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Anna Simon - One of the best experts on this subject based on the ideXlab platform.
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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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Mutations in the Mevalonate Kinase (MVK) Gene Cause Nonsyndromic Retinitis Pigmentosa
Ophthalmology, 2013Co-Authors: Anna M. Siemiatkowska, Monique Stoffels, L. Ingeborgh Van Den Born, P. Martin Van Hagen, Kornelia Neveling, Arjen Henkes, Mieke Kipping-geertsema, Lies H. Hoefsloot, Carel B. Hoyng, Anna SimonAbstract:Objective Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP. Design We present a case series with mutations in the Mevalonate Kinase ( MVK ) gene. Participants A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study. Methods Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination. Main Outcome Measures Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate Kinase (MK) enzyme activity was analyzed in cultured lymphoblastoid cells, and mevalonic acid levels were measured in urine samples. Results Exome variant filtering and prioritization led to the identification of compound heterozygous mutations in MVK (p.I268T and p.A334T) in the proband and her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid. Conclusions Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic Mevalonate Kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK . Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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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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Hyper-IgD syndrome or Mevalonate Kinase deficiency.
Current opinion in rheumatology, 2011Co-Authors: Monique Stoffels, Anna SimonAbstract:PURPOSE OF REVIEW: The hyper-IgD and periodic fever syndrome (HIDS) is one of the classical monogenetic hereditary autoinflammatory disorders, and together with the more severe mevalonic aciduria it is also known as 'Mevalonate Kinase deficiency' (MKD). In this study, we will give an overview of the primary research on Mevalonate Kinase deficiency published in the past 2 years. RECENT FINDINGS: Besides an inventory of a number of recent case reports, literature review shows there are several interesting developments in the basic field of research. First, a group of articles was recently published on chemically instead of genetically induced MKD mouse and cell models, investigating the effects of several isoprenoid pathway intermediates. Second, another study confirms a role for small GTPases and their isoprenylation in the inflammatory response in Mevalonate Kinase deficiency. Lastly, there are now, finally, modest new indications about the role of IgD. SUMMARY: Both pathophysiological studies and clinical observations in the last 2 years have supported the central role of IL-1 in HIDS. There are some intriguing results and hypotheses about the link between isoprenoid metabolism and the IL-1 pathway through geranylgeranylation that deserve to be further examined.
Georg F. Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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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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Mevalonate Kinase deficiency: enlarging the clinical and biochemical spectrum.
Pediatrics, 2003Co-Authors: Viola Prietsch, Ertan Mayatepek, K. Michael Gibson, Hans R. Waterham, Hermann Krastel, Dorothea Haas, Dorothee Zundel, Ronald J.a. Wanders, Georg F. HoffmannAbstract: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. We report the clinical history and biochemical findings of 3 patients with mevalonic aciduria. 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. 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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Mevalonate Kinase deficiency: enlarging the clinical and biochemical spectrum.
Pediatrics, 2003Co-Authors: Viola Prietsch, Ertan Mayatepek, K. Michael Gibson, Hans R. Waterham, Hermann Krastel, Dorothea Haas, 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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Hematological abnormalities and cholestatic liver disease in two patients with Mevalonate Kinase deficiency.
American journal of medical genetics, 1998Co-Authors: Debra D. Hinson, Georg F. Hoffmann, Zora R. Rogers, M. Schachtele, Ralph Fingerhut, Alfried Kohlschütter, Richard I. Kelley, K. Michael GibsonAbstract:We describe two patients with Mevalonate Kinase deficiency and prominent hematologic abnormalities and cholestatic liver disease. Patient R.B. was not anemic at birth, but developed petechiae and cutaneous extramedullary hematopoiesis, hepatosplenomegaly, leukocytosis, and recurrent febrile events without positive bacterial or viral cultures. Patient N.M. manifested minor anomalies, hepatosplenomegaly, anemia, thrombocytopenia, recurrent febrile crises, and facial rashes. Mevalonic aciduria was found by urinary organic acid analysis, and Mevalonate Kinase deficiency was documented in both. The clinical spectrum of normocytic hypoplastic anemia, leukocytosis, thrombocytopenia, and abnormal blood cell forms led to diagnoses of congenital infection, myelodysplastic syndromes, or chronic leukemia in these patients before recognition of Mevalonate Kinase deficiency. Mevalonate Kinase deficiency represents a single-gene abnormality that may be associated with significant hematologic findings. Recognition of the variability of this disorder with some patients manifesting only mild neurologic findings, yet significant hepatosplenomegaly, normocytic anemia, thrombocytopenia, and leukocytosis is important for all specialists who need to be aware of this organic aciduria.
