Mutations In Mevalonate Kinase Research Articles

Vasculitis in a patient with mevalonate kinase deficiency (MKD): a case report

BackgroundMevalonate kinase deficiency (MKD) is a rare autoinflammatory condition caused by biallelic loss-of-function (LOF) mutations in mevalonate kinase (MVK) gene encoding the enzyme mevalonate kinase. Patients with MKD display a variety of non-specific clinical manifestations, which can lead to diagnostic delay. We report the case of a child presenting with vasculitis that was found by genetic testing to be caused by MKD, and now add this autoinflammatory disease to the ever-expanding list of causes of monogenic vasculitides.Case presentationA 2-year-old male presented with an acute 7-day history of high-grade fever, abdominal pain, diarrhoea, rectal bleeding and extensive purpuric and necrotic lesions, predominantly affecting the lower limbs. He had been suffering from recurrent episodes of fever from early in infancy, associated with maculopapular/petechial rashes triggered by intercurrent infection, and after vaccines. Extensive infection screen was negative. Skin biopsy revealed small vessel vasculitis. Visceral digital subtraction arteriography was normal. With a diagnosis of severe idiopathic cutaneous vasculitis, he was treated with corticosteroids and mycophenolate mofetil. Despite that his acute phase reactants remained elevated, fever persisted and the vasculitic lesions progressed. Next-generation sequencing revealed compound heterozygous mutation in MVK c.928G > A (p.V310M) and c.1129G > A (p.V377I) while reduced mevalonate enzyme activity was confirmed suggesting a diagnosis of MKD as a cause of the severe vasculitis. Prompt targeted treatment with IL-1 blockade was initiated preventing escalation to more toxic vasculitis therapies and reducing unnecessary exposure to cytotoxic treatment.ConclusionsOur report highlights the broad clinical phenotype of MKD that includes severe cutaneous vasculitis and emphasizes the need to consider early genetic screening for young children presenting with vasculitis to exclude a monogenic vasculitis which may be amenable to targeted treatment.

Periodic fever syndromes: a patient diagnosed with recurrent Kawasaki disease.

Kawasaki disease, known as mucocutaneous lymph node syndrome, is a multi-system disease of unknown aetiology that occurs in young children under 5 years of age. The recurrence rate of Kawasaki disease is as rare as 1-3%. Especially in cases with coronary artery involvement, recurrent Kawasaki disease should be investigated in terms of underlying rheumatologic diseases such as periodic fever syndromes, microscopic polyangiitis, polyarteritis nodosa, and systemic-onset juvenile arthritis. In this study, we report homozygote mutations in mevalonate kinase and familial Mediterranean fever genes in a recurrent Kawasaki disease with coronary dilatation.

Novel mutations in mevalonate kinase cause disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant disease. In our previous research, we found that a linkage region of DSAP in a large family is located at 12q23·2-q24·1. Subsequently, the mevalonate kinase gene (MVK) was shown to be pathogenic in DSAP. To elucidate the mechanism by which MVK mutations lead to keratinocyte apoptosis and DSAP, and to report a new missense mutation, c.566 C>T (p.A189V), in MVK in a Chinese DSAP pedigree. The half-life of wild-type (WT) MVK protein and mutants was assessed using cycloheximide treatment of cells. Dimerization of MVK was analysed by coimmunoprecipitation and glutathione S transferase pull-down assay. MVK kinase activity, production of cell cholesterol, mitochondrial complex activity and apoptosis were detected, using the corresponding commercial kits, in cells overexpressing MVK WT and mutants. Mechanically, we demonstrated that both the pathogenic p.A189V mutant and a sporadic mutation p.H312R (c.935A>G), which we reported previously, have rapid degradation, decreased kinase activity and reduced production of cell cholesterol. Also, we found the p.H312R mutation confers on the MVK protein an inability to dimerize. Further, we demonstrated that the mutants are impaired in mitochondrial function and lead to increased apoptosis. Our results provide an important basis for elucidating the mechanism by which MVK missense mutations contribute to DSAP.

