RARE DISEASE
Mevalonic aciduria
Mevalonic aciduria
Mevalonic aciduria
Synonyms: Complete mevalonate kinase deficiency, MVA
Synonyms: Complete mevalonate kinase deficiency, MVA
Synonyms: Complete mevalonate kinase deficiency, MVA
Drug discovery
0
drugs
With orphan designations
Overview
Mevalonic Aciduria (MVA) is a rare, autosomal recessive disorder caused by deficient mevalonate kinase activity due to biallelic MVK gene mutations. It manifests in infancy with dysmorphic features, failure to thrive, recurrent febrile attacks (hepatosplenomegaly, lymphadenopathy), and progressive neurological/ocular complications (ataxia, developmental delay, uveitis, cataracts) [1][4][6]. Severity correlates with residual enzyme activity (<0.5%), leading to life-threatening crises or chronic disability [4][6][12].
Therapies
IL-1 inhibitors (canakinumab, anakinra): First-line for inflammation control [3][13][18].
Allogeneic stem cell transplantation: Curative option for severe refractory cases [3][8][13].
Supportive care: Corticosteroids during flares, ubiquinone/vitamin supplementation, and symptom management [3][8][13].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood
Research Papers
182 drug discovery papers about Mevalonic aciduria. Recent publications:
182 drug discovery papers about Mevalonic aciduria. Recent publications:
categories:
Small molecules
small molecules
2026-05-02 | NK cell dysfunction and interferon-γ production underlie autoinflammation in mevalonate kinase deficiency.
Prenylopathies such as mevalonate kinase deficiency (MKD) are an emerging family of monogenic autoinflammatory diseases with an underlying defect in isoprenoid lipid synthesis and protein prenylation. The mechanisms linking defective protein prenylation to systemic inflammation remain unclear. We revealed that mice and humans with MKD had significant decreases in the frequency of mature natural killer (NK) cells, impaired trafficking of cytolytic granules, reduced cytotoxic activity, and increased production of the cytokine interferon γ (IFN-γ). Mice with MKD failed to clear murine cytomegalovirus (MCMV) infections and had elevated serum IFN-γ and inflammatory pathology, likely the result of decreased and dysregulated cytotoxic cells. Finally, we describe the beneficial effect of cytokine signaling blockade with a Janus kinase (JAK) inhibitor in an infant with severe MKD. Together, these findings reveal a fundamental role for dysregulated cytotoxic cells and IFN-γ production in MKD and likely other prenylopathies. Importantly, this work provides a rationale for the use of JAK inhibitors in the treatment of MKD.
2026-04-28 | Autophagy Enhancement with Spermidine and Rapamycin Microdosing
Spermidine induces autophagy through mTOR-independent mechanisms while ultra-low dose rapamycin provides mTOR inhibition. Enhanced autophagy could clear accumulated metabolites and misfolded proteins in mevalonic aciduria while supporting cellular energy homeostasis through improved mitochondrial quality control.
2026-03-12 | Pyrin inflammasome activation triggers an IL-18-driven IFN-γ response in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to a lowering of the threshold for pyrin inflammasome activation. A cellular model of MKD was established to discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and IFN-γ signaling. Using CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harboring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses after stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived peripheral blood mononuclear cells were performed to validate in vitro findings. MVKI268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVKI268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD peripheral blood mononuclear cells hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and natural killer cells were characterized by enhanced IL-18-driven IFN-γ production. Elevated IFN-γ and IL-18 binding protein levels in MKD plasma as well as transcriptomic data of MKD peripheral blood mononuclear cells further confirmed the presence of an IFN-γ signature in MKD. A pyrin inflammasome-driven IL-18/IFN-γ axis is a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.
2025-04-23 | Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.
Vδ2 T cells, a predominant human peripheral γδ T cell population, are a promising candidate for the development of immunotherapies against cancer and infected cells. Aminobisphosphonate drugs, such as zoledronate, are commonly used to expand Vδ2 T cells. Yet, such in vitro generated cells have limited efficacy in the clinic. We found that despite inducing excessive proliferation of Vδ2 T cells, zoledronate impaired their effector function and caused the upregulation of the inhibitory receptor TIM3. This effect was due to the inhibition of mevalonate metabolism and dysregulation of downstream biological processes such as protein prenylation and intracellular signalling. In vitro and in vivo inhibition of mevalonate metabolism with zoledronate, statins, and 6-fluoromevalonate, as well as genetic deficiency of the mevalonate kinase, all resulted in compromised cytokine and cytotoxic molecule production by Vδ2 T cells. Impaired Vδ2 T cell function was accompanied by transcriptome and kinome changes. Our findings reveal the importance of mevalonate metabolism for the proper functioning of Vδ2 T cells. This observation provides important considerations for improving their therapeutic use and has repercussions for patients with statin or aminobisphosphonate treatments.
2025-03-05 | Intrauterine intestinal obstruction in a preterm infant with severe mevalonate kinase deficiency - a case report.
Mevalonate kinase deficiency is an inherited autoinflammatory disorder that can present with a wide clinical spectrum, ranging from mild forms with recurrent episodes of fever, lymphadenopathy, splenomegaly and skin rash to the much rarer severe form, which is characterized by additional occurrences of psychomotor impairment, cholestatic jaundice, ophthalmological symptoms, and failure to thrive. The few cases described with perinatal onset often showed a very severe clinical course. Here, we report the case of a preterm infant born at 30 + 2 weeks of gestation with a prenatal genetic diagnosis of mevalonate kinase deficiency presenting with intrauterine bowel dilatation, mild hydrops fetalis, and microcephaly. Laparotomy on the second day of life revealed intestinal obstruction necessitating partial ileum resection and ileostomy. The neonate had recurrent inflammatory reactions with elevated C-reactive protein levels, severe cholestasis, a progressive liver dysfunction, and an increasingly distended abdomen with subsequent respiratory insufficiency. Urinary mevalonic acid was highly elevated. The patient received anti-inflammatory therapy with prednisone and anakinra. Unfortunately, the patient died at the age of 77 days due to cardiorespiratory failure. This case shows that intestinal obstruction with dilated fetal bowel loops can be an initially leading clinical symptom of severe mevalonate kinase deficiency. Diagnostics should be considered at an early stage, especially in the presence of other anomalies such as hydrops fetalis, growth restriction, or microcephaly. Data on the neonatal course of severe mevalonate kinase deficiency are still scarce and further studies are needed, particularly on treatment in neonates and young infants.
proteins
2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-07-30 | Novel compound heterozygous MVK variants cause early-onset mevalonic aciduria in a Chinese infant.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder caused by mevalonate kinase (MVK) gene mutations, with phenotypes ranging from mild hyper-IgD syndrome (HIDS) to severe mevalonic aciduria (MA). Here, we report a 7-month-old Chinese male infant presenting with neonatal-onset MA. The proband presented with growth retardation, intractable diarrhea, recurrent fever, generalized rash, progressive hepatosplenomegaly, and persistent systemic inflammation. Laboratory tests revealed marked leukocytosis, elevated C-reactive protein, hyper-IgD and increased urinary mevalonic acid. Whole-exome sequencing identified two novel compound heterozygous MVK variants: c.64G > A (p.Val22Met) and c.1063G > C (p.Ala355Pro). Both variants were absent in global population databases. In silico analyses, including cross-species conservation, structural modeling, and pathogenicity prediction, confirmed significant structural perturbations. The patient achieved sustained remission with canakinumab. This is the first worldwide report of the MVK c.1063G > C variant causing severe MA, expanding the MVK mutational spectrum in Chinese populations.
