The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Sander M. Houten - One of the best experts on this subject based on the ideXlab platform.
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Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation.
Cellular and Molecular Life Sciences, 2003Co-Authors: Sander M. Houten, Joost FrenkelAbstract:Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited autoinflammatory disorders Mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. Since the discovery of the genetic defect, considerable progress has been made in understanding the molecular, biochemical and immunological basis of MK deficiency. Important questions such as which specific protein(s) and/or signaling pathway(s) are affected, however, remain unanswered. Resolving the complete pathophysiology of this disorder is a major challenge, but eventually will give insight into the in vivo role of MK and isoprenoid biosynthesis in inflammation and fever. This may open novel options for antiinflammatory therapies in general. Here, we give a general introduction on isoprenoid biosynthesis, the regulation thereof and deficiencies therein. We review the molecular, biochemical and immunological aspects of MK deficiency and discuss the relations between isoprenoid biosynthesis and inflammation. Finally, we compare MK deficiency with other autoinflammatory syndromes.
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regulation of isoprenoid cholesterol biosynthesis in cells from mevalonate kinase deficient patients
Journal of Biological Chemistry, 2003Co-Authors: Sander M. Houten, Ronald J.a. Wanders, Marit S. Schneiders, Hans R. WaterhamAbstract:Mevalonic aciduria (MA) and hyper-IgD and periodic fever syndrome (HIDS) are two inherited disorders both caused by depressed mevalonate kinase (MK) activity. MK is the first enzyme to follow the highly regulated 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), which catalyzes the rate-limiting step in the isoprenoid/cholesterol biosynthesis pathway. In fibroblasts of MA patients, but not of HIDS patients, HMGR activity is elevated under normal growth conditions. This activity is down-regulated when cells are supplemented with the isoprenoid precursors geraniol, farnesol, and geranylgeraniol, and a mixture of 25-hydroxycholesterol and cholesterol. This indicates that the regulation of the pathway in these cells is not disturbed. The elevated HMGR activity is probably due to a shortage of non-sterol isoprenoid end products, as indicated by normal HMGR mRNA levels in MA fibroblasts. Furthermore, the HMGR activity in MA cells was more sensitive to geranylgeraniol suppression and less sensitive to sterol suppression than the HMGR activity in low density lipoprotein receptor-deficient cells. HMGR activity in MA cells was down-regulated also by addition of its product mevalonate to the culture medium. Thus, it appears that the elevation of mevalonate levels, which are high in MA patients and moderate in HIDS patients, allows the cells to compensate for the depressed MK activity. Indeed, the isoprenylation of Ras and RhoA protein appeared normal in HIDS and MA fibroblasts under normal conditions but showed increased sensitivity toward inhibition of HMGR by simvastatin. Our results indicate that MK-deficient cells maintain the flux through the isoprenoid/cholesterol biosynthesis pathway by elevating intracellular mevalonate levels.
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carrier frequency of the v377i 1129g a mvk mutation associated with hyper igd and periodic fever syndrome in the netherlands
European Journal of Human Genetics, 2003Co-Authors: Sander M. Houten, Ronald J.a. Wanders, Christiaan S Van Woerden, Frits A Wijburg, Hans R. WaterhamAbstract:Hyper-IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria (MA) are two autosomal recessive disorders that both are caused by a deficient activity of the enzyme mevalonate kinase (MK) due to mutations in the encoding gene (MVK). The most frequently occurring MVK mutation, V377I (1129G>A), has been identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MA. To estimate the incidence of MK deficiency in the Netherlands, we determined the carrier frequency of the V377I mutation in genomic DNA extracted from anonymised newborn screening cards by PCR-RFLP. We found 14 carriers among 2138 analysed samples (1 : 153). Based on the V377I allele frequency of 42% in patients diagnosed with MK deficiency, the carrier frequency of any MVK mutation in the Dutch population can be calculated as 1 : 65. This predicts a disease incidence between1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis ofpatients with MK deficiency remains possible, this discrepancy probably is due to a reduced penetrance of V377I homozygosity. Analysis of the distribution of the V377I allele within patients carrying MVK mutations revealed that this was not according to the Hardy–Weinberg equilibrium principle, most probably due to an under-representation of V377I homozygotes in HIDS. Homozygotes for V377I might exhibit a much milder phenotype of MK deficiency or no disease-phenotype at all.
