Mevalonate Kinase Deficiency Patients Research Articles

Canakinumab treatment real world evidence in 3 monogenic periodic fever syndromes in 2009–2022: an interim analysis using the French JIR cohort database

BackgroundOur study aimed to provide real-world evidence on the treatment patterns, effectiveness and safety of canakinumab in France in Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD), and Tumor necrosis factor Receptor Associated Periodic Syndrome (TRAPS).MethodsThis study used the JIR cohort, a multicentre international registry created in 2013 to collect data on patients with juvenile inflammatory rheumatic diseases. French patients diagnosed with FMF, MKD or TRAPS and treated with canakinumab were included in this study.Results31 FMF, 26 MKD and 7 TRAPS patients received canakinumab during the study period. Most of them initiated canakinumab at the recommended dose of 2 mg/kg or 150 mg, but less than half of FMF and MKD patients initiated it at the recommended frequency (every 4 weeks). Two years after initiation, the rate of patients still on treatment was 78.1% in FMF, 73.7% in MKD, and 85.7% in TRAPS patients. While the dose per injection remained globally the same over the course of the treatment, some adjustments of the dose intervals were observed. Six patients had a severe adverse event reported. Of those, three were possibly related to canakinumab.ConclusionThis interim analysis showed a good maintenance of canakinumab treatment 2 years after initiation and confirmed its safety profile in real-life practice in France in patients diagnosed with FMF, MKD and TRAPS. The high variety of dose and interval combinations observed in canakinumab treated patients let suppose that physicians adapt the posology to individual situations rather than a fixed treatment plan.

Mevalonate kinase-deficient THP-1 cells show a disease-characteristic pro-inflammatory phenotype.

Bi-allelic pathogenic variants in the MVK gene, which encodes mevalonate kinase (MK), an essential enzyme in isoprenoid biosynthesis, cause the autoinflammatory metabolic disorder mevalonate kinase deficiency (MKD). We generated and characterized MK-deficient monocytic THP-1 cells to identify molecular and cellular mechanisms that contribute to the pro-inflammatory phenotype of MKD. Using CRISPR/Cas9 genome editing, we generated THP-1 cells with different MK deficiencies mimicking the severe (MKD-MA) and mild end (MKD-HIDS) of the MKD disease spectrum. Following confirmation of previously established disease-specific biochemical hallmarks, we studied the consequences of the different MK deficiencies on LPS-stimulated cytokine release, glycolysis versus oxidative phosphorylation rates, cellular chemotaxis and protein kinase activity. Similar to MKD patients' cells, MK deficiency in the THP-1 cells caused a pro-inflammatory phenotype with a severity correlating with the residual MK protein levels. In the MKD-MA THP-1 cells, MK protein levels were barely detectable, which affected protein prenylation and was accompanied by a profound pro-inflammatory phenotype. This included a markedly increased LPS-stimulated release of pro-inflammatory cytokines and a metabolic switch from oxidative phosphorylation towards glycolysis. We also observed increased activity of protein kinases that are involved in cell migration and proliferation, and in innate and adaptive immune responses. The MKD-HIDS THP-1 cells had approximately 20% residual MK activity and showed a milder phenotype, which manifested mainly upon LPS stimulation or exposure to elevated temperatures. MK-deficient THP-1 cells show the biochemical and pro-inflammatory phenotype of MKD and are a good model to study underlying disease mechanisms and therapeutic options of this autoinflammatory disorder.

Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases

In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in two subsequent enzyme steps by mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) to generate mevalonate pyrophosphate that is further metabolized to produce sterol and non-sterol isoprenoids. Biallelic pathogenic variants in the MVK gene result in the autoinflammatory metabolic disorder MVK Deficiency (MKD). So far, however, no patients with proven PMVK deficiency due to biallelic pathogenic variants in the PMVK gene have been reported. This study aims to report the first patient with functionally confirmed PMVK deficiency, including the clinical, biochemical and immunological consequences of a homozygous missense variant in the PMVK gene. We performed whole-exome sequencing and functional studies in cells from a patient who, upon clinical and immunological evaluation, was suspected of an autoinflammatory disease. We identified a homozygous PMVK p.Val131Ala (NM_006556.4: c.392T>C,) missense variant in our patient. Pathogenicity was supported by genetic algorithms and modeling analysis and confirmed in patient cells that revealed a markedly reduced PMVK enzyme activity due to a virtually complete absence of PMVK protein. Clinically, the patient showed various similarities, but also distinct features compared to MKD patients, and responded well to therapeutic IL-1 inhibition. In this study we report the first patient with proven PMVK deficiency due to a homozygous missense variant in PMVK leading to an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of systemic autoinflammatory diseases (SAID), characterized by recurrent fevers, arthritis and cytopenia and thus should be included in the differential diagnosis and genetic testing for SAIDs.