2026-05-25 | Neonatal Hydrops and Biliary Atresia as an Early Presentation of Mevalonate Kinase Deficiency: A Case Report.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder with a broad clinical spectrum. Neonatal presentation is uncommon and may mimic severe infection, leading to diagnostic delay. We report a preterm female infant who presented with non-immune hydrops fetalis and persistent systemic inflammation from the first week of life, despite repeated negative blood and CSF cultures and multiple courses of broad-spectrum antibiotics. The infant subsequently developed progressive cholestasis with pale stools, and biliary atresia was confirmed by hepatobiliary imaging and intraoperative cholangiography, followed by portoenterostomy. Extensive metabolic, immunologic, and infectious evaluations were unrevealing. Whole-exome sequencing identified compound heterozygous pathogenic variants in the MVK gene, confirming the diagnosis of MKD. Perinatal-onset MKD is exceptionally rare and often presents with non-specific systemic inflammation that can mimic neonatal sepsis, resulting in delayed diagnosis and significant diagnostic and therapeutic challenges. The infant was treated with supportive care, corticosteroids, and the IL-1 receptor antagonist anakinra, but the clinical course was complicated by progressive multiorgan failure, and she died at 3.5 months of age. This case highlights the diagnostic challenges of neonatal-onset MKD and suggests a possible association between MKD, hydrops fetalis, and biliary atresia that requires further investigation. Early consideration of autoinflammatory disorders and timely genetic testing may facilitate diagnosis and guide management in neonates with unexplained systemic inflammation.
2026-03-16 | Phenotype-genotype correlation and treatment outcomes in mevalonate kinase deficiency: A large Turkish cohort.
This study aimed to comprehensively assess the clinical spectrum, genotype-phenotype correlations, and treatment responses in a large cohort of Turkish pediatric patients with genetically confirmed mevalonate kinase deficiency (MKD). This retrospective, multicenter cohort study included 107 genetically confirmed MKD patients followed between 2010 and 2024 across 25 pediatric rheumatology centers in Turkey. Demographic characteristics, clinical features, laboratory parameters, genotypic data, and treatment outcomes were recorded and analyzed. Of the 107 patients, 48 (44.9%) were female. The median age at symptom onset was 7 (3-24) months, and the median age at diagnosis was 71 (27-115) months. The most frequent clinical features included fever in 105 (98.1%) patients, abdominal pain in 92 (86%), arthralgia in 74 (69.2%), diarrhea in 73 (68.2%), lymphadenopathy in 64 (59.8%), vomiting in 52 (48.6%), and oral aphthae in 50 (46.7%). Less frequent findings included pancreatitis in 2 (1.9%), genital aphthae in 2 (1.9%), neurosensory hearing loss in 3 (2.8%), and hidradenitis suppurativa in 1 (0.9%) patients. Amyloidosis and MAS were reported in 4 (3.7%) and 4 (3.7%) patients, respectively. Among the 107 patients, 45 (42%) had a homozygous V377I mutation (Group 1), 28 (26.2%) had a compound heterozygous mutation involving V377I and a non-V377I allele (Group 2), 15 (14%) had two non-V377I alleles (Group 3), and 19 (17.8%) had a single heterozygous mevalonate kinase gene mutation (Group 4). No statistically significant differences were observed between the groups in demographic features, attack characteristics, clinical manifestations, laboratory findings, or treatment outcomes. IL-1 antagonists were the primary therapeutic agents. Anakinra yielded no clinical response in 14 (13.1%), partial response in 17 (15.9%), and complete response in 13 (12.1%) patients. Canakinumab treatment resulted in no response in 2 (1.9%) patients, partial response in 34 (31.8%), and complete response in 56 (52.3%). The variability in clinical manifestations and treatment responses across genotypes highlights the complexity and heterogeneity of MKD, suggesting that factors beyond genotype may influence disease expression and therapeutic outcomes. We also confirm that heterozygous individuals may express the disease phenotype.
2026-02-04 | A Diagnostic Challenge: Recurrent Uveitis Leading to the Diagnosis of Hyper-IgD Syndrome in a 28-Year-Old Patient.
Mevalonate Kinase Deficiency (MKD), which includes the clinical phenotype known as Hyperim munoglobulin D Syndrome (HIDS), is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene. While typically characterized by childhood-onset recurrent febrile episodes and systemic symptoms like lymphadenopathy and abdominal pain, ocular involvement is usually limited to conjunctivitis. Uveitis is a rare manifestation, often associated with more severe forms of the disease. This report describes a 28-year-old male who presented with bilateral, recurrent anterior uveitis and vitritis. Although the patient reported self-limiting febrile episodes during childhood, the presentation of ocular inflammation in adulthood as the primary symptom posed a significant diagnostic challenge. Initial treatment with topical and systemic corticosteroids provided only temporary relief, with the patient developing cystoid macular edema and further recurrences. A multidisciplinary evaluation and genetic testing confirmed the diagnosis of HIDS. Following the diagnosis, the patient was started on targeted anti-IL-1 therapy (anakinra or canakinumab). This intervention led to a significant improvement in symptoms and was essential in halting recurrences and preventing chronic ocular damage. Recurrent uveitis, even in adult patients, should prompt the investigation of rare autoinflammatory syndromes. A timely genetic diagnosis and a multidisciplinary approach are crucial for initiating targeted biological treatments, which offer a superior visual and systemic prognosis compared to conventional therapies.
antibodies
2026-05-22 | Effective interleukin-6 inhibition in a pediatric patient with mevalonate kinase deficiency and chronic nonbacterial osteomyelitis-like bone lesions under interleukin-1 blockade.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease. Chronic nonbacterial osteomyelitis (CNO) represents another autoinflammatory disorder characterized by sterile bone inflammation. Although musculoskeletal pain is common in MKD, CNO-like bone lesions have rarely been described. Tocilizumab has been used separately in MKD / hyper-IgD syndrome (HIDS) and in CNO; however, pediatric cases showing both conditions together and responding completely to IL-6 blockade have not been previously reported. We present a 16-year-old boy born to consanguineous parents who experienced early-onset recurrent fever episodes with abdominal pain, maculopapular rash, oral ulcers, and conjunctival injection. He was initially misdiagnosed with FMF and IgA vasculitis and treated with colchicine with partial improvement. Persistent systemic inflammation prompted referral to our tertiary center at age 9. A periodic fever gene panel revealed a homozygous MVK p.V377I mutation, confirming MKD. Anakinra therapy was initiated. Although no attacks occurred during the first month, flares characterized by fever, abdominal pain, rash, and elevated acute-phase reactants recurred in the second and third months, reflecting a partial response. Consequently, treatment was switched to canakinumab. Toward the end of the second year of IL-1 blockade, attack frequency increased to once every three months, and at age 12 he developed diffuse musculoskeletal pain. Whole-body magnetic resonance imaging demonstrated multifocal metaphyseal bone marrow edema compatible with CNO-like lesions. Sulfasalazine was added but discontinued after drug-induced pancreatitis. Given persistent systemic inflammation and inadequate response to IL-1 inhibitors, canakinumab was replaced with weekly subcutaneous tocilizumab, resulting in rapid improvement in bone pain and systemic inflammation. Since the third month of tocilizumab therapy, he has remained clinically stable with normalized inflammatory markers and only a single mild flare over the last year. This case highlights the potential role of IL-6 inhibition in complicated MKD presenting with autoinflammatory bone disease refractory to standard therapies.
