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1.
J Inherit Metab Dis ; 44(5): 1272-1287, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34145613

RESUMO

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD/HIDS) are disorders of cholesterol biosynthesis caused by variants in the MVK gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in-depth analysis of the phenotypic spectrum of MVA and provide an in-silico pathogenicity model analysis of MVK missense variants. The phenotypic spectrum of 11 MVA patients (age range 0-51 years) registered in the Unified European Registry for Inherited Metabolic Disorders database was systematically analyzed using terms of the Human Phenotype Ontology. Biochemical, radiological as well as genetic characteristics were investigated. Six of eleven patients have reached adulthood and four have reached adolescence. One of the adolescent patients died at the age of 16 years and one patient died shortly after birth. Symptoms started within the first year of life, including episodic fever, developmental delay, ataxia, and ocular involvement. We also describe a case with absence of symptoms despite massive excretion of mevalonic acid. Pathogenic variants causing MVA cluster within highly conserved regions, which are involved in mevalonate and ATP binding. The phenotype of adult and adolescent MVA patients is more heterogeneous than previously assumed. Outcome varies from an asymptomatic course to early death. MVK variants cluster in functionally important and highly conserved protein domains and show high concordance regarding their expected pathogenicity.


Assuntos
Deficiência de Mevalonato Quinase/patologia , Ácido Mevalônico/metabolismo , Mutação de Sentido Incorreto , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Deficiência de Mevalonato Quinase/metabolismo , Ácido Mevalônico/urina , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Adulto Jovem
2.
Clin Exp Dermatol ; 45(8): 962-966, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32901977

RESUMO

The systemic autoinflammatory disorders (SAIDs) or periodic fever syndromes are disorders of innate immunity, which can be inherited or acquired. They are almost all very rare and easily overlooked; typically, patients will have seen multiple specialities prior to diagnosis, so a high level of clinical suspicion is key. It is important to note that these are 'high-value' diagnoses as the majority of these syndromes can be very effectively controlled, dramatically improving quality of life and providing protection against the development of irreversible complications such as AA amyloidosis. In this article, we take an overview of SAIDs and look at the common features; in Part 2, we take a more in-depth look at the better recognized or more dermatologically relevant conditions.


Assuntos
Amiloidose/prevenção & controle , Dermatologistas/estatística & dados numéricos , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças do Sistema Imunitário/imunologia , Amiloidose/etiologia , Amiloidose/patologia , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/metabolismo , Síndromes Periódicas Associadas à Criopirina/patologia , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/metabolismo , Febre Familiar do Mediterrâneo/patologia , Febre/diagnóstico , Febre/metabolismo , Febre/patologia , Testes Genéticos/normas , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/metabolismo , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/patologia , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/metabolismo , Deficiência de Mevalonato Quinase/patologia , Qualidade de Vida , Índice de Gravidade de Doença
3.
Clin Exp Dermatol ; 45(8): 967-973, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32882069

RESUMO

The systemic autoinflammatory disorders (SAIDS) or periodic fever syndromes are disorders of innate immunity, which can be inherited or acquired. They are almost all very rare and easily overlooked; typically, patients will have seen multiple specialities prior to diagnosis, so a high level of clinical suspicion is key. It is important to note that these are 'high-value' diagnoses as the majority of these syndromes can be very effectively controlled, dramatically improving quality of life and providing protection against the development of irreversible complications such as AA amyloidosis. In Part 1 of this review, we took an overview of SAIDS and described the common features; in this article, we take a more in-depth look at the better recognized or more dermatologically relevant conditions.


