalence. Our aim was to develop a system of clinical observations to evaluate effectiveness of treatment-on-demand. Seven fever episodes in three HIDS patients were monitored, with and without administration of etanercept or anakinra. We developed a clinical score, which includes 12 symptoms. In one patient, inflammatory attacks were provoked by vaccination. At the onset of an attack, all patients reported a clinical score between 20 and 25. The score was used to quantify severity and define the end of an attack. Reproducible monitoring of inflammatory episodes was difficult, even in this pilot study. The effect of early administration of etanercept was variable. In one patient, a fever episode could be readily provoked within 12 to 24 hours by vaccination. In this patient, the IL-1ra analogue anakinra was more successful in aborting the inflammatory attack than etanercept. We propose that this vaccination model will allow evaluation of treatment-on-demand in a controlled setting.
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Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD Syndrome.
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis, 2005Co-Authors: J.c.h. Van Der Hilst, J.w.m. Van Der Meer, J.p.h. Drenth, Evelien J. Bodar, J. Bijzet, Anna SimonAbstract:Hyper-IgD and periodic fever Syndrome (HIDS) is an autosomal recessively inherited disorder characterized by recurrent episodes of fever and inflammation. Unlike other chronic inflammatory conditions, amyloidosis is very rare in HIDS. For deposition of amyloid of the AA type, high concentrations of SAA are a prerequisite, together with certain SAA1 gene polymorphisms. The SAA1.1 genotype predisposes for amyloidosis, while SAA1.5 genotype exerts a protective effect. To determine if SAA concentrations and SAA1 gene polymorphisms could explain the virtual absence of amyloidosis in HIDS patients. We measured SAA and CRP concentrations in serum of 20 HIDS patients during an attack and during the asymptomatic phase. Genotype of SAA1 gene was determined in 60 HIDS patients. SAA serum concentrations during attacks were very high (median 205 mg/l; range 75-520 mg/l, normal <3.1 mg/l). During attack-free periods 45% of patients still had elevated SAA concentrations. The distribution of the genotype of SAA1 gene in HIDS was similar to healthy controls (SAA1.1 0.41 vs. 0.50 p=0.32). Patients with HIDS have high SAA during attacks and show sub-clinical inflammation when asymptomatic. The low incidence of amyloidosis cannot be explained by a predominance of non amyloidogenic SAA related genotypes.
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Mevalonate kinase deficiency: Evidence for a phenotypic continuum
Neurology, 2004Co-Authors: Anna Simon, Hubertus P. H. Kremer, Ron A. Wevers, Hans Scheffer, J.g.n. De Jong, J.w.m. Van Der Meer, J.p.h. DrenthAbstract:Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, recurrent fever attacks, and death in early childhood, and hyper-immunoglobulin D (Hyper-IgD) Syndrome, with recurrent fever attacks without neurologic symptoms, are caused by a functional deficiency of mevalonate kinase. In a systematic review of known mevalonate kinase-deficient patients, the authors identified five adults with phenotypic overlap between these two Syndromes, which argues for a continuous spectrum of disease. Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic fever attacks.
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Effect of inflammatory attacks in the classical type Hyper-IgD Syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response
Journal of internal medicine, 2004Co-Authors: Anna Simon, J.w.m. Van Der Meer, J. Bijzet, H.a.m. Voorbij, A. Mantovani, J.p.h. DrenthAbstract:BACKGROUND: Classical type hyper-immunoglobulin D (IgD) Syndrome (HIDS) is an hereditary auto-inflammatory disorder, characterized by recurrent episodes of fever, lymphadenopathy, abdominal distress and a high serum concentration of IgD. It is caused by mevalonate kinase deficiency. OBJECTIVE: To further characterize the acute phase response during fever attacks in HIDS in order to improve diagnosis. SUBJECTS: Twenty-two mevalonate kinase-deficient HIDS patients. METHODS: Blood samples were drawn during and in between febrile attacks, and concentrations ofC-reactive protein (CRP), ferritin, procalcitonin, pentraxin 3, IgD and cholesterol in several lipoprotein fractions were determined. RESULTS: The marked acute phase response at the time of a fever attack in classical type HIDS is reflected by a rise in CRP accompanied by a moderate but statistically significant rise in procalcitonin and pentraxin 3. In only two of 22 patients, procalcitonin concentration rose above 2 ng mL(-1) during fever attack, compatible with the noninfectious nature of these attacks. Ferritin does not reach the high concentrations found in adult-onset Still's disease. Despite the defect in mevalonate kinase, a component of cholesterol metabolism, serum cholesterol did not change during attacks. IgD concentration is elevated regardless of disease activity, although there is appreciable variation during life. Its role in HIDS remains unclear. CONCLUSION: The combination of high CRP concentration plus procalcitonin concentration