2025-10-20 | Case Report: Mevalonate kinase deficiency: an underdiagnosed cause of ischemic stroke-characterization of a novel genetic variant.
Mevalonate kinase deficiency (MKD) is an inherited autoinflammatory syndrome resulting from impaired isoprenoid biosynthesis due to biallelic mevalonate kinase (MVK) mutations. This metabolic defect leads to dysregulated innate immunity, particularly excessive interleukin-1β release. While typically presenting in childhood with periodic fevers, expanding evidence links MKD to heterogeneous adult phenotypes with immune-mediated end-organ damage. We report an adult male presenting with leg pain and finger cyanosis followed by acute ischemic stroke, macular rash, and lymphadenopathies. He exhibited classical markers of innate immune activation, including persistent elevation of C-reactive protein. Genetic testing identified compound heterozygosity for the known MVK pathogenic variant c.1129G>A (V377I) and a novel missense variant, c.1049A>C (Q350P). Structural modeling of Q350P revealed disruption of the GHMP kinase domain, predicted to destabilize mevalonate kinase conformation and impair its function. The measurement of mevalonate kinase activity in lymphocytes was at 55% (normal >60%). Interleukin-1β blockade with canakinumab was initiated, and the blood markers of inflammation normalized, further supporting a central role for innate immune dysregulation. This case highlights a novel MVK missense variant (Q350P) with subnormal mevalonate kinase activity. The patient's compound heterozygous state with partially preserved mevalonate kinase activity may explain the attenuated systemic features and the delayed clinical onset. Remarkably, ischemic stroke was part of the initial presentation, suggesting that mevalonate kinase deficiency can manifest primarily through thrombo-inflammatory complications in adulthood, even in the absence of recurrent febrile episodes. This expands the phenotypic spectrum of MKD and underscores the need to consider adult-onset autoinflammatory syndromes in the differential diagnosis of cryptogenic ischemic strokes with markers of systemic inflammation. It also supports the utility of cytokine-targeted therapies in such contexts.
2024-12-26 | Long-Term Safety and Effectiveness of Canakinumab in Patients with MKD/HIDS: Interim Analysis of the RELIANCE Registry.
Interim analysis of the long-term safety and effectiveness of canakinumab, at a patient level, in the mevalonate kinase deficiency/hyperimmunoglobulin-D syndrome (MKD/HIDS) cohort of the RELIANCE registry. From June 2018, the RELIANCE registry enrolled paediatric (aged ≥ 2 years) and adult patients (aged ≥ 18 years) with MKD/HIDS who were receiving canakinumab as part of their routine medical care. Safety, physician- and patient-reported measures of disease activity and dosing patterns were evaluated at baseline and every 6 months until end-of-study visit. At the analysis cut-off date of December 2022, eight patients with MKD/HIDS were enrolled. Five (62.5%) were children (< 18 years) and five (62.5%) were female. The median patient age was 8.0 (range 2.0-39.0) years, and all patients were pre-treated with canakinumab prior to enrolment (median duration of canakinumab treatment: 3.8 years). Canakinumab was well tolerated, with seven (87.5%) patients reporting 48 adverse events (incidence rate/100 patient years: 218.1). No serious adverse drug reactions were reported. Patients continued to receive vaccinations during long-term treatment with canakinumab. Disease activity, evaluated by physician-reported (physician's global assessment, disease remission, C-reactive protein, serum amyloid A, erythrocyte sedimentation rate) and patient-reported (autoinflammatory disease activity index diary, disease activity, fatigue, impact on social life) measures, was generally well controlled throughout the study. Over 50.0% of patients maintained disease remission from baseline to month 24, and medians of all inflammatory markers remained within normal limits throughout the study. Most patients received higher than the recommended starting dose of canakinumab throughout the study. Data from this interim analysis of a unique registry of patients with a rare disease support the long-term safety and effectiveness of the IL-1-blocking agent canakinumab for the treatment of MKD/HIDS.
2024-03-19 | A case of mevalonate kinase deficiency, neonatal Sweet syndrome, and inflammatory bowel disease.
Mevalonate kinase deficiency is a group of rare metabolic autoinflammatory disorders that present with recurrent fevers, abdominal pain, arthralgias, adenopathy, and a variety of cutaneous manifestations. The skin findings may mimic cellulitis, erythema elevatum diutinum, IgA vasculitis, and Sweet syndrome, and there is often a morbilliform or urticarial rash and aphthous stomatitis. Mevalonate kinase deficiency is one of the identified monogenic variants that can cause very early onset inflammatory bowel disease (IBD). We present a rare case of a patient with mevalonate kinase deficiency, neonatal Sweet syndrome, and infantile-onset IBD, who has been successfully treated with canakinumab therapy.
2024-02-01 | Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry
Objective Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). Methods From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. Results At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0–79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician’s global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. Conclusion Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.
cell therapies
2022-08-02 | The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency.
Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome. Several reports have described allogeneic hematopoietic stem cell transplantation in severely affected patients, sometimes with promising results. In view of the scarcity of data, this study aims to analyse the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) to give a more complete overview of this treatment. This multicentre retrospective study on behalf of the European Society for Blood and Marrow Transplantation aimed to include all MKD patients who had undergone allogeneic HSCT. All centres related to EMBT and centres that have reported cases of allogeneic HSCT in the literature were contacted via the EBMT data office. We analyzed 9 patients (5 male). Treosulfan based conditioning was the most frequently used conditioning regimen. Engraftment occurred in all but one patient. Source of stem cells was cord blood (n = 2), peripheral blood stem cells (n = 4) and bone marrow (n = 5). Two patients needed a second transplantation due to an incomplete response or primary graft failure. Seven patients went into complete remission after stem cell transplantation. At final follow-up these patients reported no symptoms of MKD. Four patients suffered from grade II-IV acute graft-versus-host disease (GvHD). During follow-up two patients died due to transplantation related complications. In conclusion, allogeneic stem cell transplantation represents an effective treatment for the most severely affected MKD patients. However, treatment-related morbidity and mortality are significant. Transplantation may be justified in patients with a severe disease course on conservative therapy.