Assuntos
Amiloidose/prevenção & controle , Dermatologistas/estatística & dados numéricos , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças do Sistema Imunitário/imunologia , Receptores de Interleucina-1/deficiência , Amiloidose/etiologia , Amiloidose/patologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Produtos Biológicos/uso terapêutico , Colchicina/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/patologia , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/patologia , Febre/diagnóstico , Febre/tratamento farmacológico , Febre/genética , Febre/patologia , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/patologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Inflamação/patologia , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/imunologia , Interleucina-1/metabolismo , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/tratamento farmacológico , Deficiência de Mevalonato Quinase/genética , Deficiência de Mevalonato Quinase/patologia , Receptores de Interleucina-1/efeitos dos fármacos , Receptores de Interleucina-1/genética , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/uso terapêutico , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/imunologia , Síndrome de Schnitzler/patologia , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/imunologia , Dermatopatias Genéticas/patologia , Esteroides/uso terapêutico , Moduladores de Tubulina/uso terapêutico
4.
Curr Genet ; 64(4): 871-881, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29374778

RESUMO

Mevalonate kinase deficiency (MKD) an orphan drug rare disease affecting humans with different clinical presentations, is still lacking information about its pathogenesis; no animal or cell model mimicking the genetic defect, mutations at MVK gene, and its consequences on the mevalonate pathway is available. Trying to clarify the effects of MVK gene impairment on the mevalonate pathway we used a yeast model, the erg12-d mutant strain Saccharomyces cerevisiae (orthologous of MKV) retaining only 10% of mevalonate kinase (MK) activity, to describe the effects of reduced MK activity on the mevalonate pathway. Since shortage of isoprenoids has been described in MKD, we checked this observation using a physiologic approach: while normally growing on glucose, erg12-d showed growth deficiency in glycerol, a respirable carbon source, that was not rescued by supplementation with non-sterol isoprenoids, such as farnesol, geraniol nor geranylgeraniol, produced by the mevalonate pathway. Erg12-d whole genome expression analysis revealed specific downregulation of RSF2 gene encoding general transcription factor for respiratory genes, explaining the absence of growth on glycerol. Moreover, we observed the upregulation of genes involved in sulphur amino acids biosynthesis that coincided with the increasing in the amount of proteins containing sulfhydryl groups; upregulation of ubiquinone biosynthesis genes was also detected. Our findings demonstrated that the shortage of isoprenoids is not the main mechanism involved in the respiratory deficit and mitochondrial malfunctioning of MK-defective cells, while the scarcity of ubiquinone plays an important role, as already observed in MKD patients.


Assuntos
Deficiência de Mevalonato Quinase/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Respiração/genética , Saccharomyces cerevisiae/genética , Regulação Fúngica da Expressão Gênica , Genoma Fúngico , Humanos , Deficiência de Mevalonato Quinase/metabolismo , Deficiência de Mevalonato Quinase/patologia , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/genética , Terpenos/metabolismo , Fatores de Transcrição/genética , Ubiquinona/genética , Ubiquinona/metabolismo
5.
Cell Physiol Biochem ; 41(4): 1649-1660, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28359055

RESUMO

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.


Assuntos
Apoptose , Autofagia , Deficiência de Mevalonato Quinase/metabolismo , Modelos Biológicos , Prenilação de Proteína , Animais , Linhagem Celular Tumoral , Macrolídeos/farmacologia , Deficiência de Mevalonato Quinase/genética , Deficiência de Mevalonato Quinase/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ratos
7.
Immunol Cell Biol ; 94(10): 994-999, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27377765

RESUMO

Mevalonate kinase deficiency (MKD) is caused by mutations in a key enzyme of the mevalonate-cholesterol biosynthesis pathway, leading to recurrent autoinflammatory disease characterised by enhanced release of interleukin-1ß (IL-1ß). It is currently believed that the inflammatory phenotype of MKD is triggered by temperature-sensitive loss of mevalonate kinase activity and reduced biosynthesis of isoprenoid lipids required for the prenylation of small GTPase proteins. However, previous studies have not clearly shown any change in protein prenylation in patient cells under normal conditions. With lymphoblast cell lines from two compound heterozygous MKD patients, we used a highly sensitive in vitro prenylation assay, together with quantitative mass spectrometry, to reveal a subtle accumulation of unprenylated Rab GTPases in cells cultured for 3 days or more at 40 °C compared with 37 °C. This included a 200% increase in unprenylated Rab7A, Rab14 and Rab1A. Inhibition of sterol regulatory element-binding protein (SREBP) activation by fatostatin led to more pronounced accumulation of unprenylated Rab proteins in MKD cells but not parent cells, suggesting that cultured MKD cells may partially overcome the loss of isoprenoid lipids by SREBP-mediated upregulation of enzymes required for isoprenoid biosynthesis. Furthermore, while inhibition of Rho/Rac/Rap prenylation promoted the release of IL-1ß, specific inhibition of Rab prenylation by NE10790 had no effect in human peripheral blood mononuclear cells or human THP-1 monocytic cells. These studies demonstrate for the first time that mutations in mevalonate kinase can lead to a mild, temperature-induced defect in the prenylation of small GTPases, but that loss of prenylated Rab GTPases is not the cause of enhanced IL-1ß release in MKD.


