scholarly journals Temperature and Drug Treatments in Mevalonate Kinase Deficiency: AnEx VivoStudy

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Paola Maura Tricarico ◽  
Giulio Kleiner ◽  
Elisa Piscianz ◽  
Valentina Zanin ◽  
Lorenzo Monasta ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Mevalonate Pathway ◽  
Cholesterol Biosynthesis ◽  
Effect Of Temperature ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Febrile Condition ◽  
Inflammatory Phenotype ◽  
Drug Treatments

Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused by mutations 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-1βrelease. In MKD, febrile temperature can further decrease the residual MK activity, leading to mevalonate pathway modulation and to possible disease worsening. We previously demonstrated that the administration of exogenous isoprenoids such as geraniol or the modulation of the enzymatic pathway with drugs, such as Tipifarnib, partially rescues the inflammatory phenotype associated with the defective mevalonic pathway. However, it has not been investigated yet how temperature can affect the success of these treatments. Thus, we investigated the effect of temperature on primary human monocytes from MKD patients. Furthermore the ability of geraniol and Tipifarnib to reduce the abnormal inflammatory response, already described at physiological temperature in MKD, was studied in a febrile condition. We evidenced the role of temperature in the modulation of the inflammatory events and suggested strongly considering this variable in future researches aimed at finding a treatment for MKD.

Mevalonate Kinase Deficiency: Disclosing the Role of Mevalonate Pathway Modulation in Inflammation

2012 ◽  
Vol 18 (35) ◽  
pp. 5746-5752 ◽  
Author(s):  
Annalisa Marcuzzi ◽  
Sergio Crovella ◽  
Lorenzo Monasta ◽  
Liza Vecchi Brumatti ◽  
Marco Gattorno ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase

Mevalonic aciduria: Family studies in mevalonate kinase deficiency, an inborn error of cholesterol biosynthesis

1987 ◽  
Vol 10 (S2) ◽  
pp. 282-285 ◽  
Author(s):  
K. M. Gibson ◽  
G. Hoffmann ◽  
W. L. Nyhan ◽  
L. Sweetman ◽  
I. K. Brandt ◽  
...  
Keyword(s):  
Inborn Error ◽  
Cholesterol Biosynthesis ◽  
Family Studies ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Mevalonic Aciduria

scholarly journals Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency

2021 ◽  
Vol 12 ◽  
Author(s):  
Frouwkje A. Politiek ◽  
Hans R. Waterham
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Biosynthesis Pathway ◽  
Protein Prenylation ◽  
Pathogenic Variants ◽  
Essential Enzyme

Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.

Mevalonate Kinase Deficiency

2016 ◽  
Author(s):  
Joost Frenkel ◽  
Hans R. Waterham
Keyword(s):  
Autosomal Recessive ◽  
Severe Infection ◽  
Innate Immune ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Intellectual Impairment ◽  
Immune System Activation ◽  
Progressive Cerebellar Ataxia ◽  
System Activation ◽  
Encoding Gene

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.

scholarly journals Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

2017 ◽  
Vol 41 (4) ◽  
pp. 1649-1660 ◽  
Author(s):  
Paola Maura Tricarico ◽  
Alessandra Romeo ◽  
Rossella Gratton ◽  
Sergio Crovella ◽  
Fulvio Celsi
Keyword(s):  
Cell Death ◽  
Mevalonate Pathway ◽  
Cell Model ◽  
Neuroblastoma Cell ◽  
Neuronal Cell ◽  
Autophagic Flux ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Protein Prenylation ◽  
Prenylated Proteins

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.

A Clinical Criterion to Exclude the Hyperimmunoglobulin D Syndrome (Mild Mevalonate Kinase Deficiency) in Patients with Recurrent Fever

2009 ◽  
Vol 36 (8) ◽  
pp. 1677-1681 ◽  
Author(s):  
OLIVIER STEICHEN ◽  
JEROEN van der HILST ◽  
ANNA SIMON ◽  
LAURENCE CUISSET ◽  
GILLES GRATEAU
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Recursive Partitioning ◽  
Clinical Criterion ◽  
Recurrent Fever ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Single Patient ◽  
Kinase Gene ◽  
Mevalonate Kinase Gene

Objective.The hyperimmunoglobulin D syndrome (HIDS) is an autosomal recessive autoinflammatory disease caused by mutations in the mevalonate kinase gene. Our objective was to define a clinical criterion able to exclude HIDS without the need of genetic testing.Methods.A recursive partitioning algorithm was applied to derive the clinical criterion in 149 patients with genetic testing in a French laboratory, among whom 35 had HIDS. The criterion was validated in 93 patients with genetic testing in a Dutch laboratory, among whom 28 had HIDS.Results.The most discriminatory composite clinical criterion satisfied by all patients with HIDS in the derivation group was [onset age < 5 years old OR (joint pain during attacks AND length of attacks < 14 days)]. It had a sensitivity of 100% (95% confidence interval 88% to 100%) and a specificity of 28% (95% CI 17% to 40%) in the validation group. If genetic testing had been limited to patients fulfilling this criterion, 18 tests (19%) would have been avoided in this highly selected validation sample, without missing a single patient with HIDS.Conclusion.Even among patients already selected by expert physicians, this criterion could help prevent unnecessary genetic testing, which is resource- and time-consuming.

scholarly journals Cholesterol biosynthetic pathway induces cellular senescence through ERRa

2021 ◽  
Author(s):  
Dorian V Ziegler ◽  
Mathieu Vernier ◽  
Joanna Czarnecka-Herok ◽  
Charlotte Scholtes ◽  
Christelle Machon ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Biosynthetic Pathway ◽  
Mevalonate Pathway ◽  
Cholesterol Biosynthesis ◽  
Age Related ◽  
Diet Regimen ◽  
Cholesterol Biosynthetic Pathway ◽  
A Cell ◽  
Normal Human

Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular metabolism associated to senescence phenotype. Nonetheless, the functional contribution of metabolic homeostasis in regulating senescence is barely understood. In this work, we describe how the mevalonate pathway, an anabolic pathway leading to the endogenous biosynthesis of poly-isoprenoids, such as cholesterol, acts as a positive regulator of cellular senescence in normal human cells. Mechanistically, this mevalonate-induced senescence is partly mediated by the downstream cholesterol biosynthetic pathway. This pathway promotes transcriptional activity of ERRα leading to dysfunctional mitochondria, ROS production, DNA damage and a p53-dependent senescence. Supporting the relevance of these observations, increase of senescence in liver due to a high-fat diet regimen is abrogated in ERRα knockout mouse. Overall, this work unravels the role of cholesterol biosynthesis in the induction of an ERRα-dependent mitochondrial program leading to cellular senescence and related pathological alterations.

scholarly journals Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice

2018 ◽  
Vol 25 (24) ◽  
pp. 2783-2796 ◽  
Author(s):  
Annalisa Marcuzzi ◽  
Claudia Loganes ◽  
Claudio Celeghini ◽  
Giulio Kleiner
Keyword(s):  
Mevalonate Pathway ◽  
Clinical Symptoms ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Similar Action ◽  
Cellular Models ◽  
Inflammatory Stimuli

Background: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. <p> Objective: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints’ conditions and their quality of life. <p> Methods: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block. <p> Results: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile. <p> Conclusions: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

Sign in / Sign up

Export Citation Format

Share Document