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temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper igd and periodic fever syndrome
Human Molecular Genetics, 2002Co-Authors: Sander M. Houten, Joost Frenkel, Wietse Kuis, Ronald J.a. Wanders, Ger T. Rijkers, Hans R. WaterhamAbstract:Hyper-IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of fever and generalized inflammation. Both syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 � C as compared to 37 � C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 � C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy- 3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever.
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organization of the mevalonate kinase mvk gene and identification of novel mutations causing Mevalonic aciduria and hyperimmunoglobulinaemia d and periodic fever syndrome
European Journal of Human Genetics, 2001Co-Authors: Sander M. Houten, Janet Koster, Joost Frenkel, Wietse Kuis, G J Romeijn, Richard I. Kelley, U Caruso, Pierre Landrieu, Maja Di Rocco, Bwee Tien PolltheAbstract:Organization of the mevalonate kinase ( MVK ) gene and identification of novel mutations causing Mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome
Georg F Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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Coenzyme Q(10) is decreased in fibroblasts of patients with methylmalonic aciduria but not in Mevalonic aciduria.
Journal of Inherited Metabolic Disease, 2009Co-Authors: Dorothea Haas, Friederike Horster, E. Regula Baumgartner, Chitra Prasad, Richard J. Rodenburg, Petra Niklowitz, Thomas Menke, Georg F Hoffmann, Juergen Guenther OkunAbstract:The content of coenzyme Q10 (CoQ10) was examined in skin fibroblasts of 10 patients with Mevalonic aciduria (MVA) and of 22 patients with methylmalonic aciduria (MMA). Patients with these inborn errors of metabolism are thought to be at risk for CoQ10 depletion either by direct inhibition of the proximal pathway of CoQ10 synthesis (MVA) or indirectly by inhibition of mitochondrial energy metabolism (MMA). We demonstrated that CoQ10 concentrations were not significantly different from controls in MVA patients, suggesting that there may be upregulatory effects. On the other hand the CoQ10 content in fibroblasts of patients with MMA was significantly reduced.
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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, Georg F Hoffmann, Robert D. Steiner, Hubert M. Tse, Jon D. Piganelli, Maneesh Gupta, M. Baetscher, T. E. Tse, Anuradha S. Pappu, 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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Mevalonate kinase deficiency and autoinflammatory disorders.
The New England journal of medicine, 2007Co-Authors: Dorothea Haas, Georg F HoffmannAbstract:Drs. Dorothea Haas and Georg Hoffmann write that Mevalonic aciduria and hyperimmunoglobulinemia D syndrome are rare disorders, but they represent a unique link among inborn errors of metabolism, side effects of statin therapy, and inflammatory and rheumatic disorders.
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Mevalonate kinase deficiencies: from Mevalonic aciduria to hyperimmunoglobulinemia D syndrome.
Orphanet journal of rare diseases, 2006Co-Authors: Dorothea Haas, Georg F HoffmannAbstract:Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of Mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of Mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.
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Orphanet Journal of Rare Diseases BioMed Central Review
2006Co-Authors: Dorothea Haas, Georg F HoffmannAbstract:Mevalonate kinase deficiencies: from Mevalonic aciduria to hyperimmunoglobulinemia D syndrom
Joost Frenkel - One of the best experts on this subject based on the ideXlab platform.
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Mevalonate Kinase Deficiency
2019Co-Authors: Joost FrenkelAbstract:Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease caused by loss of function mutations in both alleles of MVK, the gene encoding the enzyme mevalonate kinase. Deficiency of this enzyme results in impaired isoprenoid biosynthesis. The inflammatory attacks in MKD are characterized by fever, lymphadenopathy, gastrointestinal symptoms, aphthous ulcers, rash, arthralgias and/or arthritis. Severely affected patients may in addition have neurological involvement, cataract, uveitis, and failure to thrive, often dying in early childhood. This severe end of the phenotypic spectrum is called Mevalonic aciduria (MA) as opposed to the milder phenotype also known as hyperimmunoglobulinemia D periodic fever syndrome (HIDS). In this chapter, we detail clinical phenotype and pathophysiological background as well as treatment options.