Assuntos
Deficiência de Mevalonato Quinase/enzimologia , Prenilação de Proteína , Proteínas rab de Ligação ao GTP/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Feminino , Humanos , Interleucina-1beta/metabolismo , Marcação por Isótopo , Leucócitos Mononucleares/metabolismo , Masculino , Deficiência de Mevalonato Quinase/patologia , Piridinas/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Temperatura , Tiazóis/farmacologia
8.
Int J Mol Sci ; 17(3): 365, 2016 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-26978350

RESUMO

Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.


Assuntos
Diterpenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Deficiência de Mevalonato Quinase/metabolismo , Ácido Mevalônico/farmacologia , Mitocôndrias/efeitos dos fármacos , Apoptose , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Deficiência de Mevalonato Quinase/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos
9.
J Biol Chem ; 289(8): 5000-12, 2014 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-24356959

RESUMO

Most hereditary periodic fever syndromes are mediated by deregulated IL-1ß secretion. The generation of mature IL-1ß requires two signals: one that induces synthesis of inflammasome components and substrates and a second that activates inflammasomes. The mechanisms that mediate autoinflammation in mevalonate kinase deficiency, a periodic fever disease characterized by a block in isoprenoid biosynthesis, are poorly understood. In studying the effects of isoprenoid shortage on IL-1 ß generation, we identified a new inflammasome activation signal that originates from defects in autophagy. We find that hypersecretion of IL-1ß and IL-18 requires reactive oxygen species and is associated with an oxidized redox status of monocytes but not lymphocytes. IL-1ß hypersecretion by monocytes involves decreased mitochondrial stability, release of mitochondrial content into the cytosol and attenuated autophagosomal degradation. Defective autophagy, as established by ATG7 knockdown, results in prolonged cytosolic retention of damaged mitochondria and increased IL-1ß secretion. Finally, activation of autophagy in healthy but not mevalonate kinase deficiency patient cells reduces IL-1ß secretion. Together, these results indicate that defective autophagy can prime monocytes for mitochondria-mediated NLRP3 inflammasome activation, thereby contributing to hypersecretion of IL-1ß in mevalonate kinase deficiency.


Assuntos
Suscetibilidade a Doenças/metabolismo , Suscetibilidade a Doenças/patologia , Interleucina-1beta/metabolismo , Mitocôndrias/metabolismo , Monócitos/metabolismo , Monócitos/patologia , Adolescente , Autofagia , Linhagem Celular , Criança , Pré-Escolar , Citosol/metabolismo , DNA Mitocondrial/metabolismo , Humanos , Inflamassomos/metabolismo , Potencial da Membrana Mitocondrial , Deficiência de Mevalonato Quinase/metabolismo , Deficiência de Mevalonato Quinase/patologia , Modelos Biológicos , Oxirredução , Terpenos/metabolismo
10.
Int J Mol Sci ; 16(7): 16067-84, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26184189

RESUMO

The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with diminished protein prenylation, an important post-translational modification necessary to localize certain proteins, such as small GTPases, to membranes. Mevalonate pathway blockade has been linked to mitochondrial dysfunction: especially involving lower mitochondrial membrane potential and increased release of pro-apoptotic factors in cytosol. Furthermore a severe reduction of protein prenylation has also been associated with defective autophagy, possibly causing inflammasome activation and subsequent cell death. So, it is tempting to hypothesize a mechanism in which defective autophagy fails to remove damaged mitochondria, resulting in increased cell death. This mechanism could play a significant role in Mevalonate Kinase Deficiency, an autoinflammatory disease characterized by a defect in Mevalonate Kinase, a key enzyme of the mevalonate pathway. Patients carrying mutations in the MVK gene, encoding this enzyme, show increased inflammation and lower protein prenylation levels. This review aims at analysing the correlation between mevalonate pathway defects, mitochondrial dysfunction and defective autophagy, as well as inflammation, using Mevalonate Kinase Deficiency as a model to clarify the current pathogenetic hypothesis as the basis of the disease.