2021-12-07 | Case Report: Mevalonic Aciduria Complicated by Acute Myeloid Leukemia After Hematopoietic Stem Cell Transplantation
Mevalonic aciduria (MA) is the most severe clinical subtype of mevalonate kinase deficiency (MKD) caused by an inherited defect in the mevalonate pathway. The treatment of MKD focuses on the suppression of recurrent hyperinflammatory attacks using anti-inflammatory drugs. Recently, allogeneic hematopoietic stem cell transplantation (HCT) was shown to successfully ameliorate autoinflammatory attacks in patients with MKD. Here, we report a case of an infant who showed severe recurrent systemic inflammation and was diagnosed with MA. Although she responded to steroids, her symptoms relapsed after the dose was tapered, and organ deterioration occurred. Therefore, at the age of 11 months, HCT from a matched, unrelated donor was performed for curative treatment. However, at 50 days after transplantation, acute myeloid leukemia was diagnosed, which was chemo-refractory. A second HCT from her haploidentical father was performed to treat the acute myeloid leukemia, but the patient died of sepsis on day 4 after transplantation. This is the first report of malignancy following HCT for MA. Our findings suggest that normalizing the mevalonate pathway after HCT in patients with MKD impacts patients differently depending on the clinical spectrum and severity of disease.
2021-01-25 | Mevalonic aciduria: Does stem cell transplant fully cure disease?
MA is a rare, autosomal recessive disorder characterized by episodes of inflammation and periodic fevers. In its most severe form, it can result in facial dysmorphism, growth inhibition, ataxia, liver dysfunction, intellectual disability, and at times can be fatal. A number of case reports exist stating that SCT is curative in these patients. We present the case of a patient diagnosed with MA at birth, who underwent SCT at the age of 14 months with intent to cure. She achieved complete engraftment and urine mevalonate became undetectable. However, 18 months following transplant, she developed frequent episodes of fevers, rashes, arthritis, and a rising urinary mevalonate. She was subsequently diagnosed with relapse. She now requires treatment with steroids and canakinumab to manage her disease. This case is the first report of disease relapse following transplant for MA. It runs contrary to prior reports that SCT is fully curative of MA and suggests that transplant may instead provide a means of decreasing disease severity without entirely eradicating the condition.
2021-01-07 | Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency
Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first.Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs.Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
2015-03-05 | Long-term outcome of a successful cord blood stem cell transplant in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype that may be expressed as a spectrum of disease phenotypes, from those with prevailing autoinflammatory syndrome and variable response to anti-inflammatory therapies, to mevalonic aciduria, which is associated with dysmorphic features, severe neurologic involvement, and the worst prognosis. We describe a boy, aged 2 years, 10 months, with severe phenotype of mevalonate kinase deficiency who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical unrelated cord blood because his condition had failed to improve with antiinflammatory treatment as first-line therapy and an anticytokine drug as second-line therapy. The child had a sustained remission of febrile attacks and inflammation after transplant, and during a 5-year follow-up period, psychomotor and neurologic development were normal, without signs of underlying disease or late transplant-related effects. This case confirms that allogeneic HSCT is a safe and effective cure for patients affected by MKD in whom anticytokine drugs alone are insufficient for the management of autoinflammatory syndrome and for the unfavorable outcome of the disease.
other
2025-07-21 | Mevalonate kinase deficiency: Neuropathologic findings in an autopsy brain
To the Editor: Mevalonate kinase deficiency (MKD) is a rare, autosomal recessive, autoinflammatory disease with multiple organ involvement. The true prevalence of MKD is unknown, and the reported prevalence is from 0.39 to 6.2 per 1,000,000.1,2 The majority of reported patients are European or of European ancestry.2 Mevalonate kinase deficiency is caused by a homozygous or compound heterozygous mutation in the gene encoding mevalonate kinase (MVK) on chromosome 12q24, which leads to reduced or deficient activity of MVK. Mevalonate kinase deficiency encompasses a spectrum of phenotypes, ranging from milder MKD, known as hyper-IgD syndrome (HIDS), to a rarer and more severe phenotype, mevalonic aciduria (MVA). It is important to note that conditions such as porokeratosis, phosphomevalonate kinase deficiency, and macrophage activation syndrome are also related to abnormalities in the mevalonate pathway.1 Mevalonate kinase deficiency is characterized by recurrent febrile attacks that are frequently accompanied by lymphadenopathy, gastrointestinal symptoms, arthralgia, myalgia, skin rash, and aphthous ulcers. Patients with MVA also have intrauterine growth retardation, congenital defects (cataracts, shortened limbs, and dysmorphic craniofacial features), neurological disease, and failure to thrive. Mevalonate kinase deficiency is associated with rare long-term complications such as type AA amyloidosis, joint contractures, abdominal adhesions, renal angiomyolipoma, and severe pneumococcal infections.2
2023-06-05 | The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis
Cholesterol levels are an initiating risk factor for atherosclerosis.Many genes play a central role in cholesterol synthesis, including HMGCR, SQLE, HMGCS1, FDFT1, LSS, MVK, PMK, MVD, FDPS, CYP51, TM7SF2, LBR, MSMO1, NSDHL, HSD17B7, DHCR24, EBP, SC5D, DHCR7, IDI1/2.Especially, HMGCR, SQLE, FDFT1, LSS, FDPS, CYP51, and EBP are promising therapeutic targets for drug development due to many drugs have been approved and entered into clinical research by targeting these genes.However, new targets and drugs still need to be discovered.Interestingly, many small nucleic acid drugs and vaccines were approved for the market, including Inclisiran, Patisiran, Inotersen, Givosiran, Lumasiran, Nusinersen, Volanesorsen, Eteplirsen, Golodirsen, Viltolarsen, Casimersen, Elasomeran, Tozinameran.However, these agents are all linear RNA agents.Circular RNAs (circRNAs) may have longer half-lives, higher stability, lower immunogenicity, lower production costs, and higher delivery efficiency than these agents due to their covalently closed structures.CircRNA agents are developed by several companies, including Orna Therapeutics, Laronde, and CirCode, Therorna.Many studies have shown that circRNAs regulate cholesterol synthesis by regulating HMGCR, SQLE, HMGCS1, ACS, YWHAG, PTEN, DHCR24, SREBP-2, and PMK expression.MiRNAs are essential for circRNA-mediated cholesterol biosynthesis.Notable, the phase II trial for inhibiting miR-122 with nucleic acid drugs has been completed.Suppressing HMGCR, SQLE, and miR-122 with circRNA_ABCA1, circ-PRKCH, circEZH2, circRNA-SCAP, and circFOXO3 are the promising therapeutic target for drug development, specifically the circFOXO3.This review focuses on the role and mechanism of the circRNA/miRNA axis in cholesterol synthesis in the hope of providing knowledge to identify new targets.
2022-02-11 | Rapid design and prototyping of biocatalytic virus-like particle nanoreactors
Abstract Protein cages are attractive as molecular scaffolds for the fundamental study of enzymes and metabolons, and for the creation of biocatalytic nanoreactors for in vitro and in vivo use. Virus-like particles (VLPs) such as those derived from the P22 bacteriophage capsid protein make versatile self-assembling protein cages and can be used to encapsulate a broad range of protein cargos. In vivo encapsulation of enzymes within VLPs requires fusion to the coat protein or a scaffold protein. However, the expression level, stability and activity of cargo proteins can vary upon fusion. Moreover, it has been shown that molecular crowding of enzymes inside virus-like particles can affect their catalytic properties. Consequently, testing of numerous parameters is required for production of the most efficient nanoreactor for a given cargo enzyme. Here we present a set of acceptor vectors that provide a quick and efficient way to build, test and optimise cargo loading inside P22 virus-like particles. We prototyped the system using yellow fluorescent protein then applied it to mevalonate kinases, a key enzyme class in the industrially important terpene (isoprenoid) synthesis pathway. Different mevalonate kinases required considerably different approaches to deliver maximal encapsulation as well as optimal kinetic parameters, demonstrating the value of being able to rapidly access a variety of encapsulation strategies. The vector system described here provides an approach to optimise cargo enzyme behaviour in bespoke P22 nanoreactors. This will facilitate industrial applications as well as basic research on nanoreactor-cargo behaviour. Abstract Figure
small molecules
2026-05-02 | NK cell dysfunction and interferon-γ production underlie autoinflammation in mevalonate kinase deficiency.