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Periodic fevers enter the era of molecular diagnosis: And they are throwing some light on inflammatory mechanisms
BMJ (Clinical research ed.), 2000Co-Authors: J.p.h. Drenth, J.w.m. Van Der MeerAbstract:Periodic fever Syndromes are a group of disorders characterised by attacks of fever separated by symptom free intervals. So far four types, all inherited, have been described. Familial Mediterranean fever and Hyper-IgD and periodic fever Syndrome (Hyper-IgD Syndrome) are transmitted as autosomal recessive traits while familial Hibernian fever and Muckle-Wells Syndrome are autosomal dominant periodic fevers. Over the past decade the gene for Muckle-Wells Syndrome has been localised and those for the other three disorders identified. This work has resulted in better means of diagnosing these rare conditions and has also thrown new light on the molecular basis of inflammation. Familial Mediterranean fever is the commonest periodic fever disorder, occurring mainly in people originating from the Mediterranean basin.1 In Israel alone over 5000 people are estimated to suffer from this disorder. Attacks start before the age of 20 and are characterised by short (1-4 days) attacks of fever and serositis. Most patients have recurrent peritonitis, but pleuritis also occurs. Asymmetric monoarthritis of the large joints is common, while an erysipelas-like rash develops less often. Familial Mediterranean fever can be complicated by nephropathic amyloidosis of the AA type, but in most patients colchicine up …
Seza Ozen - One of the best experts on this subject based on the ideXlab platform.
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THU0509 Improvement of disease activity in patients with colchicine-resistant FMF, HIDS/MKD and traps assessed by autoinflammatory disease activity index (AIDAI): results from the cluster trial
Poster Presentations, 2017Co-Authors: Isabelle Koné-paut, Marco Gattorno, Joost Frenkel, Maryam Piram, Susanne M. Benseler, Michael Hofer, Helen J. Lachmann, H. Hoffman, Jb Kuemmerle-deschner, Seza OzenAbstract:Background AIDAI is a novel validated tool for assessment of disease activity in autoinflammatory diseases. 1 CLUSTER study (NCT02059291) demonstrated that canakinumab (CAN; an anti- IL-1β antibody) is efficacious in resolving active flare and in preventing new flare in patients (pts) with colchicine resistant familial Mediterranean fever (crFMF), Hyper-IgD Syndrome/mevalonate kinase deficiency (HIDS/MKD) and TNF receptor-associated periodic Syndrome (TRAPS). 2 Objectives To assess AIDAI score and evaluate correlation between AIDAI and disease/response characteristics over 16 weeks (wks) of CAN treatment in CLUSTER. Methods CLUSTER study design and results have been presented. 2 AIDAI was calculated as the sum of 12 items 1 for 30 consecutive days. AIDAI score was calculated if the first score was recorded ≥29 days before baseline (BL). Missing items were imputed beyond last evaluable measurement by LOCF. Proportion of pts with inactive disease (ID; AIDAI score Results Median AIDAI scores decreased over time (Fig 1). Proportion of pts with ID at Wk 16 was 52% in crFMF, 40% in HIDS/MKD and 46% in TRAPS cohorts. AIDAI at Wk 16 correlated significantly with: SDS in all 3 cohorts; PGA in HIDS/MKD and TRAPS; SF12–MCS in crFMF and HIDS/MKD (Table 1). CRP and SAA did not correlate with AIDAI. Conclusions CAN demonstrated rapid and sustained disease control assessed with AIDAI over 16 wks. Approximately half of crFMF and TRAPS pts, and 40% of HIDS/MKD patients had inactive disease after 16 wks of treatment. AIDAI improvements at Wk 16 correlated with patient and physician driven evaluations (PGA, SF12–MCS and SDS). CRP and SAA are indicators of response to treatment, rather than a disease activity parameter. References Piram M, et al. Ann Rheum Dis. 2014;73: 2168–73. De Benedetti F, et al. Ann Rheum Dis. 2016;75:615–6. Disclosure of Interest I. Kone-Paut Grant/research support from: Novartis, SOBI and Roche, Consultant for: Novartis, SOBI, Pfizer, AbbVie and Roche, M. Piram Consultant for: Novartis, Pfizer, AbbVie, Speakers bureau: Novartis, S. Benseler Consultant for: Novartis, SOBI and AbbVie, M. Hofer Consultant for: Novartis and AbbVie, H. Lachmann Consultant for: Novartis, SOBI, Takeda and GSK, Speakers bureau: Novartis and SOBI, H. Hoffman Consultant for: Novartis, Speakers bureau: Novartis, M. Gattorno Grant/research support from: Novartis and SOBI, Consultant for: Novartis and SOBI, J. Frenkel Grant/research support from: Novartis and SOBI, J. Kuemmerle-Deschner Grant/research support from: Novartis, Consultant for: Novartis, SOBI and Baxalta, S. Ozen Speakers bureau: Novartis and SOBI, J. Levy Paid instructor for: Novartis, C. Karyekar Employee of: Novartis, F. De Benedetti Grant/research support from: Pfizer, AbbVie, Roche, Novartis, Novimmune and BMS
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A clinical update on inflammasomopathies.
