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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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an international delphi survey for the definition of new classification criteria for familial mediterranean fever Mevalonate Kinase Deficiency tnf receptor associated periodic fever syndromes and cryopyrin associated periodic syndrome
The Journal of Rheumatology, 2019Co-Authors: Silvia Federici, Eldad Benchetrit, Joost Frenkel, Hal M Hoffman, Luca Cantarini, Ahmet Gül, Isabelle Konepaut, Federica Vanoni, Raphaela Goldbachmansky, Jasmin B KuemmerledeschnerAbstract:Objective. Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF. Methods. Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1. Results. The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for Mevalonate Kinase Deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor–associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF. Conclusion. Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.
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Mevalonate Kinase Deficiency
2019Co-Authors: Joost Frenkel, Anna SimonAbstract: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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canakinumab for the treatment of autoinflammatory recurrent fever syndromes
The New England Journal of Medicine, 2018Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, I Konepaut, Jordi Anton, Eldad Benchetrit, Joost Frenkel, Hal M Hoffman, Seza Ozen, Anna SimonAbstract:BACKGROUND: Familial Mediterranean fever, Mevalonate Kinase Deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, Mevalonate Kinase Deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with Mevalonate Kinase Deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with Mevalonate Kinase Deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with Mevalonate Kinase Deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with Mevalonate Kinase Deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, Mevalonate Kinase Deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
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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.
Sergio Crovella - One of the best experts on this subject based on the ideXlab platform.
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MMAB, a novel candidate gene to be screened in the molecular diagnosis of Mevalonate Kinase Deficiency
Rheumatology International, 2017Co-Authors: Massimo Mezzavilla, Ronald Rodrigues Moura, Paola Maura Tricarico, Fulvio Celsi, Sergio CrovellaAbstract:Mevalonate Kinase Deficiency (MKD) is an autosomal recessive inflammatory disease. Mutations in MVK gene are associated with MKD with modest genotype–phenotype correlation. In spite of recent guidelines indicating specific MVK mutations for the more severe form or the milder one, little is known about MVK variability within and between populations. The aim of this work is to provide supplementary information about MVK variability useful in the molecular diagnosis of MKD, as well as to unravel the presence of novel genes potentially involved as involved in the clinical heterogeneity of MKD phenotype. We used a population-based approach, coupled with Combined Annotation–Dependent Depletion (CADD) score, to analyze the level of genetic variability for common and putatively deleterious MVK variants. We also performed Exome screening with the Illumina Human Exome Bead Chip on 21 MKD patients to double-check our in silico findings. Haplotype block detection in different populations revealed the existence of two blocks in MVK; interestingly, the first haploblock comprises the promoter region shared with MMAB gene. Analyses of MMAB and MVK genetic variants in 21 MKD patients strengthen our observations showing a novel scenario in which the same mutations commonly associated with MKD are found coupled with different combination of MMAB rs7134594 SNP was already described as associated with HDL cholesterol level and present in the haploblock promoter region. The rs7134594 SNP is reported as an eQTL for MVK and MMAB. Hypothesizing the presence of genetic variants modulating the complex phenotypic spectrum of MKD, we suggest that future directions in screening for MKD pathogenic variants should focus both MMAB and MVK genes.
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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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Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency
Karger Publishers, 2017Co-Authors: Paola maura Tricarico, Alessandra Romeo, Sergio Crovella, Rossella Gratton, Fulvio CelsiAbstract:Background/Aims: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in Mevalonate Kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. Methods: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. Results: MVK mutants’ over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. Conclusions: We hypothesize that Mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation
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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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Putative modifier genes in Mevalonate Kinase Deficiency.
Molecular medicine reports, 2016Co-Authors: Annalisa Marcuzzi, Paola Maura Tricarico, Sergio Crovella, Alberto Tommasini, Elisa Piscianz, Josef Vuch, Diego Vozzi, Martina Girardelli, Alessandra Knowles, Anna Monica BiancoAbstract:Mevalonate Kinase Deficiency (MKD) is an autosomal recessive auto‑inflammatory disease, caused by impairment of the Mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non‑homogeneous genotype‑phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the Mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.
Annalisa Marcuzzi - One of the best experts on this subject based on the ideXlab platform.