Prenylopathies such as mevalonate kinase deficiency (MKD) are an emerging family of monogenic autoinflammatory diseases with an underlying defect in isoprenoid lipid synthesis and protein prenylation. The mechanisms linking defective protein prenylation to systemic inflammation remain unclear. We revealed that mice and humans with MKD had significant decreases in the frequency of mature natural killer (NK) cells, impaired trafficking of cytolytic granules, reduced cytotoxic activity, and increased production of the cytokine interferon γ (IFN-γ). Mice with MKD failed to clear murine cytomegalovirus (MCMV) infections and had elevated serum IFN-γ and inflammatory pathology, likely the result of decreased and dysregulated cytotoxic cells. Finally, we describe the beneficial effect of cytokine signaling blockade with a Janus kinase (JAK) inhibitor in an infant with severe MKD. Together, these findings reveal a fundamental role for dysregulated cytotoxic cells and IFN-γ production in MKD and likely other prenylopathies. Importantly, this work provides a rationale for the use of JAK inhibitors in the treatment of MKD.
2026-04-28 | Autophagy Enhancement with Spermidine and Rapamycin Microdosing
Spermidine induces autophagy through mTOR-independent mechanisms while ultra-low dose rapamycin provides mTOR inhibition. Enhanced autophagy could clear accumulated metabolites and misfolded proteins in mevalonic aciduria while supporting cellular energy homeostasis through improved mitochondrial quality control.
2026-03-12 | Pyrin inflammasome activation triggers an IL-18-driven IFN-γ response in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to a lowering of the threshold for pyrin inflammasome activation. A cellular model of MKD was established to discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and IFN-γ signaling. Using CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harboring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses after stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived peripheral blood mononuclear cells were performed to validate in vitro findings. MVKI268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVKI268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD peripheral blood mononuclear cells hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and natural killer cells were characterized by enhanced IL-18-driven IFN-γ production. Elevated IFN-γ and IL-18 binding protein levels in MKD plasma as well as transcriptomic data of MKD peripheral blood mononuclear cells further confirmed the presence of an IFN-γ signature in MKD. A pyrin inflammasome-driven IL-18/IFN-γ axis is a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.
2025-04-23 | Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.
Vδ2 T cells, a predominant human peripheral γδ T cell population, are a promising candidate for the development of immunotherapies against cancer and infected cells. Aminobisphosphonate drugs, such as zoledronate, are commonly used to expand Vδ2 T cells. Yet, such in vitro generated cells have limited efficacy in the clinic. We found that despite inducing excessive proliferation of Vδ2 T cells, zoledronate impaired their effector function and caused the upregulation of the inhibitory receptor TIM3. This effect was due to the inhibition of mevalonate metabolism and dysregulation of downstream biological processes such as protein prenylation and intracellular signalling. In vitro and in vivo inhibition of mevalonate metabolism with zoledronate, statins, and 6-fluoromevalonate, as well as genetic deficiency of the mevalonate kinase, all resulted in compromised cytokine and cytotoxic molecule production by Vδ2 T cells. Impaired Vδ2 T cell function was accompanied by transcriptome and kinome changes. Our findings reveal the importance of mevalonate metabolism for the proper functioning of Vδ2 T cells. This observation provides important considerations for improving their therapeutic use and has repercussions for patients with statin or aminobisphosphonate treatments.
2025-03-05 | Intrauterine intestinal obstruction in a preterm infant with severe mevalonate kinase deficiency - a case report.
Mevalonate kinase deficiency is an inherited autoinflammatory disorder that can present with a wide clinical spectrum, ranging from mild forms with recurrent episodes of fever, lymphadenopathy, splenomegaly and skin rash to the much rarer severe form, which is characterized by additional occurrences of psychomotor impairment, cholestatic jaundice, ophthalmological symptoms, and failure to thrive. The few cases described with perinatal onset often showed a very severe clinical course. Here, we report the case of a preterm infant born at 30 + 2 weeks of gestation with a prenatal genetic diagnosis of mevalonate kinase deficiency presenting with intrauterine bowel dilatation, mild hydrops fetalis, and microcephaly. Laparotomy on the second day of life revealed intestinal obstruction necessitating partial ileum resection and ileostomy. The neonate had recurrent inflammatory reactions with elevated C-reactive protein levels, severe cholestasis, a progressive liver dysfunction, and an increasingly distended abdomen with subsequent respiratory insufficiency. Urinary mevalonic acid was highly elevated. The patient received anti-inflammatory therapy with prednisone and anakinra. Unfortunately, the patient died at the age of 77 days due to cardiorespiratory failure. This case shows that intestinal obstruction with dilated fetal bowel loops can be an initially leading clinical symptom of severe mevalonate kinase deficiency. Diagnostics should be considered at an early stage, especially in the presence of other anomalies such as hydrops fetalis, growth restriction, or microcephaly. Data on the neonatal course of severe mevalonate kinase deficiency are still scarce and further studies are needed, particularly on treatment in neonates and young infants.
proteins
2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-07-30 | Novel compound heterozygous MVK variants cause early-onset mevalonic aciduria in a Chinese infant.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder caused by mevalonate kinase (MVK) gene mutations, with phenotypes ranging from mild hyper-IgD syndrome (HIDS) to severe mevalonic aciduria (MA). Here, we report a 7-month-old Chinese male infant presenting with neonatal-onset MA. The proband presented with growth retardation, intractable diarrhea, recurrent fever, generalized rash, progressive hepatosplenomegaly, and persistent systemic inflammation. Laboratory tests revealed marked leukocytosis, elevated C-reactive protein, hyper-IgD and increased urinary mevalonic acid. Whole-exome sequencing identified two novel compound heterozygous MVK variants: c.64G > A (p.Val22Met) and c.1063G > C (p.Ala355Pro). Both variants were absent in global population databases. In silico analyses, including cross-species conservation, structural modeling, and pathogenicity prediction, confirmed significant structural perturbations. The patient achieved sustained remission with canakinumab. This is the first worldwide report of the MVK c.1063G > C variant causing severe MA, expanding the MVK mutational spectrum in Chinese populations.