International immunology, 2017Co-Authors: Hafize Emine Sönmez, Seza OzenAbstract:Inflammasomes are important elements of the innate immune defense. The most common autoinflammatory Syndromes, as well a number of rare ones, are due to hereditary defects in the inflammasomes, hence are called inflammasomopathies. The recent clinical advances in these diseases will be reviewed, with special emphasis on reflecting the international collaborative work in the field. Recent recommendations for familial Mediterranean fever, cryopyrin-associated periodic Syndromes and Hyper-IgD Syndrome/mevalonate kinase deficiency will be presented and diagnostics tests, treatment alternatives and follow-up recommendations will be summarized. The other rare inflammasomopathies will be briefly discussed based on clinical features; these diseases are pyogenic arthritis, pyoderma gangrenosum and acne, NLRC4-related macrophage-activation Syndrome of enterocolitis, mutations in NLRP12 that cause hereditary periodic fever Syndromes (familial cold inflammatory Syndrome 2) and NLRP1-associated autoinflammation with arthritis and dyskeratosis.
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A patient with Hyper-IgD Syndrome responding to anti-TNF treatment
Clinical rheumatology, 2006Co-Authors: Erkan Demirkaya, M. Kazim Caglar, H. R. Waterham, Rezan Topaloglu, Seza OzenAbstract:The hyperimmunoglobulinemia D periodic fever Syndrome (HIDS) is caused by recessive mutations in the mevalonate kinase gene, which encodes an enzyme involved in cholesterol and nonsterol isoprenoid biosynthesis. The pathogenesis and treatment remains unclear. We describe a 6-year-old Turkish girl with severe disease. Her clinical features were accompanied with very high acute-phase reactants including a very high serum amyloid A level. The patient responded well to anti-tumor necrosis factor treatment. Our findings support the use of this anti-cytokine treatment in HIDS.
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Familial mediterranean fever: revisiting an ancient disease
European Journal of Pediatrics, 2003Co-Authors: Seza OzenAbstract:Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterised by periodic attacks of fever and serositis. Recent genetic and epidemiological research have highlighted the importance of this disease. FMF is the most frequent periodic fever Syndrome and is transmitted in an autosomal recessive fashion. The disease is caused by mutations in the gene on the short arm of chromosome 16, coding for the protein "pyrin". Pyrin is mainly expressed in neutrophils and monocytes and is among the proteins involved in the interleukin-1 inflammatory pathway. The recurrent attacks of fever are accompanied by severe abdominal pain, arthritis and/or chest pain along with a marked increase in acute phase reactants. Among these, serum amyloid A protein is especially important since it is the precursor of the amyloid A fibrils deposited in secondary renal amyloidosis. Renal amyloidosis has a grave prognosis. Differential diagnosis from other periodic fever Syndromes is especially important in western European countries. Among these hyper IgD Syndrome is common in Netherlands and the tumour necrosis factor receptor-associated periodic Syndrome is especially common among Scottish and Irish families. Mutation analysis of the gene may be helpful in diagnosing FMF; however, if this is not possible, a trial of colchicine is a helpful diagnostic tool. The indications for life-long colchicine treatment should be discussed with the family. Conclusion: familial mediterranean fever and other auto-inflammatory Syndromes should be suspected in children with recurrent febrile attacks. Early diagnosis will save the child from unnecessary work-up and kidney involvement.
J.w.m. Van Der Meer - One of the best experts on this subject based on the ideXlab platform.