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Mevalonate Kinase Deficiency: therapeutic targets, treatments, and outcomes
Expert Opinion on Orphan Drugs, 2017Co-Authors: Annalisa Marcuzzi, Elisa Piscianz, Liza Vecchi Brumatti, Alberto TommasiniAbstract:ABSTRACTIntroduction: Mevalonate Kinase Deficiency (MKD) is a rare inborn disease caused by the mutation of Mevalonate Kinase gene.The clinical phenotype encompasses recurrent fever episodes in combination with gastrointestinal, immunological, rheumatological and neurological complaints. No specific treatment is available, apart from the newly approved biologics (canakinumab), but MKD can be still considered an orphan-drug disease, since the identification of a reliable therapeutic target needs an improved knowledge on the pathogenesis of the disease, which is so far controversial.Areas covered: On one hand, shortage of isoprenoid compounds downstream of Mevalonate led to a defective geranylgeranylation of RhoA/Rac proteins and increased caspase-1-dependent inflammation. On the other hand, recent studies pointed the attention to the pathogenic role of the mitochondrial dysfunction and to defective production of 25-hydroxycholesterol. These mechanisms are not exclusive of each other, as they can contribute...
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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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Putative modifier genes in Mevalonate Kinase Deficiency.
Molecular medicine reports, 2016Co-Authors: Annalisa Marcuzzi, Paola Maura Tricarico, Sergio Crovella, Alberto Tommasini, Elisa Piscianz, Josef Vuch, Diego Vozzi, Martina Girardelli, Alessandra Knowles, Anna Monica BiancoAbstract:Mevalonate Kinase Deficiency (MKD) is an autosomal recessive auto‑inflammatory disease, caused by impairment of the Mevalonate pathway. Although the molecular mechanism remains to be elucidated, there is clinical evidence suggesting that other regulatory genes may be involved in determining the phenotype. The identification of novel target genes may explain non‑homogeneous genotype‑phenotype correlations, and provide evidence in support of the hypothesis that novel regulatory genes predispose or amplify deregulation of the Mevalonate pathway in this orphan disease. In the present study, DNA samples were obtained from five patients with MKD, which were then analyzed using whole exome sequencing. A missense variation in the PEX11γ gene was observed in homozygosis in P2, possibly correlating with visual blurring. The UNG rare gene variant was detected in homozygosis in P5, without correlating with a specific clinical phenotype. A number of other variants were found in the five analyzed DNA samples from the MKD patients, however no correlation with the phenotype was established. The results of the presents study suggested that further analysis, using next generation sequencing approaches, is required on a larger sample size of patients with MKD, who share the same MVK mutations and exhibit 'extreme' clinical phenotypes. As MVK mutations may be associated with MKD, the identification of specific modifier genes may assist in providing an earlier diagnosis.
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Microglia activation and interaction with neuronal cells in a biochemical model of Mevalonate Kinase Deficiency
Apoptosis, 2015Co-Authors: Paola Maura Tricarico, Sergio Crovella, Elisa Piscianz, Lorenzo Monasta, Giulio Kleiner, Annalisa MarcuzziAbstract:Mevalonate Kinase Deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the Mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the Mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of Mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines’ release and cells’ morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in Mevalonate Kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are activated and contribute to neuronal cell death. We can thus hypothesise that the use of microglial activation blockers could prevent this additional neuronal death.
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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.
Véronique Hentgen - One of the best experts on this subject based on the ideXlab platform.
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international retrospective chart review of treatment patterns in severe familial mediterranean fever tumor necrosis factor receptor associated periodic syndrome and Mevalonate Kinase Deficiency hyperimmunoglobulinemia d syndrome
Arthritis Care and Research, 2017Co-Authors: Seza Ozen, Pierre Quartier, Rolando Cimaz, Avi Livneh, Andrew Zeft, Steve Spalding, Ahmet Gül, Jasmin B Kuemmerledeschner, Isabelle Konepaut, Véronique HentgenAbstract:Objective Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), and Mevalonate Kinase Deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). Methods PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de-identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. Results A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute-phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8-year delay in FMF patients. An equal proportion of TRAPS patients first received anti–interleukin-1 (anti-IL-1) and anti–tumor necrosis factor (anti-TNF) biologic agents, whereas IL-1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti-TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. Conclusion Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real-world treatment assessment supports the need for further refinement of treatment practices.
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International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome.