2026-05-25 | Neonatal Hydrops and Biliary Atresia as an Early Presentation of Mevalonate Kinase Deficiency: A Case Report.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder with a broad clinical spectrum. Neonatal presentation is uncommon and may mimic severe infection, leading to diagnostic delay. We report a preterm female infant who presented with non-immune hydrops fetalis and persistent systemic inflammation from the first week of life, despite repeated negative blood and CSF cultures and multiple courses of broad-spectrum antibiotics. The infant subsequently developed progressive cholestasis with pale stools, and biliary atresia was confirmed by hepatobiliary imaging and intraoperative cholangiography, followed by portoenterostomy. Extensive metabolic, immunologic, and infectious evaluations were unrevealing. Whole-exome sequencing identified compound heterozygous pathogenic variants in the MVK gene, confirming the diagnosis of MKD. Perinatal-onset MKD is exceptionally rare and often presents with non-specific systemic inflammation that can mimic neonatal sepsis, resulting in delayed diagnosis and significant diagnostic and therapeutic challenges. The infant was treated with supportive care, corticosteroids, and the IL-1 receptor antagonist anakinra, but the clinical course was complicated by progressive multiorgan failure, and she died at 3.5 months of age. This case highlights the diagnostic challenges of neonatal-onset MKD and suggests a possible association between MKD, hydrops fetalis, and biliary atresia that requires further investigation. Early consideration of autoinflammatory disorders and timely genetic testing may facilitate diagnosis and guide management in neonates with unexplained systemic inflammation.
2026-03-16 | Phenotype-genotype correlation and treatment outcomes in mevalonate kinase deficiency: A large Turkish cohort.
This study aimed to comprehensively assess the clinical spectrum, genotype-phenotype correlations, and treatment responses in a large cohort of Turkish pediatric patients with genetically confirmed mevalonate kinase deficiency (MKD). This retrospective, multicenter cohort study included 107 genetically confirmed MKD patients followed between 2010 and 2024 across 25 pediatric rheumatology centers in Turkey. Demographic characteristics, clinical features, laboratory parameters, genotypic data, and treatment outcomes were recorded and analyzed. Of the 107 patients, 48 (44.9%) were female. The median age at symptom onset was 7 (3-24) months, and the median age at diagnosis was 71 (27-115) months. The most frequent clinical features included fever in 105 (98.1%) patients, abdominal pain in 92 (86%), arthralgia in 74 (69.2%), diarrhea in 73 (68.2%), lymphadenopathy in 64 (59.8%), vomiting in 52 (48.6%), and oral aphthae in 50 (46.7%). Less frequent findings included pancreatitis in 2 (1.9%), genital aphthae in 2 (1.9%), neurosensory hearing loss in 3 (2.8%), and hidradenitis suppurativa in 1 (0.9%) patients. Amyloidosis and MAS were reported in 4 (3.7%) and 4 (3.7%) patients, respectively. Among the 107 patients, 45 (42%) had a homozygous V377I mutation (Group 1), 28 (26.2%) had a compound heterozygous mutation involving V377I and a non-V377I allele (Group 2), 15 (14%) had two non-V377I alleles (Group 3), and 19 (17.8%) had a single heterozygous mevalonate kinase gene mutation (Group 4). No statistically significant differences were observed between the groups in demographic features, attack characteristics, clinical manifestations, laboratory findings, or treatment outcomes. IL-1 antagonists were the primary therapeutic agents. Anakinra yielded no clinical response in 14 (13.1%), partial response in 17 (15.9%), and complete response in 13 (12.1%) patients. Canakinumab treatment resulted in no response in 2 (1.9%) patients, partial response in 34 (31.8%), and complete response in 56 (52.3%). The variability in clinical manifestations and treatment responses across genotypes highlights the complexity and heterogeneity of MKD, suggesting that factors beyond genotype may influence disease expression and therapeutic outcomes. We also confirm that heterozygous individuals may express the disease phenotype.
2026-02-04 | A Diagnostic Challenge: Recurrent Uveitis Leading to the Diagnosis of Hyper-IgD Syndrome in a 28-Year-Old Patient.
Mevalonate Kinase Deficiency (MKD), which includes the clinical phenotype known as Hyperim munoglobulin D Syndrome (HIDS), is an autosomal recessive autoinflammatory disorder caused by mutations in the MVK gene. While typically characterized by childhood-onset recurrent febrile episodes and systemic symptoms like lymphadenopathy and abdominal pain, ocular involvement is usually limited to conjunctivitis. Uveitis is a rare manifestation, often associated with more severe forms of the disease. This report describes a 28-year-old male who presented with bilateral, recurrent anterior uveitis and vitritis. Although the patient reported self-limiting febrile episodes during childhood, the presentation of ocular inflammation in adulthood as the primary symptom posed a significant diagnostic challenge. Initial treatment with topical and systemic corticosteroids provided only temporary relief, with the patient developing cystoid macular edema and further recurrences. A multidisciplinary evaluation and genetic testing confirmed the diagnosis of HIDS. Following the diagnosis, the patient was started on targeted anti-IL-1 therapy (anakinra or canakinumab). This intervention led to a significant improvement in symptoms and was essential in halting recurrences and preventing chronic ocular damage. Recurrent uveitis, even in adult patients, should prompt the investigation of rare autoinflammatory syndromes. A timely genetic diagnosis and a multidisciplinary approach are crucial for initiating targeted biological treatments, which offer a superior visual and systemic prognosis compared to conventional therapies.
antibodies
2026-05-22 | Effective interleukin-6 inhibition in a pediatric patient with mevalonate kinase deficiency and chronic nonbacterial osteomyelitis-like bone lesions under interleukin-1 blockade.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease. Chronic nonbacterial osteomyelitis (CNO) represents another autoinflammatory disorder characterized by sterile bone inflammation. Although musculoskeletal pain is common in MKD, CNO-like bone lesions have rarely been described. Tocilizumab has been used separately in MKD / hyper-IgD syndrome (HIDS) and in CNO; however, pediatric cases showing both conditions together and responding completely to IL-6 blockade have not been previously reported. We present a 16-year-old boy born to consanguineous parents who experienced early-onset recurrent fever episodes with abdominal pain, maculopapular rash, oral ulcers, and conjunctival injection. He was initially misdiagnosed with FMF and IgA vasculitis and treated with colchicine with partial improvement. Persistent systemic inflammation prompted referral to our tertiary center at age 9. A periodic fever gene panel revealed a homozygous MVK p.V377I mutation, confirming MKD. Anakinra therapy was initiated. Although no attacks occurred during the first month, flares characterized by fever, abdominal pain, rash, and elevated acute-phase reactants recurred in the second and third months, reflecting a partial response. Consequently, treatment was switched to canakinumab. Toward the end of the second year of IL-1 blockade, attack frequency increased to once every three months, and at age 12 he developed diffuse musculoskeletal pain. Whole-body magnetic resonance imaging demonstrated multifocal metaphyseal bone marrow edema compatible with CNO-like lesions. Sulfasalazine was added but discontinued after drug-induced pancreatitis. Given persistent systemic inflammation and inadequate response to IL-1 inhibitors, canakinumab was replaced with weekly subcutaneous tocilizumab, resulting in rapid improvement in bone pain and systemic inflammation. Since the third month of tocilizumab therapy, he has remained clinically stable with normalized inflammatory markers and only a single mild flare over the last year. This case highlights the potential role of IL-6 inhibition in complicated MKD presenting with autoinflammatory bone disease refractory to standard therapies.
2025-10-20 | Case Report: Mevalonate kinase deficiency: an underdiagnosed cause of ischemic stroke-characterization of a novel genetic variant.