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periodic fever in mvk deficiency a patient initially diagnosed with incomplete kawasaki disease
Pediatrics, 2014Co-Authors: Valtyr S Thors, Joost Frenkel, Sebastiaan J Vastert, Nico M Wulffraat, Annet Van Royen, Monique G M De Sainvan Der Velden, Tom J De KoningAbstract:Mevalonate kinase deficiency (MKD) is a rare autosomal recessive disorder causing 1 of 2 phenotypes, hyperimmunoglobulin D syndrome and Mevalonic aciduria, presenting with recurrent fever episodes, often starting in infancy, and sometimes evoked by stress or vaccinations. This autoinflammatory disease is caused by mutations encoding the mevalonate kinase (MVK) gene and is classified in the group of periodic fever syndromes. There is often a considerable delay in the diagnosis among pediatric patients with recurrent episodes of fever. We present a case of an 8-week-old girl with fever of unknown origin and a marked systemic inflammatory response. After excluding infections, a tentative diagnosis of incomplete Kawasaki syndrome was made, based on the finding of dilated coronary arteries on cardiac ultrasound and fever, and she was treated accordingly. However, the episodes of fever recurred, and alternative diagnoses were considered, which eventually led to the finding of increased excretion of Mevalonic acid in urine. The diagnosis of MKD was confirmed by mutation analysis of the MVK gene. This case shows that the initial presentation of MKD can be indistinguishable from incomplete Kawasaki syndrome. When fever recurs in Kawasaki syndrome, other (auto-)inflammatory diseases must be ruled out to avoid inappropriate diagnostic procedures, ineffective interventions, and treatment delay.
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Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation.
Cellular and Molecular Life Sciences, 2003Co-Authors: Sander M. Houten, Joost FrenkelAbstract:Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited autoinflammatory disorders Mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. Since the discovery of the genetic defect, considerable progress has been made in understanding the molecular, biochemical and immunological basis of MK deficiency. Important questions such as which specific protein(s) and/or signaling pathway(s) are affected, however, remain unanswered. Resolving the complete pathophysiology of this disorder is a major challenge, but eventually will give insight into the in vivo role of MK and isoprenoid biosynthesis in inflammation and fever. This may open novel options for antiinflammatory therapies in general. Here, we give a general introduction on isoprenoid biosynthesis, the regulation thereof and deficiencies therein. We review the molecular, biochemical and immunological aspects of MK deficiency and discuss the relations between isoprenoid biosynthesis and inflammation. Finally, we compare MK deficiency with other autoinflammatory syndromes.
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temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper igd and periodic fever syndrome
Human Molecular Genetics, 2002Co-Authors: Sander M. Houten, Joost Frenkel, Wietse Kuis, Ronald J.a. Wanders, Ger T. Rijkers, Hans R. WaterhamAbstract:Hyper-IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of fever and generalized inflammation. Both syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 � C as compared to 37 � C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 � C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy- 3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever.
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Periodic fever and mevalonate kinase deficiency
2002Co-Authors: Joost FrenkelAbstract:Mevalonate kinase (MK) deficiency is an autosomal recessive disorder, caused by mutations in the MVK-gene on chromosome 12q24. The affected enzyme catalyzes an early step in isoprenoid biosynthesis, the pathway that produces cholesterol and several non-sterol isoprenoids. The clinical spectrum includes hyper IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria. Both phenotypes are characterized by recurrent generalized inflammation and fever attacks from infancy,. accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgias, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. In addition, the Mevalonic aciduria phenotype is characterized by mental retardation and facial malformation. The severe phenotype reflects a more profound enzyme deficiency due to distinct mutations in the MVK gene. Urinary excretion of the accumulating substrate of MK, Mevalonic acid is about a thousand fold higher in MA than in HIDS. By definition, serum IgD is elevated in HIDS. However, 20% of clinically diagnosed HIDS patients have normal MK activity and IgD may be normal in MK deficiency. Ex vivo, mononuclear cells from MK deficiency patients secrete more IL-1beta. We could demonstrate that this was due to decreased generation of isoprenoid products and not to accumulation of the substrate of MK, mevalonate, linking the metabolic defect directly to inflammation. The enzyme activity in HIDS proved to be discontinuous, dropping with increasing temperature, both in vitro and in vivo. This finding provides a possible explanation for he episodic nature of inflammation in HIDS. Despite the raised serum IgD, the affected leukocyte populations were not lymphocytes, but phagocytes, as judged by the surface expression of cellular activation markers. .This was further supported by the increased urinary excretion of leukotriene E4, a product of activated monocytes and macrophages, during febrile crises. In summary, distinct mutations in MVK, lead to varying degrees of MK deficiency. This is reflected in a variable phenotype of episodic generalized inflammation with (MA) or without (HIDS) neurological and facial abnormalities. Due to the shortage of an as yet unidentified isoprenoid product, activated mononuclear phagocytes secrete more IL-1beta, a potent primary pro-inflammatory cytokine, giving rise to realized inflammation. Thisinflammation is episodic due to the increased temperature sensitivity of mutant MK.