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Effect of etanercept and anakinra on inflammatory attacks in the Hyper-IgD Syndrome: introducing a vaccination provocation model.
The Netherlands journal of medicine, 2005Co-Authors: Evelien J. Bodar, J.p.h. Drenth, J.w.m. Van Der Meer, J.c.h. Van Der Hilst, Anna SimonAbstract:Hyper-IgD and periodic fever Syndrome (HIDS) is an hereditary autoinflammatory Syndrome, characterised by recurrent inflammatory attacks. Treatment of HIDS is difficult, although simvastatin is beneficial and etanercept might be effective. Studying the treatment of a rare periodic Syndrome is complicated by the varying frequency and severity of symptoms and low prevalence. Our aim was to develop a system of clinical observations to evaluate effectiveness of treatment-on-demand. Seven fever episodes in three HIDS patients were monitored, with and without administration of etanercept or anakinra. We developed a clinical score, which includes 12 symptoms. In one patient, inflammatory attacks were provoked by vaccination. At the onset of an attack, all patients reported a clinical score between 20 and 25. The score was used to quantify severity and define the end of an attack. Reproducible monitoring of inflammatory episodes was difficult, even in this pilot study. The effect of early administration of etanercept was variable. In one patient, a fever episode could be readily provoked within 12 to 24 hours by vaccination. In this patient, the IL-1ra analogue anakinra was more successful in aborting the inflammatory attack than etanercept. We propose that this vaccination model will allow evaluation of treatment-on-demand in a controlled setting.
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Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD Syndrome.
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis, 2005Co-Authors: J.c.h. Van Der Hilst, J.w.m. Van Der Meer, J.p.h. Drenth, Evelien J. Bodar, J. Bijzet, Anna SimonAbstract:Hyper-IgD and periodic fever Syndrome (HIDS) is an autosomal recessively inherited disorder characterized by recurrent episodes of fever and inflammation. Unlike other chronic inflammatory conditions, amyloidosis is very rare in HIDS. For deposition of amyloid of the AA type, high concentrations of SAA are a prerequisite, together with certain SAA1 gene polymorphisms. The SAA1.1 genotype predisposes for amyloidosis, while SAA1.5 genotype exerts a protective effect. To determine if SAA concentrations and SAA1 gene polymorphisms could explain the virtual absence of amyloidosis in HIDS patients. We measured SAA and CRP concentrations in serum of 20 HIDS patients during an attack and during the asymptomatic phase. Genotype of SAA1 gene was determined in 60 HIDS patients. SAA serum concentrations during attacks were very high (median 205 mg/l; range 75-520 mg/l, normal <3.1 mg/l). During attack-free periods 45% of patients still had elevated SAA concentrations. The distribution of the genotype of SAA1 gene in HIDS was similar to healthy controls (SAA1.1 0.41 vs. 0.50 p=0.32). Patients with HIDS have high SAA during attacks and show sub-clinical inflammation when asymptomatic. The low incidence of amyloidosis cannot be explained by a predominance of non amyloidogenic SAA related genotypes.
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Mevalonate kinase deficiency: Evidence for a phenotypic continuum
Neurology, 2004Co-Authors: Anna Simon, Hubertus P. H. Kremer, Ron A. Wevers, Hans Scheffer, J.g.n. De Jong, J.w.m. Van Der Meer, J.p.h. DrenthAbstract:Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, recurrent fever attacks, and death in early childhood, and hyper-immunoglobulin D (Hyper-IgD) Syndrome, with recurrent fever attacks without neurologic symptoms, are caused by a functional deficiency of mevalonate kinase. In a systematic review of known mevalonate kinase-deficient patients, the authors identified five adults with phenotypic overlap between these two Syndromes, which argues for a continuous spectrum of disease. Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic fever attacks.