Assuntos
Ácido Mevalônico/metabolismo , Mitocôndrias/metabolismo , Autofagia/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Deficiência de Mevalonato Quinase/tratamento farmacológico , Deficiência de Mevalonato Quinase/genética , Deficiência de Mevalonato Quinase/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Prenilação de Proteína , Serina-Treonina Quinases TOR/metabolismo
11.
Int J Mol Sci ; 15(4): 6843-56, 2014 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-24758928

RESUMO

Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines' release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.


Assuntos
Ácido Mevalônico/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carotenoides/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Citocinas/metabolismo , Diterpenos/farmacologia , Humanos , Licopeno , Deficiência de Mevalonato Quinase/metabolismo , Deficiência de Mevalonato Quinase/patologia , Camundongos , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Óxido Nítrico/metabolismo , Fitol/farmacologia , Terpenos/toxicidade
12.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167177, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38636615

RESUMO

Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder associated with recurrent autoinflammatory episodes. The disorder is caused by bi-allelic loss-of-function variants in the MVK gene, which encodes mevalonate kinase (MK), an early enzyme in the isoprenoid biosynthesis pathway. To identify molecular and cellular consequences of MKD, we studied primary fibroblasts from severely affected patients with mevalonic aciduria (MKD-MA) and more mildly affected patients with hyper IgD and periodic fever syndrome (MKD-HIDS). As previous findings indicated that the deficient MK activity in MKD impacts protein prenylation in a temperature-sensitive manner, we compared the subcellular localization and activation of the small Rho GTPases RhoA, Rac1 and Cdc42 in control, MKD-HIDS and MKD-MA fibroblasts cultured at physiological and elevated temperatures. This revealed a temperature-induced altered subcellular localization and activation in the MKD cells. To study if and how the temperature-induced ectopic activation of these signalling proteins affects cellular processes, we performed comparative transcriptome analysis of control and MKD-MA fibroblasts cultured at 37 °C or 40 °C. This identified cell cycle and actin cytoskeleton organization as respectively most down- and upregulated gene clusters. Further studies confirmed that these processes were affected in fibroblasts from both patients with MKD-MA and MKD-HIDS. Finally, we found that, similar to immune cells, the MK deficiency causes metabolic reprogramming in MKD fibroblasts resulting in increased expression of genes involved in glycolysis and the PI3K/Akt/mTOR pathway. We postulate that the ectopic activation of small GTPases causes inappropriate signalling contributing to the molecular and cellular aberrations observed in MKD.


Assuntos
Fibroblastos , Deficiência de Mevalonato Quinase , Deficiência de Mevalonato Quinase/genética , Deficiência de Mevalonato Quinase/metabolismo , Deficiência de Mevalonato Quinase/patologia , Humanos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Células Cultivadas , Transdução de Sinais
13.
Int J Mol Sci ; 14(12): 23274-88, 2013 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-24287904

RESUMO

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.


Assuntos
Apoptose , Deficiência de Mevalonato Quinase/enzimologia , Animais , Caspases/metabolismo , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/metabolismo , Humanos , Inflamassomos/metabolismo , Deficiência de Mevalonato Quinase/metabolismo , Deficiência de Mevalonato Quinase/patologia , Modelos Biológicos , Estresse Oxidativo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
14.
Am J Transplant ; 12(6): 1627-31, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22405037

RESUMO

Mevalonic aciduria because of mutations of the gene for mevalonate kinase causes limited synthesis of isoprenoids, the effects of which are widespread. The outcome for affected children is poor. A child with severe multisystem manifestations underwent orthotopic liver transplantation at age 50 months for the indication of end-stage liver disease. This procedure corrected liver function and eliminated portal hypertension, and the patient showed substantial improvement in neurological function. However, autoinflammatory episodes continued unabated until hematopoietic stem cell transplantation was performed at 80 months. Through this complex therapy, the patient now enjoys a high quality of life without significant disability.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante de Fígado , Deficiência de Mevalonato Quinase/cirurgia , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Deficiência de Mevalonato Quinase/patologia , Transplante Homólogo
15.
Biochim Biophys Acta Mol Basis Dis ; 1867(4): 166053, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33385519

RESUMO

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.