Hans R. Waterham - One of the best experts on this subject based on the ideXlab platform.
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regulation of isoprenoid cholesterol biosynthesis in cells from mevalonate kinase deficient patients
Journal of Biological Chemistry, 2003Co-Authors: Sander M. Houten, Ronald J.a. Wanders, Marit S. Schneiders, Hans R. WaterhamAbstract:Mevalonic aciduria (MA) and hyper-IgD and periodic fever syndrome (HIDS) are two inherited disorders both caused by depressed mevalonate kinase (MK) activity. MK is the first enzyme to follow the highly regulated 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), which catalyzes the rate-limiting step in the isoprenoid/cholesterol biosynthesis pathway. In fibroblasts of MA patients, but not of HIDS patients, HMGR activity is elevated under normal growth conditions. This activity is down-regulated when cells are supplemented with the isoprenoid precursors geraniol, farnesol, and geranylgeraniol, and a mixture of 25-hydroxycholesterol and cholesterol. This indicates that the regulation of the pathway in these cells is not disturbed. The elevated HMGR activity is probably due to a shortage of non-sterol isoprenoid end products, as indicated by normal HMGR mRNA levels in MA fibroblasts. Furthermore, the HMGR activity in MA cells was more sensitive to geranylgeraniol suppression and less sensitive to sterol suppression than the HMGR activity in low density lipoprotein receptor-deficient cells. HMGR activity in MA cells was down-regulated also by addition of its product mevalonate to the culture medium. Thus, it appears that the elevation of mevalonate levels, which are high in MA patients and moderate in HIDS patients, allows the cells to compensate for the depressed MK activity. Indeed, the isoprenylation of Ras and RhoA protein appeared normal in HIDS and MA fibroblasts under normal conditions but showed increased sensitivity toward inhibition of HMGR by simvastatin. Our results indicate that MK-deficient cells maintain the flux through the isoprenoid/cholesterol biosynthesis pathway by elevating intracellular mevalonate levels.
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carrier frequency of the v377i 1129g a mvk mutation associated with hyper igd and periodic fever syndrome in the netherlands
European Journal of Human Genetics, 2003Co-Authors: Sander M. Houten, Ronald J.a. Wanders, Christiaan S Van Woerden, Frits A Wijburg, Hans R. WaterhamAbstract:Hyper-IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria (MA) are two autosomal recessive disorders that both are caused by a deficient activity of the enzyme mevalonate kinase (MK) due to mutations in the encoding gene (MVK). The most frequently occurring MVK mutation, V377I (1129G>A), has been identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MA. To estimate the incidence of MK deficiency in the Netherlands, we determined the carrier frequency of the V377I mutation in genomic DNA extracted from anonymised newborn screening cards by PCR-RFLP. We found 14 carriers among 2138 analysed samples (1 : 153). Based on the V377I allele frequency of 42% in patients diagnosed with MK deficiency, the carrier frequency of any MVK mutation in the Dutch population can be calculated as 1 : 65. This predicts a disease incidence between1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis ofpatients with MK deficiency remains possible, this discrepancy probably is due to a reduced penetrance of V377I homozygosity. Analysis of the distribution of the V377I allele within patients carrying MVK mutations revealed that this was not according to the Hardy–Weinberg equilibrium principle, most probably due to an under-representation of V377I homozygotes in HIDS. Homozygotes for V377I might exhibit a much milder phenotype of MK deficiency or no disease-phenotype at all.
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temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper igd and periodic fever syndrome
Human Molecular Genetics, 2002Co-Authors: Sander M. Houten, Joost Frenkel, Wietse Kuis, Ronald J.a. Wanders, Ger T. Rijkers, Hans R. WaterhamAbstract:Hyper-IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of fever and generalized inflammation. Both syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 � C as compared to 37 � C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 � C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy- 3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever.