Spectrum of auto-inflammatory diseases in Morocco: a monocentric experience.

Auto-inflammatory diseases (AIDs) result from mutations in genes of the innate immune system leading to periodic multisystemic inflammation. We aimed to describe the clinical, biological and molecular features (when available) and outcomes of Moroccan patients with AIDs. Patient data were collected retrospectively and analysed over a 13-year period. Among 30 patients, 60% had FMF, 16% mevalonate kinase deficiency (MKD) and 24% other AIDs. The mean age at first consultation was 6.9 years, and the mean diagnostic delay was 3 years. Consanguinity was reported in 16 cases. IgA vasculitis was associated with 33% of FMF patients, in whom the main clinical features were fever (88.8%), abdominal pain (100%), arthralgias (88.8%) and arthritis (50%), and the most frequent mutation was M694V (66%). All FMF patients were treated with colchicine. Most MKD patients were confirmed by elevated urinary mevalonic acid levels, and four of five MKD patients received targeted therapy. Chronic recurrent osteomyelitis patients were confirmed by radiological and histological analysis. Two cases of Marshall syndrome were diagnosed according to validated criteria. A case of familial pustular psoriasis was diagnosed based on histological analysis and a patient with Muckle-Wells syndrome by clinical features. The outcome was favourable in 76%, partial in 13%, and three deaths were reported. FMF and MKD are the most reported diseases. AIDs are probably underestimated because they are unknown to clinicians. The aim of this work is to raise awareness among paediatricians about AIDs and create a network for best practice.

Gene Expression Analysis of Mevalonate Kinase Deficiency Affected Children Identifies Molecular Signatures Related to Hematopoiesis.

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory genetic disorder characterized by recurrent fever attacks and systemic inflammation with potentially severe complications. Although it is recognized that the lack of protein prenylation consequent to mevalonate pathway blockade drives IL1β hypersecretion, and hence autoinflammation, MKD pathogenesis and the molecular mechanisms underlaying most of its clinical manifestations are still largely unknown. In this study, we performed a comprehensive bioinformatic analysis of a microarray dataset of MKD patients, using gene ontology and Ingenuity Pathway Analysis (IPA) tools, in order to identify the most significant differentially expressed genes and infer their predicted relationships into biological processes, pathways, and networks. We found that hematopoiesis linked biological functions and pathways are predominant in the gene ontology of differentially expressed genes in MKD, in line with the observed clinical feature of anemia. We also provided novel information about the molecular mechanisms at the basis of the hematological abnormalities observed, that are linked to the chronic inflammation and to defective prenylation. Considering the broad and unspecific spectrum of MKD clinical manifestations and the difficulty in its diagnosis, a better understanding of MKD molecular bases could be translated to the clinical level to facilitate diagnosis, and improve management and therapy.

Incomplete mitophagy in the mevalonate kinase-deficient Saccharomyces cerevisiae and its relation to the MKD-related autoinflammatory disease in humans

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.

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

Management of Mevalonate Kinase Deficiency: A Pediatric Perspective

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.

Monocyte Production of IFN-γ Is Interleukin-12 Dependent in a Model of Mevalonate Kinase Deficiency.

Mevalonate Kinase Deficiency (MKD) is an autoinflammatory disease caused by mutations in the mevalonate kinase gene, which produces an enzyme responsible for the production of isoprenoids in the mevalonate pathway. Patient data indicate that MKD is a multicytokine disease with increased plasma levels of cytokines such as tumor necrosis factor-α, interleukin (IL)-6, and interferon (IFN)-γ. To study the mechanisms responsible for these changes, the mevalonate pathway was inhibited with lovastatin in peripheral blood mononuclear cells (PBMCs) and monocytes isolated from the blood of healthy donors followed by stimulation with lipopolysaccharide (LPS) to induce an inflammatory response. Lovastatin treatment resulted in increased levels of IL-6, IL-12p40, and IFN-γ mRNA in both PBMCs and monocytes following LPS stimulation compared with control cells. An IL-12 neutralizing antibody blocked the increased levels of IFN-γ mRNA following lovastatin treatment in PBMCs indicating that this effect is dependent on IL-12. Flow cytometry experiments indicated that monocytes, not lymphocytes or granulocytes, are the source of increased IFN-γ and that both classical and nonclassical/intermediate monocytes express IFN-γ. These results indicate that blocking IL-12 or IFN- γ may be therapeutic options for MKD patients.