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Decreased Plasma Ubiquinone-10 Concentration in Patients with Mevalonate Kinase Deficiency
Pediatric Research, 1993Co-Authors: Christoph Hübner, Georg F. Hoffmann, K. Michael Gibson, Christiane Charpentier, Barbara Finckh, Herbert Puhl, Hans-anton Lehr, Alfred KohlschütterAbstract:ABSTRACT: Patients with Mevalonate Kinase deficiency suffer from psychomotor retardation, ataxia with progredient cerebellar atrophy, and myopathy. The pathophysiology of the disease remains unclear. The Mevalonate Kinase product, cholesterol, is within the normal range in patient plasma and fibroblasts. In search of the pathophysiology of this disorder, another Mevalonate Kinase product, ubiquinone-10, was studied. The concentrations of ubiquinone-10 in patient plasma (n = 6) and ubiquinol-10 in patient LDL (n = 2) and the synthesis of ubiquinone-10 in patient fibroblasts (n = 4) were determined. After oxidative modification of LDL by copper in vitro, the concentrations of α-tocopherol and polyunsaturated fatty acids in LDL and the relative electrophoretic mobility of LDL were measured to determine the antioxidant capacity of LDL samples of two affected siblings. The ubiquinone-10 concentrations in plasma samples (median = 508 μg/L, range = 488–642 μg/L) versus controls (median = 613 μg/L, range = 564–809 μg/L; p < 0.005) were decreased. In LDL samples of two affected siblings, the concentration of ubiquinol-10 and the resistance to oxidation in vitro were found decreased during intercurrent patient crisis condition. In patient fibroblasts (median = 533 dpm/mg protein, range = 399–1 047 dpm/mg protein) versus controls (median = 40 731 dpm/mg protein, range = 12 774–54 739 dpm/mg protein), the synthesis of ubiquinone was found to be decreased. We conclude that Mevalonate Kinase deficiency leads to a decreased synthesis of ubiquinone-10 and that ubiquinone-10 deficiency is responsible for the clinical progression of this disease characterized by increased lipid peroxidation, cerebellar atrophy, cataract development, and myopathy with increased creatine Kinase activity.
Joost Frenkel - One of the best experts on this subject based on the ideXlab platform.
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Management of Mevalonate Kinase Deficiency: A Pediatric Perspective.
Frontiers in immunology, 2020Co-Authors: Jerold Jeyaratnam, Joost FrenkelAbstract:Background: Mevalonate Kinase deficiency (MKD) is an inborn error of metabolism leading to a syndrome characterized by recurrent inflammation. This clinically manifests itself as fever and can be accompanied by gastrointestinal symptoms, oral ulcers, cervical lymphadenopathy, and skin rash. Methods: We searched Pubmed, Embase, Cochrane, and CINAHL for relevant articles. All articles were screened by both authors. Relevant articles were included in this review. Results: The interleukin-1 antagonist canakinumab is the only well-studied and effective treatment for MKD patients with 35% of patients reaching complete remission in a large randomized controlled trial. Other therapeutic options include glucocorticoids and the IL-1 antagonist anakinra, although the level of evidence for these treatments is weaker. If patients fail to these treatments, the biologicals etanercept or tocilizumab can be used. Mildly affected patients might benefit from cheaper, less invasive treatments such as paracetamol and NSAIDs. Conclusion: Canakinumab is the only evidence-based treatment for Mevalonate Kinase deficiency. However, the costs limit availability for many patients. Cheaper and more readily available options include glucocorticoids, anakinra, etanercept, and tocilizumab, although there is limited evidence supporting these treatments.