Mevalonate kinase deficiency (MKD) is an inherited autoinflammatory syndrome resulting from impaired isoprenoid biosynthesis due to biallelic mevalonate kinase (MVK) mutations. This metabolic defect leads to dysregulated innate immunity, particularly excessive interleukin-1β release. While typically presenting in childhood with periodic fevers, expanding evidence links MKD to heterogeneous adult phenotypes with immune-mediated end-organ damage. We report an adult male presenting with leg pain and finger cyanosis followed by acute ischemic stroke, macular rash, and lymphadenopathies. He exhibited classical markers of innate immune activation, including persistent elevation of C-reactive protein. Genetic testing identified compound heterozygosity for the known MVK pathogenic variant c.1129G>A (V377I) and a novel missense variant, c.1049A>C (Q350P). Structural modeling of Q350P revealed disruption of the GHMP kinase domain, predicted to destabilize mevalonate kinase conformation and impair its function. The measurement of mevalonate kinase activity in lymphocytes was at 55% (normal >60%). Interleukin-1β blockade with canakinumab was initiated, and the blood markers of inflammation normalized, further supporting a central role for innate immune dysregulation. This case highlights a novel MVK missense variant (Q350P) with subnormal mevalonate kinase activity. The patient's compound heterozygous state with partially preserved mevalonate kinase activity may explain the attenuated systemic features and the delayed clinical onset. Remarkably, ischemic stroke was part of the initial presentation, suggesting that mevalonate kinase deficiency can manifest primarily through thrombo-inflammatory complications in adulthood, even in the absence of recurrent febrile episodes. This expands the phenotypic spectrum of MKD and underscores the need to consider adult-onset autoinflammatory syndromes in the differential diagnosis of cryptogenic ischemic strokes with markers of systemic inflammation. It also supports the utility of cytokine-targeted therapies in such contexts.
2024-12-26 | Long-Term Safety and Effectiveness of Canakinumab in Patients with MKD/HIDS: Interim Analysis of the RELIANCE Registry.
Interim analysis of the long-term safety and effectiveness of canakinumab, at a patient level, in the mevalonate kinase deficiency/hyperimmunoglobulin-D syndrome (MKD/HIDS) cohort of the RELIANCE registry. From June 2018, the RELIANCE registry enrolled paediatric (aged ≥ 2 years) and adult patients (aged ≥ 18 years) with MKD/HIDS who were receiving canakinumab as part of their routine medical care. Safety, physician- and patient-reported measures of disease activity and dosing patterns were evaluated at baseline and every 6 months until end-of-study visit. At the analysis cut-off date of December 2022, eight patients with MKD/HIDS were enrolled. Five (62.5%) were children (< 18 years) and five (62.5%) were female. The median patient age was 8.0 (range 2.0-39.0) years, and all patients were pre-treated with canakinumab prior to enrolment (median duration of canakinumab treatment: 3.8 years). Canakinumab was well tolerated, with seven (87.5%) patients reporting 48 adverse events (incidence rate/100 patient years: 218.1). No serious adverse drug reactions were reported. Patients continued to receive vaccinations during long-term treatment with canakinumab. Disease activity, evaluated by physician-reported (physician's global assessment, disease remission, C-reactive protein, serum amyloid A, erythrocyte sedimentation rate) and patient-reported (autoinflammatory disease activity index diary, disease activity, fatigue, impact on social life) measures, was generally well controlled throughout the study. Over 50.0% of patients maintained disease remission from baseline to month 24, and medians of all inflammatory markers remained within normal limits throughout the study. Most patients received higher than the recommended starting dose of canakinumab throughout the study. Data from this interim analysis of a unique registry of patients with a rare disease support the long-term safety and effectiveness of the IL-1-blocking agent canakinumab for the treatment of MKD/HIDS.
2024-03-19 | A case of mevalonate kinase deficiency, neonatal Sweet syndrome, and inflammatory bowel disease.
Mevalonate kinase deficiency is a group of rare metabolic autoinflammatory disorders that present with recurrent fevers, abdominal pain, arthralgias, adenopathy, and a variety of cutaneous manifestations. The skin findings may mimic cellulitis, erythema elevatum diutinum, IgA vasculitis, and Sweet syndrome, and there is often a morbilliform or urticarial rash and aphthous stomatitis. Mevalonate kinase deficiency is one of the identified monogenic variants that can cause very early onset inflammatory bowel disease (IBD). We present a rare case of a patient with mevalonate kinase deficiency, neonatal Sweet syndrome, and infantile-onset IBD, who has been successfully treated with canakinumab therapy.
2024-02-01 | Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry
Objective Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). Methods From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. Results At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0–79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician’s global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. Conclusion Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.
cell therapies
2022-08-02 | The efficacy and safety of allogeneic stem cell transplantation in Mevalonate Kinase Deficiency.
Mevalonate kinase deficiency (MKD) is a rare autoinflammatory syndrome. Several reports have described allogeneic hematopoietic stem cell transplantation in severely affected patients, sometimes with promising results. In view of the scarcity of data, this study aims to analyse the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) to give a more complete overview of this treatment. This multicentre retrospective study on behalf of the European Society for Blood and Marrow Transplantation aimed to include all MKD patients who had undergone allogeneic HSCT. All centres related to EMBT and centres that have reported cases of allogeneic HSCT in the literature were contacted via the EBMT data office. We analyzed 9 patients (5 male). Treosulfan based conditioning was the most frequently used conditioning regimen. Engraftment occurred in all but one patient. Source of stem cells was cord blood (n = 2), peripheral blood stem cells (n = 4) and bone marrow (n = 5). Two patients needed a second transplantation due to an incomplete response or primary graft failure. Seven patients went into complete remission after stem cell transplantation. At final follow-up these patients reported no symptoms of MKD. Four patients suffered from grade II-IV acute graft-versus-host disease (GvHD). During follow-up two patients died due to transplantation related complications. In conclusion, allogeneic stem cell transplantation represents an effective treatment for the most severely affected MKD patients. However, treatment-related morbidity and mortality are significant. Transplantation may be justified in patients with a severe disease course on conservative therapy.
2021-12-07 | Case Report: Mevalonic Aciduria Complicated by Acute Myeloid Leukemia After Hematopoietic Stem Cell Transplantation
Mevalonic aciduria (MA) is the most severe clinical subtype of mevalonate kinase deficiency (MKD) caused by an inherited defect in the mevalonate pathway. The treatment of MKD focuses on the suppression of recurrent hyperinflammatory attacks using anti-inflammatory drugs. Recently, allogeneic hematopoietic stem cell transplantation (HCT) was shown to successfully ameliorate autoinflammatory attacks in patients with MKD. Here, we report a case of an infant who showed severe recurrent systemic inflammation and was diagnosed with MA. Although she responded to steroids, her symptoms relapsed after the dose was tapered, and organ deterioration occurred. Therefore, at the age of 11 months, HCT from a matched, unrelated donor was performed for curative treatment. However, at 50 days after transplantation, acute myeloid leukemia was diagnosed, which was chemo-refractory. A second HCT from her haploidentical father was performed to treat the acute myeloid leukemia, but the patient died of sepsis on day 4 after transplantation. This is the first report of malignancy following HCT for MA. Our findings suggest that normalizing the mevalonate pathway after HCT in patients with MKD impacts patients differently depending on the clinical spectrum and severity of disease.