Vasculitis in Systemic Autoinflammatory Diseases.

Autoinflammatory diseases (AID) are diseases of the innate immune system, characterized by recurrent episodes of localized or systemic inflammation. Vasculitis may accompany AID. The causes of the association of vasculitis with monogenic AID are still debated. Among the monogenic AID, Familial Mediterranean Fever (FMF) is the most common. IgA-related vasculitis (IgAV) and Polyarteritis Nodosa (PAN) involving small and/or medium-sized vessels have an increased frequency among FMF patients. There are also case reports revealing vasculitic features in Cryopyrin-Associated Periodic Fever Syndrome (CAPS), Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Mevalonate Kinase Deficiency (MKD), also known as Hyper IgD syndrome (HIDS), Deficiency of IL-1 Receptor Antagonist (DIRA) and Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) patients. Central nervous system vasculitis and vasculopathy have been reported in DIRA and PAPA patients whereas small vessel involvement affecting skin has been reported in CAPS, TRAPS, and MKD patients. Alternatively, vasculitis can also be a leading feature especially in the recently defined monogenic AID (Otulipenia, Deficiency of Adenosine Deaminase 2-DADA2, Haploinsufficiency of A20) and interferonopathies (STING-associated vasculopathy with onset in infancy-SAVI). DADA2 often presents as a PAN-like disease. In otulipenia, patients have painful subcutaneous nodules caused by septal panniculitis with small and medium vessel vasculitis. Haploinsufficiency of A20 (also called Familial Behcet-like Autoinflammatory Syndrome) results in a phenotype very similar to the variable vessel vasculitis of Behcet's disease with recurrent oral-genital ulcers, in addition to, skin rash, uveitis, and polyarthritis. SAVI is an autoinflammatory vasculopathy with increased Interferon (IFN) signature, causing severe skin lesions resulting in ulceration, necrosis, and in some cases, amputation. Behcet's Disease (BD) is a multifactorial polygenic AID characterized by recurrent attacks of oral-genital ulcers, skin lesions, uveitis and a unique vasculitis affecting both arteries and veins of all sizes. Many clinical features overlap with other autoinflammatory diseases and overexpression of proinflammatory cytokines is an important feature of the disease.

National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics

Objectives: Mevalonate kinase deficiency (MKD), a rare autosomal recessive autoinflammatory syndrome, is caused by disease-causing variants of the mevalonate kinase (MVK) gene. A national survey was undertaken to investigate clinical and genetic features of MKD patients in Japan.Methods: The survey identified ten patients with MKD. Clinical information and laboratory data were collected from medical records and by direct interviews with patients, their families, and their attending physicians. Genetic analysis and measurement of MVK activity and urinary excretion of mevalonic acid were performed.Results: None of the 10 patients harbored MVK disease-causing variants that are common in European patients. However, overall symptoms were in line with previous European reports. Continuous fever was observed in half of the patients. Elevated transaminase was observed in four of the 10 patients, two of whom fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. About half of the patients responded to temporary administration of glucocorticoids and NSAIDs; the others required biologics such as anti-IL-1 drugs.Conclusion: This is the first national survey of MKD patients in a non-European country. Although clinical symptoms were similar to those reported in Europe, the incidence of continuous fever and elevated transaminase was higher, probably due to differences in disease-causing variants.

Respiratory deficiency in yeast mevalonate kinase deficient may explain MKD-associate metabolic disorder in humans.

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.

MMAB, a novel candidate gene to be screened in the molecular diagnosis of Mevalonate Kinase Deficiency.

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.

The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry.

Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients. All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases. The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10-20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD. We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected.

Anti-inflammatory and cytoprotective effects of a squalene synthase inhibitor, TAK-475 active metabolite-I, in immune cells simulating mevalonate kinase deficiency (MKD)-like condition.