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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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Mevalonate Kinase Deficiency
Oxford Medicine Online, 2016Co-Authors: Joost Frenkel, Hans R. WaterhamAbstract:Mevalonate Kinase deficiency (MKD) is an autosomal recessive inborn error of isoprenoid biosynthesis, a pathway yielding sterols and nonsterol isoprenoids.In patients, the enzyme activity of Mevalonate Kinase is severely reduced due to mutations in the encoding gene, MVK. The substrate, Mevalonate, accumulates and is elevated in blood and urine. Shortage of certain downstream products of the pathway, nonsterol isoprenoids, leads to dysregulation of the innate immune system, activation of inflammasomes, and interleukin (IL)-1 mediated inflammation.Symptoms start in early childhood with recurrent attacks of fever, vomiting, diarrhea, headache, sore throat, abdominal pain, arthralgias, painful lymphadenopathy, hepatosplenomegaly, skin rash, and mucosal ulcers. Severely affected patients have additional symptoms, such as intellectual impairment, progressive cerebellar ataxia, and tapetoretinal degeneration. Complications include intestinal obstruction, AA-amyloidosis, hemophagocytosis, and severe infection.Management of MKD is directed at controlling inflammation.
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Diagnostic value of urinary mevalonic acid excretion in patietns with a clinical suspicion of Mevalonate Kinase deficiency (MKD).
Pediatric Rheumatology, 2015Co-Authors: Jerold Jeyaratnam, Hans R. Waterham, N Ter Haar, M. G. M. De Sain-van Der Velden, M. E. Van Gijn, Joost FrenkelAbstract:Objective: In patients suffering from Mevalonate Kinase deficiency (MKD), the reduced enzyme activity leads to an accumulation of mevalonic acid which is excreted in the urine. This study aims to evaluate the diagnostic value of urinary mevalonic acid measurement in patients with a clinical suspicion of Mevalonate Kinase deficiency.
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Diagnostic value of urinary mevalonic acid excretion in Mevalonate Kinase deficiency (MKD)
Pediatric Rheumatology, 2014Co-Authors: Jerold Jeyaratnam, M. G. M. De Sain-van Der Velden, M. E. Van Gijn, Nienke M. Ter Haar, Joost FrenkelAbstract:Mevalonate Kinase deficiency (MKD) is a rare hereditary autoinflammatory syndrome, characterized by recurrent fever episodes with gastrointestinal complaints, rash and arthralgia. The deficient Mevalonate Kinase activity leads to elevated mevalonic acid, which is excreted in the urine. Therefore, an elevated mevalonic acid excretion is suggestive of MKD. However, the diagnostic value of this analysis has not been investigated yet and remains unclear.
Hans R. Waterham - One of the best experts on this subject based on the ideXlab platform.
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Mevalonate Kinase Deficiency
Oxford Medicine Online, 2016Co-Authors: Joost Frenkel, Hans R. WaterhamAbstract:Mevalonate Kinase deficiency (MKD) is an autosomal recessive inborn error of isoprenoid biosynthesis, a pathway yielding sterols and nonsterol isoprenoids.In patients, the enzyme activity of Mevalonate Kinase is severely reduced due to mutations in the encoding gene, MVK. The substrate, Mevalonate, accumulates and is elevated in blood and urine. Shortage of certain downstream products of the pathway, nonsterol isoprenoids, leads to dysregulation of the innate immune system, activation of inflammasomes, and interleukin (IL)-1 mediated inflammation.Symptoms start in early childhood with recurrent attacks of fever, vomiting, diarrhea, headache, sore throat, abdominal pain, arthralgias, painful lymphadenopathy, hepatosplenomegaly, skin rash, and mucosal ulcers. Severely affected patients have additional symptoms, such as intellectual impairment, progressive cerebellar ataxia, and tapetoretinal degeneration. Complications include intestinal obstruction, AA-amyloidosis, hemophagocytosis, and severe infection.Management of MKD is directed at controlling inflammation.
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Diagnostic value of urinary mevalonic acid excretion in patietns with a clinical suspicion of Mevalonate Kinase deficiency (MKD).
Pediatric Rheumatology, 2015Co-Authors: Jerold Jeyaratnam, Hans R. Waterham, N Ter Haar, M. G. M. De Sain-van Der Velden, M. E. Van Gijn, Joost FrenkelAbstract:Objective: In patients suffering from Mevalonate Kinase deficiency (MKD), the reduced enzyme activity leads to an accumulation of mevalonic acid which is excreted in the urine. This study aims to evaluate the diagnostic value of urinary mevalonic acid measurement in patients with a clinical suspicion of Mevalonate Kinase deficiency.