Assuntos
Deficiência de Mevalonato Quinase/genética , Mitofagia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Deleção de Genes , Humanos , Deficiência de Mevalonato Quinase/patologia
16.
Curr Rheumatol Rep ; 12(2): 101-7, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20425018

RESUMO

Hyperimmunoglobulinemia D and periodic fever syndrome, an autoinflammatory syndrome, is caused by mutations in the gene coding for mevalonate kinase. The disease is clinically characterized by recurrent attacks of fever accompanied by an array of inflammatory symptoms including lymphadenopathy, rash, arthritis, and gastrointestinal complaints. Most patients have their first attack in the first year of life, typically after a childhood vaccination. The frequency of attacks is highest during childhood, with a gradual decrease after adolescence. Frequent fever attacks impair quality of life and the achievement of educational milestones. Recent reports show promising results with anakinra and etanercept to treat the attacks.


Assuntos
Deficiência de Mevalonato Quinase/patologia , Atividades Cotidianas , Adolescente , Criança , Pré-Escolar , Etanercepte , Febre/fisiopatologia , Humanos , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Deficiência de Mevalonato Quinase/tratamento farmacológico , Deficiência de Mevalonato Quinase/genética , Fosfotransferases (Aceptor do Grupo Álcool)/sangue , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Qualidade de Vida , Receptores do Fator de Necrose Tumoral/uso terapêutico , Síndrome
17.
PLoS One ; 15(8): e0237999, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822427

RESUMO

Hyper-IgD syndrome (HIDS, OMIM #260920) is a rare autosomal recessive autoinflammatory disorder caused by pathogenic variants in the mevalonate kinase (MVK) gene. HIDS has an incidence of 1:50,000 to 1:5,000, and is thought to be prevalent mainly in northern Europe. Here, we report a case series of HIDS from India, which includes ten patients from six families who presented with a wide spectrum of clinical features such as recurrent fever, oral ulcers, rash, arthritis, recurrent diarrhea, hepatosplenomegaly, and high immunoglobulin levels. Using whole exome sequencing (WES) and/or Sanger capillary sequencing, we identified five distinct genetic variants in the MVK gene from nine patients belonging to six families. The variants were classified as pathogenic or likely pathogenic as per the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for annotation of sequence variants. Over 70% of patients in the present study had two recurrent mutations in MVK gene i.e. a nonsynonymous variant p.V377I, popularly known as the 'Dutch mutation', along with a splicing variant c.226+2delT in a compound heterozygous form. Identity by descent analysis in two patients with the recurrent variants identified a 6.7 MB long haplotype suggesting a founder effect in the South Indian population. Our analysis suggests that a limited number of variants account for the majority of the patients with HIDS in South India. This has implications in clinical diagnosis, as well as in the development of cost-effective approaches for genetic diagnosis and screening. To our best knowledge, this is the first and most comprehensive case series of clinically and genetically characterized patients with HIDS from India.


Assuntos
Povo Asiático/genética , Deficiência de Mevalonato Quinase/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Pré-Escolar , Feminino , Deleção de Genes , Estudos de Associação Genética , Haplótipos , Heterozigoto , Humanos , Índia , Lactente , Masculino , Deficiência de Mevalonato Quinase/genética , Linhagem , Fosfotransferases (Aceptor do Grupo Álcool)/química , Polimorfismo de Nucleotídeo Único , Estrutura Terciária de Proteína , Sequenciamento do Exoma
18.
J Evid Based Med ; 13(3): 227-245, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32627322