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mevalonate kinase deficiency and dutch type periodic fever
Clinical and Experimental Rheumatology, 2000Co-Authors: Joost Frenkel, Bwee Tien Pollthe, Sander M. Houten, Hans R. Waterham, R. J. A. Wanders, Ger T. Rijkers, J L L Kimpen, R Duran, Wietse KuisAbstract:Dutch type periodic fever (DPF) is an autosomal recessive hereditary fever syndrome. Cases have been reported worldwide, the majority from France and The Netherlands. From infancy the patients suffer fever attacks that recur every 2-8 weeks, often precipitated by immunizations, infections or emotional stress. Fever lasts 2-7 days and can be accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. Laboratory evaluation during fever shows granulocytosis and elevated acute phase reactants. DPF is caused by a deficiency of the enzyme mevalonate kinase (MK). Besides DPF, the spectrum of MK deficiency includes a severe phenotype, Mevalonic aciduria (MA). MA patients have less residual MK activity, leading to substantially higher urinary Mevalonic acid excretion than in DPF. Mevalonic aciduria is characterized by mental retardation and dysmorphic features in addition to the clinical features of DPF. At the genomic level, several mutations of varying severity have been identified. The DPF phenotype is caused by one particular mild missense mutation. Most patients are compound heterozygotes for this mutation and a more severe mutation. The mechanism by which MK deficiency leads to fever is not understood. The vast majority of DPF patients have persistently elevated serum IgD and can be classified as having hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Conversely, most HIDS patients have MK deficiency and hence DPF, but the two disorders do not overlap entirely.
Ronald J.a. Wanders - One of the best experts on this subject based on the ideXlab platform.
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regulation of isoprenoid cholesterol biosynthesis in cells from mevalonate kinase deficient patients
Journal of Biological Chemistry, 2003Co-Authors: Sander M. Houten, Ronald J.a. Wanders, Marit S. Schneiders, Hans R. WaterhamAbstract:Mevalonic aciduria (MA) and hyper-IgD and periodic fever syndrome (HIDS) are two inherited disorders both caused by depressed mevalonate kinase (MK) activity. MK is the first enzyme to follow the highly regulated 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), which catalyzes the rate-limiting step in the isoprenoid/cholesterol biosynthesis pathway. In fibroblasts of MA patients, but not of HIDS patients, HMGR activity is elevated under normal growth conditions. This activity is down-regulated when cells are supplemented with the isoprenoid precursors geraniol, farnesol, and geranylgeraniol, and a mixture of 25-hydroxycholesterol and cholesterol. This indicates that the regulation of the pathway in these cells is not disturbed. The elevated HMGR activity is probably due to a shortage of non-sterol isoprenoid end products, as indicated by normal HMGR mRNA levels in MA fibroblasts. Furthermore, the HMGR activity in MA cells was more sensitive to geranylgeraniol suppression and less sensitive to sterol suppression than the HMGR activity in low density lipoprotein receptor-deficient cells. HMGR activity in MA cells was down-regulated also by addition of its product mevalonate to the culture medium. Thus, it appears that the elevation of mevalonate levels, which are high in MA patients and moderate in HIDS patients, allows the cells to compensate for the depressed MK activity. Indeed, the isoprenylation of Ras and RhoA protein appeared normal in HIDS and MA fibroblasts under normal conditions but showed increased sensitivity toward inhibition of HMGR by simvastatin. Our results indicate that MK-deficient cells maintain the flux through the isoprenoid/cholesterol biosynthesis pathway by elevating intracellular mevalonate levels.
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Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum.