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Compromized geranylgeranylation of RhoA and Rac1 in Mevalonate Kinase deficiency
Journal of inherited metabolic disease, 2010Co-Authors: L. Henneman, Marit S. Schneiders, Marjolein Turkenburg, Hans R. WaterhamAbstract:Mevalonate Kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme Mevalonate Kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases.
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12.2 Mevalonate Kinase deficiency: Impaired isoprenoid synthesis induces IL-1beta production via activation of Rac1
Pediatric Rheumatology, 2008Co-Authors: L.m. Kuijk, Joost Frenkel, Hans R. Waterham, Janet Koster, Paul J. CofferAbstract:Mevalonate Kinase deficiency is an autosomal recessive disorder characterized by recurring episodes of fever and inflammation. Peripheral blood mononuclear cells from Mevalonate Kinase deficiency patients secrete high levels of IL-1β when stimulated with lipopolysaccharide (LPS) due to the presence of hyperactive caspase-1. The molecular mechanism of Mevalonate Kinase deficiency-induced caspase-1 activation remains unclear. We artificially impaired isoprenoid biosynthesis in the monocytic cells (THP-1) with simvastatin, after which cells were stimulated with LPS. Simvastatin-treated THP-1 cells stimulated with LPS demonstrated enhanced release of IL-1β. LPS enhanced transcription of IL-1β., whereas simvastatin enhanced proteolytic activation of IL-1β. This effect was mediated by phosphatidylinositol 3 Kinase (PI3K) and protein Kinase B (PKB/c-Akt). In addition, simvastatin-induced IL-1β secretion required the small GTPase Rac1. Simvastatin treatment increased the levels of biologically active GTP-bound Rac1 and inhibition of Rac1 reduced simvastatin-mediated IL-1β secretion. Rac1 functioned upstream of PKB, since Rac1 inhibition abolished the effect of simvastatin on PKB. Simvastatin-mediated activation of the Rac1/PI3K/PKB pathway enhanced IL-1β secretion through activation of caspase-1, since inhibition of both Rac1 and PI3K blocked the release of active caspase-1 subunits. The importance of Rac1 in Mevalonate Kinase deficiency was confirmed when a specific Rac1 inhibitor was shown to inhibit spontaneous IL-1β release by mononuclear cells from Mevalonate Kinase deficiency patients. Together, these results demonstrate that Rac1, PI3K and PKB are involved in simvastatin-induced secretion of IL-1β through regulation of caspase-1 activity and that Rac1 is a potential new therapeutic target in Mevalonate Kinase deficiency.
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Diagnostics and therapeutic insights in a severe case of Mevalonate Kinase deficiency.
Pediatrics, 2007Co-Authors: Marco Nevyjel, Sergio Crovella, Alberto Tommasini, Hans R. Waterham, Alessandra Pontillo, Lorenzo Calligaris, Andrea D'osualdo, Marilena Granzotto, Egidio Barbi, Alessandro VenturaAbstract:Mevalonate Kinase deficiency is a rare inborn disorder of isoprenoid and sterol biosynthesis characterized by a recurrent autoinflammatory syndrome and, in most severe cases, psychomotor delay. Clinical manifestations can be very complex and, in some cases, mimic a chronic inflammatory disease. Diagnosis is also complex and often requires immunologic, genetic, and biochemical investigations. There is no standardized therapy, but biological agents could help to control inflammatory complaints in some cases. A severe case of Mevalonate Kinase deficiency that was associated with nephritis and successfully treated with anakinra (interleukin 1 receptor antagonist) is reported here, and new insights into diagnosis and therapy of this complex disorder are discussed.
Sergio Crovella - One of the best experts on this subject based on the ideXlab platform.
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Incomplete mitophagy in the Mevalonate Kinase-deficient Saccharomyces cerevisiae and its relation to the MKD-related autoinflammatory disease in humans.