TAK-475 (lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit squalene synthase, which catalyzes the conversion of farnesyl diphosphate (FPP) to squalene. FPP is a substrate for synthesis of other mevalonate-derived isoprenoids (MDIs) such as farnesol (FOH), geranlygeranyl diphosphate (GGPP), and geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of proteins, which is a posttranslation modification necessary for proper functioning of proteins like small guanosine triphosphatases. Malfunction of prenylation of proteins results in upregulation of the inflammatory cascade, leading to increased production of proinflammatory cytokines like interleukin-1β (IL-1β), eventually leading to episodic febrile attacks. In vitro, TAK-475 M-I incubation in a concentration dependent manner increased levels of FPP, GGPP, and FOH in human monocytic THP-1 cells. In subsequent experiments, THP-1 cells or human peripheral blood mononuclear cells (PBMCs) were incubated with simvastatin, which inhibits hydroxymethylglutaryl-coenzyme A reductase and thereby decreases levels of the precursors of MDIs, leading to the depletion of MDIs as expected in MKD patients. Increased levels of GGPP and FPP attenuated lipopolysaccharide (LPS)-induced IL-1β production in THP-1 cells and human PBMCs in statin-treated conditions. The MDIs also significantly reduced the damaged cell ratio in this active MKD-like condition. Moreover, TAK-475 M-I directly inhibited LPS-induced IL-1β production from statin-treated THP-1 cells. These results show anti-inflammatory and cytoprotective effects of MDIs via TAK-475 M-I treatment in statin-treated immune cells, suggesting that possible therapeutic effects of TAK-475 treatment in MKD patients.

Putative modifier genes in mevalonate kinase deficiency

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.

Treatment of hereditary autoinflammatory diseases

The purpose of this review is to summarize recent advances in the treatment of the hereditary autoinflammatory diseases, focusing on Familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndromes (CAPS) and mevalonate kinase deficiency (MKD). We discuss recently published studies and their implications for current patient care and future clinical research. Interleukin (IL)-1 blockade is effective in most autoinflammatory conditions. Younger patients require a higher dose per kg of body weight. In FMF, colchicine remains the treatment of choice. Single daily dosing appears adequate. When colchicine fails, IL-1 blockade is effective. In CAPS, the beneficial effect of IL-1 blockade is sustained, and side-effects are limited. There is no evidence that one IL-1 blocker is superior to the other. In TRAPS and MKD, IL-1 blockade appears effective. Some patients have sufficient suppression of inflammatory symptoms with NSAIDs or corticosteroids. Apart from CAPS and FMF, therapy of autoinflammatory diseases is based on small and retrospective studies. IL-1 blockade appears effective, but larger prospective trials are needed, especially in MKD, TRAPS and colchicine-resistant FMF patients.

PReS-FINAL-2335: Preliminary analysis of 85 patients with mevalonate kinase deficiency from the eurofever registry

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease, caused by mutations in the isoprenoid pathway that lead to fever episodes. Approximately 300 MKD patients are known.

PReS-FINAL-2232: Long-term follow-up in a national cohort of MKD patients: search for clinical predictors of a spontaneous improvement

Mevalonate-kinase deficiency (MKD) is an autosomal recessive disease caused by the deficiency of the mevalonate-kinase enzyme (MVK) and characterized by recurrent fever episodes with systemic involvement. Classically, the disease was thought to have a self-limiting course, with a spontaneous improvement in the adulthood. In 2008 the International registry showed that 50% of patients present a reduction of fever episodes in the adulthood. Up to now, it's difficult to predict the course of the disease a patient will display.

Mouse model of mevalonate kinase deficiency: comparison of cytokine and chemokine profile with that of human patients

Mevalonate kinase deficiency (MKD) is a rare genetic autoinflammatory disease caused by blocking of the enzyme mevalonate kinase in the pathway of cholesterol and isoprenoids. The pathogenic mechanism originating an immune response in MKD patients has not been clearly understood. We investigated the dysregulation of expression of selected cytokines and chemokines in the serum of MKD patients. The results have been compared with those observed in an MKD mouse model obtained by treating the mice with aminobisphosphonate, a molecule that is able to inhibit the cholesterol pathway, mimicking the genetic block characteristic of the disease. Interleukin (IL)-1β, IL-5, IL-6, IL-9, IL-17, granulocyte colony-stimulating factor, monocyte chemotactic protein-1, tumor necrosis factor-α, and IL-4 expression were dysregulated in sera from MKD patients and mice. Moreover, geraniol, an exogenous isoprenoid, when administered to MKD mice, restored cytokines and chemokines levels with values similar to those of untreated mice. Our findings, which were obtained in patients and a mouse model mimicking the human disease, suggest that these cytokines and chemokines could be MKD specific and that isoprenoids could be considered as potential therapeutic molecules. The mouse model, even if with some limitations, was robust and suitable for routine testing of potential MKD drugs.