Pediatrics, 2003Co-Authors: Viola Prietsch, Ertan Mayatepek, Dorothea Haas, K. Michael Gibson, Hermann Krastel, Dorothee Zundel, Ronald J.a. Wanders, Georg F HoffmannAbstract:Objective. Mevalonic aciduria as a result of mevalonate kinase deficiency is an inborn error of cholesterol biosynthesis characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Pathogenic mutations in the mevalonate kinase gene in both disorders have demonstrated a common genetic basis. Our aim was to describe the clinical picture of adolescent patients with mevalonate kinase deficiency and to expand the clinical and biochemical spectrum of mevalonate kinase deficiency, particularly with regard to HIDS. Methods. We report the clinical history and biochemical findings of 3 patients with Mevalonic aciduria. Results. In 2 siblings with Mevalonic aciduria, a 15-year-old girl and a 14-year-old boy, the phenotype shifted with age. Ataxia has become the predominant clinical manifestation, whereas the febrile attacks occur less frequently but as yet have not disappeared. Both of them show marked elevations of immunoglobulin D (IgD). Psychomotor development is retarded but not regressive. Short stature developed in both patients. Additional findings include the development of retinal dystrophy and cataracts in both of them. The third patient is a 6-year-old boy who presented at the age of 5 years with cerebellar ataxia and retinal dystrophy. He is different from all known patients with Mevalonic aciduria because of the mild neurologic involvement and because he has never developed febrile crises. In addition, levels of IgD were repeatedly normal. Conclusion. The clinical and biochemical spectrum of patients with Mevalonic aciduria is heterogeneous. Manifestations of the disease seem to be age dependent, as evident from this first report of adolescent patients. In patients who survive infancy, short stature, ataxia caused by cerebellar atrophy, and ocular involvement with retinal dystrophy become predominant findings. Recurrent febrile crises seem to diminish with increasing age and may not even be an obligatory finding. Elevation of IgD is most likely a secondary phenomenon that seems to be linked to recurrent febrile crises.
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carrier frequency of the v377i 1129g a mvk mutation associated with hyper igd and periodic fever syndrome in the netherlands
European Journal of Human Genetics, 2003Co-Authors: Sander M. Houten, Ronald J.a. Wanders, Christiaan S Van Woerden, Frits A Wijburg, Hans R. WaterhamAbstract:Hyper-IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria (MA) are two autosomal recessive disorders that both are caused by a deficient activity of the enzyme mevalonate kinase (MK) due to mutations in the encoding gene (MVK). The most frequently occurring MVK mutation, V377I (1129G>A), has been identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MA. To estimate the incidence of MK deficiency in the Netherlands, we determined the carrier frequency of the V377I mutation in genomic DNA extracted from anonymised newborn screening cards by PCR-RFLP. We found 14 carriers among 2138 analysed samples (1 : 153). Based on the V377I allele frequency of 42% in patients diagnosed with MK deficiency, the carrier frequency of any MVK mutation in the Dutch population can be calculated as 1 : 65. This predicts a disease incidence between1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis ofpatients with MK deficiency remains possible, this discrepancy probably is due to a reduced penetrance of V377I homozygosity. Analysis of the distribution of the V377I allele within patients carrying MVK mutations revealed that this was not according to the Hardy–Weinberg equilibrium principle, most probably due to an under-representation of V377I homozygotes in HIDS. Homozygotes for V377I might exhibit a much milder phenotype of MK deficiency or no disease-phenotype at all.
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temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper igd and periodic fever syndrome
Human Molecular Genetics, 2002Co-Authors: Sander M. Houten, Joost Frenkel, Wietse Kuis, Ronald J.a. Wanders, Ger T. Rijkers, Hans R. WaterhamAbstract:Hyper-IgD and periodic fever syndrome (HIDS) and Mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of fever and generalized inflammation. Both syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 � C as compared to 37 � C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 � C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy- 3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever.
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Biochemical and genetic aspects of mevalonate kinase and its deficiency.
Biochimica et biophysica acta, 2000Co-Authors: Sander M. Houten, Ronald J.a. WandersAbstract:Mevalonate kinase (MK) is an essential enzyme in the mevalonate pathway which produces numerous cellular isoprenoids. The enzyme has been characterized both at the biochemical and the molecular level in a variety of organisms. Despite the fact that mevalonate kinase is not the rate-limiting enzyme in isoprenoid biosynthesis, its activity is subject to feedback regulation by the branch-point intermediates geranyldiphosphate, farnesyldiphosphate and geranylgeranyldiphosphate. Recently, the importance of mevalonate kinase was demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited human disorders Mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. The pathophysiology of these disorders is not yet understood, but eventually will give insight into the in vivo role of mevalonate kinase and isoprenoid biosynthesis with respect to the acute phase response and fever. The subcellular localization of mevalonate kinase is still a matter of debate. The enzyme could be localized predominantly in the cytosol, or in peroxisomes, or it is associated differentially with peroxisomes. Here we review the biochemical and molecular properties of MK, and discuss its biological significance, the regulation of its enzyme activity and finally its subcellular localization.