Biochimica et biophysica acta. Molecular basis of disease, 2020Co-Authors: Manuella Maria Silva Santos, Sergio Crovella, Damián Gatica, Jaqueline De Azevêdo Silva, Daniel J. Klionsky, Marcos Antonio De MoraisAbstract:Mevalonate Kinase deficiency (MKD) is an autosomal recessive disorder in humans that causes systemic autoinflammatory problems to children. Previously, we used a yeast model to show that MKD results in mitochondrial malfunctioning that may finally induce mitophagy. Here, we proved that MKD indeed induced general autophagy as well as mitophagy in yeast, but these mechanisms did not go to completion. Therefore, the limitation of Mevalonate Kinase activity produces dysfunctional mitochondria that might not be recycled, causing metabolic dysfunctions in the cells. Understanding this mechanism may provide a piece in solving the nonspecific autoinflammatory response puzzle observed in MKD patients.
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Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency.
Cellular physiology and biochemistry : international journal of experimental cellular physiology biochemistry and pharmacology, 2017Co-Authors: Paola Maura Tricarico, Sergio Crovella, Alessandra Romeo, Rossella Gratton, Fulvio CelsiAbstract:Background/Aims: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in Mevalonate Kinase gene ( MVK ). MKD has heteroge
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Research Article Temperature and Drug Treatments in Mevalonate Kinase Deficiency: An Ex Vivo Study
2016Co-Authors: Lorenzo Monasta, Sergio Crovella, Annalisa MarcuzziAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused bymutations in the Mevalonate Kinase (MK) gene, leading to MK enzyme decreased activity. The consequent shortage of Mevalonate-derived isoprenoid compounds results in an inflammatory phenotype, caused by the activation of the NALP3 inflammasome that determines an increased caspase-1 activation and IL-
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GRID2 a novel gene possibly associated with Mevalonate Kinase deficiency
Rheumatology international, 2014Co-Authors: Ronald Moura, Paola Maura Tricarico, Antonio Victor Campos Coelho, Sergio CrovellaAbstract:Mevalonate Kinase deficiency (MKD) is a rare autosomal disease caused by mutations in the Mevalonate Kinase gene (MVK). The genotype–phenotype correlation is sometimes problematic due to the great genetic and clinical heterogeneity; so we hypothesize that genes other than MVK are able to modulate MKD clinical phenotypes. This hypothesis was tested by analyzing the exome of 22 patients with MKD all carrying MVK gene mutations, and 20 patients with recurrent fevers (RF) not carrying MVK mutations. Our preliminary findings suggest a possible role of GRID2 in the susceptibility to develop MKD. GRID2 gene (4q22.2), encoding for human glutamate receptor delta-2, associated with MKD: The rs1450500 SNP was differently distributed in patients with MKD with respect to those with RF. Being aware of the small number of patients analyzed, we hypothesized a possible role for GRID2 as possible phenotype modifier in MKD patients, especially in those with severe phenotypes.
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Mevalonate Kinase deficiency and neuroinflammation: balance between apoptosis and pyroptosis.
International journal of molecular sciences, 2013Co-Authors: Paola Maura Tricarico, Sergio Crovella, Annalisa Marcuzzi, Elisa Piscianz, Lorenzo Monasta, Giulio KleinerAbstract:Mevalonic aciduria, a rare autosomal recessive disease, represents the most severe form of the periodic fever, known as Mevalonate Kinase Deficiency. This disease is caused by the mutation of the MVK gene, which codes for the enzyme Mevalonate Kinase, along the cholesterol pathway. Mevalonic aciduria patients show recurrent fever episodes with associated inflammatory symptoms, severe neurologic impairments, or death, in early childhood. The typical neurodegeneration occurring in mevalonic aciduria is linked both to the intrinsic apoptosis pathway (caspase-3 and -9), which is triggered by mitochondrial damage, and to pyroptosis (caspase-1). These cell death mechanisms seem to be also related to the assembly of the inflammasome, which may, in turn, activate pro-inflammatory cytokines and chemokines. Thus, this particular molecular platform may play a crucial role in neuroinflammation mechanisms. Nowadays, a specific therapy is still lacking and the pathogenic mechanisms involving neuroinflammation and neuronal dysfunction have not yet been completely understood, making mevalonic aciduria an orphan drug disease. This review aims to analyze the relationship among neuroinflammation, mitochondrial damage, programmed cell death, and neurodegeneration. Targeting inflammation and degeneration in the central nervous system might help identify promising treatment approaches for mevalonic aciduria or other diseases in which these mechanisms are involved.