RESUMO

Disruption of innate immunity leading to systemic inflammation and multi-organ dysfunction is the basilar footprint of autoinflammatory disorders (AIDs), ranging from rare hereditary monogenic diseases to a large number of common chronic inflammatory conditions in which there is a simultaneous participation of multiple genetic components and environmental factors, sometimes combined with autoimmune phenomena and immunodeficiency. Whatever their molecular mechanism, hereditary AIDs are caused by mutations in regulatory molecules or sensors proteins leading to dysregulated production of proinflammatory cytokines or cytokine-inducing transcription factors, fever, elevation of acute phase reactants, and a portfolio of manifold inflammatory signs which might occur in a stereotyped manner, mostly with overactivity or misactivation of different inflammasomes. Symptoms might overlap in the pediatric patient, obscuring the final diagnosis of AIDs and delaying the most appropriate treatment. Actually, the fast-paced evolution of scientific knowledge has led to recognize or reclassify an overgrowing number of multifactorial diseases, which share the basic pathogenetic mechanisms with AIDs. The wide framework of classic hereditary periodic fevers, AIDs with prominent skin involvement, disorders of the ubiquitin-proteasome system, defects of actin cytoskeleton dynamics, and also idiopathic nonhereditary febrile syndromes occurring in children is herein presented. Interleukin-1 dependence of these diseases or involvement of other predominating molecules is also discussed.


Assuntos
Doenças Autoimunes/patologia , Doenças Hereditárias Autoinflamatórias/patologia , Síndrome da Imunodeficiência Adquirida/patologia , Criança , Síndromes Periódicas Associadas à Criopirina/patologia , Febre Familiar do Mediterrâneo/patologia , Humanos , Inflamação/patologia , Deficiência de Mevalonato Quinase/patologia , Fenótipo , Pele/patologia
19.
J Inherit Metab Dis ; 32(4): 570-5, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19504350

RESUMO

The content of coenzyme Q(10) (CoQ(10)) 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 CoQ(10) depletion either by direct inhibition of the proximal pathway of CoQ(10) synthesis (MVA) or indirectly by inhibition of mitochondrial energy metabolism (MMA). We demonstrated that CoQ(10) concentrations were not significantly different from controls in MVA patients, suggesting that there may be upregulatory effects. On the other hand the CoQ(10) content in fibroblasts of patients with MMA was significantly reduced.


Assuntos
Fibroblastos/metabolismo , Fibroblastos/patologia , Erros Inatos do Metabolismo/patologia , Deficiência de Mevalonato Quinase/patologia , Ubiquinona/análogos & derivados , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo , Feminino , Humanos , Erros Inatos do Metabolismo/metabolismo , Ácido Metilmalônico/urina , Deficiência de Mevalonato Quinase/metabolismo , Músculos/metabolismo , Músculos/patologia , Ubiquinona/metabolismo
20.
Med Hypotheses ; 70(5): 938-40, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18037572

RESUMO

Mevalonic aciduria belongs to a group of rare inherited metabolic disorders related to cholesterol biosynthesis. The pathogenesis of mevalonic aciduria is not clear, although the cause is known - a genetic defect leading to a deficiency in mevalonate kinase activity. The lack of non-steroid isoprenoids in patients with mevalonic aciduria might cause oxidative stress due to a decreased production of endogenous antioxidants including ubiquinone 10, selenoproteins and glutathione peroxidase. The Moosmann-Behl hypothesis of statin-induced muscular and neuronal damage mediated by oxidative stress might explain at least partially the pathogenesis of mevalonic aciduria. Studies focusing on the role of oxidative stress in patients suffering from disorders in cholesterol biosynthesis are needed to support adjuvant antioxidative treatment.


Assuntos
Deficiência de Mevalonato Quinase/tratamento farmacológico , Deficiência de Mevalonato Quinase/patologia , Estresse Oxidativo , Terpenos/metabolismo , Antioxidantes/metabolismo , Colesterol/metabolismo , Glutationa Peroxidase/metabolismo , Glicosilação , Humanos , Modelos Biológicos , Mutação , Neurônios/metabolismo , Selenocisteína/metabolismo , Selenoproteínas/metabolismo , Terpenos/química
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