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Effect of inflammatory attacks in the classical type Hyper-IgD Syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response
Journal of internal medicine, 2004Co-Authors: Anna Simon, J.w.m. Van Der Meer, J. Bijzet, H.a.m. Voorbij, A. Mantovani, J.p.h. DrenthAbstract:BACKGROUND: Classical type hyper-immunoglobulin D (IgD) Syndrome (HIDS) is an hereditary auto-inflammatory disorder, characterized by recurrent episodes of fever, lymphadenopathy, abdominal distress and a high serum concentration of IgD. It is caused by mevalonate kinase deficiency. OBJECTIVE: To further characterize the acute phase response during fever attacks in HIDS in order to improve diagnosis. SUBJECTS: Twenty-two mevalonate kinase-deficient HIDS patients. METHODS: Blood samples were drawn during and in between febrile attacks, and concentrations ofC-reactive protein (CRP), ferritin, procalcitonin, pentraxin 3, IgD and cholesterol in several lipoprotein fractions were determined. RESULTS: The marked acute phase response at the time of a fever attack in classical type HIDS is reflected by a rise in CRP accompanied by a moderate but statistically significant rise in procalcitonin and pentraxin 3. In only two of 22 patients, procalcitonin concentration rose above 2 ng mL(-1) during fever attack, compatible with the noninfectious nature of these attacks. Ferritin does not reach the high concentrations found in adult-onset Still's disease. Despite the defect in mevalonate kinase, a component of cholesterol metabolism, serum cholesterol did not change during attacks. IgD concentration is elevated regardless of disease activity, although there is appreciable variation during life. Its role in HIDS remains unclear. CONCLUSION: The combination of high CRP concentration plus procalcitonin concentration
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Periodic fevers enter the era of molecular diagnosis: And they are throwing some light on inflammatory mechanisms
BMJ (Clinical research ed.), 2000Co-Authors: J.p.h. Drenth, J.w.m. Van Der MeerAbstract:Periodic fever Syndromes are a group of disorders characterised by attacks of fever separated by symptom free intervals. So far four types, all inherited, have been described. Familial Mediterranean fever and Hyper-IgD and periodic fever Syndrome (Hyper-IgD Syndrome) are transmitted as autosomal recessive traits while familial Hibernian fever and Muckle-Wells Syndrome are autosomal dominant periodic fevers. Over the past decade the gene for Muckle-Wells Syndrome has been localised and those for the other three disorders identified. This work has resulted in better means of diagnosing these rare conditions and has also thrown new light on the molecular basis of inflammation. Familial Mediterranean fever is the commonest periodic fever disorder, occurring mainly in people originating from the Mediterranean basin.1 In Israel alone over 5000 people are estimated to suffer from this disorder. Attacks start before the age of 20 and are characterised by short (1-4 days) attacks of fever and serositis. Most patients have recurrent peritonitis, but pleuritis also occurs. Asymmetric monoarthritis of the large joints is common, while an erysipelas-like rash develops less often. Familial Mediterranean fever can be complicated by nephropathic amyloidosis of the AA type, but in most patients colchicine up …
K. M. Gibson - One of the best experts on this subject based on the ideXlab platform.
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Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of Hyper-IgD Syndrome
Journal of inherited metabolic disease, 2007Co-Authors: E. J. Hager, Hubert M. Tse, Jon D. Piganelli, Maneesh Gupta, M. Baetscher, T. E. Tse, Anuradha S. Pappu, Robert D. Steiner, Georg F. Hoffmann, K. M. GibsonAbstract:Summary In the current study our objective was to develop a murine model of human Hyper-IgD Syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase deficiency (MKD). Deletion of one Mvk allele (Mvk +/j ) yielded viable mice with significantly re
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Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of Hyper-IgD Syndrome
Journal of Inherited Metabolic Disease, 2007Co-Authors: E. J. Hager, Hubert M. Tse, Jon D. Piganelli, Maneesh Gupta, M. Baetscher, T. E. Tse, Anuradha S. Pappu, Robert D. Steiner, Georg F. Hoffmann, K. M. GibsonAbstract:In the current study our objective was to develop a murine model of human Hyper-IgD Syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase deficiency (MKD). Deletion of one Mvk allele ( Mvk ^+/−) yielded viable mice with significantly reduced liver Mvk enzyme activity; multiple matings failed to produce Mvk ^−/− mice. Cholesterol levels in tissues and blood, and isoprene end-products (ubiquinone, dolichol) in tissues were normal in Mvk ^+/− mice; conversely, mevalonate concentrations were increased in spleen, heart, and kidney yet normal in brain and liver. While the trend was for higher IgA levels in Mvk ^+/− sera, IgD levels were significantly increased (9–12-fold) in comparison to Mvk ^+/+ littermates, in both young (15 weeks) mice. Mvk ^+/− animals manifested increased serum TNF-α as compared to wild-type littermates, but due to wide variation in levels between individual Mvk ^+/− mice the difference in means was not statistically significant. Mvk ^+/− mice represent the first animal model of HIDS, and should prove useful for examining pathophysiology associated with this disorder.