Arthritis care & research, 2017Co-Authors: Seza Ozen, Pierre Quartier, Isabelle Koné-paut, Jasmin B. Kuemmerle-deschner, Rolando Cimaz, Avi Livneh, Andrew Zeft, Steve Spalding, Ahmet Gül, Véronique HentgenAbstract:Objective Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), and Mevalonate Kinase Deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). Methods PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de-identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. Results A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute-phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8-year delay in FMF patients. An equal proportion of TRAPS patients first received anti–interleukin-1 (anti-IL-1) and anti–tumor necrosis factor (anti-TNF) biologic agents, whereas IL-1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti-TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P
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Mevalonate Kinase Deficiency: A Survey of 50 Patients
Pediatrics, 2011Co-Authors: Brigitte Bader-meunier, Eric Hachulla, Benoit Florkin, Jean Sibilia, Cécile Acquaviva, Gilles Grateau, Olivier Richer, Claire Michèle Farber, Michel Fischbach, Véronique HentgenAbstract:OBJECTIVE: The goal of this study was to describe the spectrum of clinical signs of Mevalonate Kinase Deficiency (MKD). METHODS: This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations. RESULTS: Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjogren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients. CONCLUSION: MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunoDeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.
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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Diagnostic Value of Urinary Mevalonic Acid Excretion in Patients with a Clinical Suspicion of Mevalonate Kinase Deficiency (MKD).
JIMD reports, 2015Co-Authors: Jerold Jeyaratnam, Hans R. Waterham, M. G. M. De Sain-van Der Velden, M. E. Van Gijn, Nienke M. Ter Haar, 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. Methods: In this single-center, retrospective analysis, all patients in whom both measurement of mevalonic acid and genetic testing had been performed in the preceding 17 years have been included. The presence of two pathogenic MVK mutations or demonstration of decreased enzyme activity was considered to be the gold standard for the diagnosis of MKD. Results: Sixty-one patients were included in this study. Thirteen of them harbored two MVK mutations; twelve of them showed elevated levels of mevalonic acid. Forty-eight patients did not harbor any MVK mutations, yet five of them excreted increased amounts of mevalonic acid. This corresponds to a sensitivity of 92%, a specificity of 90%, a positive predictive value of 71%, and a negative predictive value of 98%. The positive likelihood ratio is 10 and the negative likelihood ratio is 0.09. Conclusion: MKD seems very unlikely in patients with a normal mevalonic acid excretion, but it cannot be excluded completely. Further, a positive urinary mevalonic acid excretion still requires MVK analysis to confirm the diagnosis of MKD. Therefore, detection of urinary mevalonic acid should not be mandatory before genetic testing. However, as long as genetic testing is not widely available and affordable, measurement of urinary mevalonic acid is a fair way to select patients for MVK gene analysis or enzyme assay.
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Unprenylated RhoA contributes to IL-1β hypersecretion in Mevalonate Kinase Deficiency model through stimulation of Rac1 activity
The Journal of biological chemistry, 2014Co-Authors: Robert Van Der Burgh, Joost Frenkel, Hans R. Waterham, Marjolein Turkenburg, Kalliopi Pervolaraki, Marianne BoesAbstract:Abstract Protein prenylation is a post-translational modification whereby non-sterol isoprenoid lipid chains are added, thereby modifying the molecular partners with which proteins interact. The autoinflammatory disease Mevalonate Kinase Deficiency (MKD) is characterized by a severe reduction in protein prenylation. A major class of proteins that are affected are small GTPases, including Rac1 and RhoA. It is not clear how protein prenylation of small GTPases relates to GTP hydrolysis activity and downstream signaling. Here, we investigated the contribution of RhoA prenylation to the biochemical pathways that underlie MKD-associated IL-1β hypersecretion using human cell cultures, Rac1 and RhoA protein variants, and pharmacological inhibitors. We found that when unprenylated, the GTP-bound levels of RhoA decrease, causing a reduction in GTPase activity and increased protein Kinase B (PKB) phosphorylation. Cells expressing unprenylated RhoA produce increased levels of interleukin 1β mRNA. Of other phenotypic cellular changes seen in MKD, increased mitochondrial potential and mitochondrial elongation, only mitochondrial elongation was observed. Finally, we show that pharmacological inactivation of RhoA boosts Rac1 activity, a small GTPase whose activity was earlier implied in MKD pathogenesis. Together, our data show that RhoA plays a pivotal role in MKD pathogenesis through Rac1/PKB signaling toward interleukin 1β production and elucidate the effects of protein prenylation in monocytes.
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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.