2021-01-25 | Mevalonic aciduria: Does stem cell transplant fully cure disease?
MA is a rare, autosomal recessive disorder characterized by episodes of inflammation and periodic fevers. In its most severe form, it can result in facial dysmorphism, growth inhibition, ataxia, liver dysfunction, intellectual disability, and at times can be fatal. A number of case reports exist stating that SCT is curative in these patients. We present the case of a patient diagnosed with MA at birth, who underwent SCT at the age of 14 months with intent to cure. She achieved complete engraftment and urine mevalonate became undetectable. However, 18 months following transplant, she developed frequent episodes of fevers, rashes, arthritis, and a rising urinary mevalonate. She was subsequently diagnosed with relapse. She now requires treatment with steroids and canakinumab to manage her disease. This case is the first report of disease relapse following transplant for MA. It runs contrary to prior reports that SCT is fully curative of MA and suggests that transplant may instead provide a means of decreasing disease severity without entirely eradicating the condition.
2021-01-07 | Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency
Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first.Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs.Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.
2015-03-05 | Long-term outcome of a successful cord blood stem cell transplant in mevalonate kinase deficiency.
Mevalonate kinase deficiency (MKD) is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype that may be expressed as a spectrum of disease phenotypes, from those with prevailing autoinflammatory syndrome and variable response to anti-inflammatory therapies, to mevalonic aciduria, which is associated with dysmorphic features, severe neurologic involvement, and the worst prognosis. We describe a boy, aged 2 years, 10 months, with severe phenotype of mevalonate kinase deficiency who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical unrelated cord blood because his condition had failed to improve with antiinflammatory treatment as first-line therapy and an anticytokine drug as second-line therapy. The child had a sustained remission of febrile attacks and inflammation after transplant, and during a 5-year follow-up period, psychomotor and neurologic development were normal, without signs of underlying disease or late transplant-related effects. This case confirms that allogeneic HSCT is a safe and effective cure for patients affected by MKD in whom anticytokine drugs alone are insufficient for the management of autoinflammatory syndrome and for the unfavorable outcome of the disease.
other
2025-07-21 | Mevalonate kinase deficiency: Neuropathologic findings in an autopsy brain
To the Editor: Mevalonate kinase deficiency (MKD) is a rare, autosomal recessive, autoinflammatory disease with multiple organ involvement. The true prevalence of MKD is unknown, and the reported prevalence is from 0.39 to 6.2 per 1,000,000.1,2 The majority of reported patients are European or of European ancestry.2 Mevalonate kinase deficiency is caused by a homozygous or compound heterozygous mutation in the gene encoding mevalonate kinase (MVK) on chromosome 12q24, which leads to reduced or deficient activity of MVK. Mevalonate kinase deficiency encompasses a spectrum of phenotypes, ranging from milder MKD, known as hyper-IgD syndrome (HIDS), to a rarer and more severe phenotype, mevalonic aciduria (MVA). It is important to note that conditions such as porokeratosis, phosphomevalonate kinase deficiency, and macrophage activation syndrome are also related to abnormalities in the mevalonate pathway.1 Mevalonate kinase deficiency is characterized by recurrent febrile attacks that are frequently accompanied by lymphadenopathy, gastrointestinal symptoms, arthralgia, myalgia, skin rash, and aphthous ulcers. Patients with MVA also have intrauterine growth retardation, congenital defects (cataracts, shortened limbs, and dysmorphic craniofacial features), neurological disease, and failure to thrive. Mevalonate kinase deficiency is associated with rare long-term complications such as type AA amyloidosis, joint contractures, abdominal adhesions, renal angiomyolipoma, and severe pneumococcal infections.2
2023-06-05 | The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis
Cholesterol levels are an initiating risk factor for atherosclerosis.Many genes play a central role in cholesterol synthesis, including HMGCR, SQLE, HMGCS1, FDFT1, LSS, MVK, PMK, MVD, FDPS, CYP51, TM7SF2, LBR, MSMO1, NSDHL, HSD17B7, DHCR24, EBP, SC5D, DHCR7, IDI1/2.Especially, HMGCR, SQLE, FDFT1, LSS, FDPS, CYP51, and EBP are promising therapeutic targets for drug development due to many drugs have been approved and entered into clinical research by targeting these genes.However, new targets and drugs still need to be discovered.Interestingly, many small nucleic acid drugs and vaccines were approved for the market, including Inclisiran, Patisiran, Inotersen, Givosiran, Lumasiran, Nusinersen, Volanesorsen, Eteplirsen, Golodirsen, Viltolarsen, Casimersen, Elasomeran, Tozinameran.However, these agents are all linear RNA agents.Circular RNAs (circRNAs) may have longer half-lives, higher stability, lower immunogenicity, lower production costs, and higher delivery efficiency than these agents due to their covalently closed structures.CircRNA agents are developed by several companies, including Orna Therapeutics, Laronde, and CirCode, Therorna.Many studies have shown that circRNAs regulate cholesterol synthesis by regulating HMGCR, SQLE, HMGCS1, ACS, YWHAG, PTEN, DHCR24, SREBP-2, and PMK expression.MiRNAs are essential for circRNA-mediated cholesterol biosynthesis.Notable, the phase II trial for inhibiting miR-122 with nucleic acid drugs has been completed.Suppressing HMGCR, SQLE, and miR-122 with circRNA_ABCA1, circ-PRKCH, circEZH2, circRNA-SCAP, and circFOXO3 are the promising therapeutic target for drug development, specifically the circFOXO3.This review focuses on the role and mechanism of the circRNA/miRNA axis in cholesterol synthesis in the hope of providing knowledge to identify new targets.
2022-02-11 | Rapid design and prototyping of biocatalytic virus-like particle nanoreactors
Abstract Protein cages are attractive as molecular scaffolds for the fundamental study of enzymes and metabolons, and for the creation of biocatalytic nanoreactors for in vitro and in vivo use. Virus-like particles (VLPs) such as those derived from the P22 bacteriophage capsid protein make versatile self-assembling protein cages and can be used to encapsulate a broad range of protein cargos. In vivo encapsulation of enzymes within VLPs requires fusion to the coat protein or a scaffold protein. However, the expression level, stability and activity of cargo proteins can vary upon fusion. Moreover, it has been shown that molecular crowding of enzymes inside virus-like particles can affect their catalytic properties. Consequently, testing of numerous parameters is required for production of the most efficient nanoreactor for a given cargo enzyme. Here we present a set of acceptor vectors that provide a quick and efficient way to build, test and optimise cargo loading inside P22 virus-like particles. We prototyped the system using yellow fluorescent protein then applied it to mevalonate kinases, a key enzyme class in the industrially important terpene (isoprenoid) synthesis pathway. Different mevalonate kinases required considerably different approaches to deliver maximal encapsulation as well as optimal kinetic parameters, demonstrating the value of being able to rapidly access a variety of encapsulation strategies. The vector system described here provides an approach to optimise cargo enzyme behaviour in bespoke P22 nanoreactors. This will facilitate industrial applications as well as basic research on nanoreactor-cargo behaviour. Abstract Figure
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