368 Novel mevalonate kinase mutation in a patient with porokeratosis ptychotropica

368 Novel mevalonate kinase mutation in a patient with porokeratosis ptychotropica

Mevalonate kinase gene mutations and their clinical correlations in Behçet's disease

Genetics is suggested to play a role in the development of Behçet's disease (BD). Shared phenotipic features requires an approach to differential diagnosis from periodic febrile syndromes. We planned to study for mevalonate kinase (MVK) as a candidate for a susceptibility gene for Behçet's disease. Consecutive Behçet patients and apperently healthy subjects were included. Severity score of Behçet disease was calculated. Genotyping of mevalonate kinase gene was performed by polymerase chain reaction/sequence-based typing technique. Fifty BD patients (median age: 38.30 ± 11.06 years) and 51 controls (median age: 33.88 ± 12.47 years) were recruited. Three types of mutations have been found: first, a single nucleotide polymorphism (SNP) c.769-38C>T (rs35191208) in 21 of 50 BD patients and in 15 of 51 controls. Both groups were comparable for the frequency of c.769-38C>T (P > 0.05). In all of the cases with c.769-38C>T, a second SNP, c885+24G>A (rs2270374) was also present (previously reported to be in linkage disequilibrium with the first SNP). A third SNP, c.769-7T>G (rs104895331) was found in three of 50 BD patients and in one of the control group. We found this SNP together with c769-38C>T and c.885+24G>A. The neurological involvement was found to be more frequent in the BD patients with c.769-3C>T when compared to the BD patients without this polymorphism (P = 0.012). Our results suggested that the effects of MVK mutations in Behçet's disease could be an additional genetic susceptibility factor for the patients with neurological involvement. However, these results need confirmation in larger study populations and in different ethnic groups.

PReS-FINAL-2239: Renal AA amyloidosis in a child with hyper-IgD syndrome and a novel MVK mutation

AA amyloidosis may develop as a consequence of chronic inflammatory conditions including autoinflammatory diseases(AID). Mevalonate-kinase(MVK) deficiency(MKD) appears to be the least frequent underlying condition among monogenic periodic syndromes. Moreover, amyloidosis rarely manifests during childhood. We report a case of a small child in whom renal biopsy performed because of the cortico-resistant nephrotic syndrome revealed amyloid A.

PReS-FINAL-2330: Canakinumab treatment in patients with HIDS

Hyper-IgD and periodic-fever syndrome (HIDS) is a recessively inherited-autoinflammatory condition caused by mevalonate-kinase mutations. It is characterized by early-onset (<1 year of age), 4-6 days-long acute inflammatory episodes that typically recur every 4-6 weeks. The main features during episodes include fever, lymphadenopathies, rash, headache, abdominal pain, diarrhea, and a marked acute phase reaction[1,2]. Previous case reports suggested IL-blockade as a potential therapy. Canakinumab (CAN) is a fully-human, selective anti-IL-1β monoclonal-antibody (MoAb). Preliminary clinical and pharmacokinetics (PK) data of CAN-therapy in active HIDS patients is presented.

P02-015 - A novel MVK mutation in a child with AA amyloid

AA amyloidosis may develop as a consequence of chronic inflammatory conditions including inherited periodic fever syndromes. Mevalonate-kinase (MVK) deficiency (MKD) appears to be the least frequent underlying condition after FMF, TRAPS and CAPS. Moreover, amyloidosis rarely manifests during childhood. We report a case of a small child in whom renal biopsy performed because of the cortico-resistant nephrotic syndrome revealed AA amyloidosis.

Mutations in the Mevalonate Kinase (MVK) Gene Cause Nonsyndromic Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP. We present a case series with mutations in the mevalonate kinase (MVK) gene. A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study. Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination. Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate kinase (MK) enzyme activity was analyzed in cultured lymphoblastoid cells, and mevalonic acid levels were measured in urine samples. Exome variant filtering and prioritization led to the identification of compound heterozygous mutations in MVK (p.I268T and p.A334T) in the proband and her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid. Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic mevalonate kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK.

Hyper IgD Syndrome Presenting as Sweet's Syndrome in a 6 week old Infant

Abstract: Sweet’s Syndrome, also known as acute febrile neutrophilic dermatosis, is a rare condition with poorly defined immunopathogenesis that may be idiopathic or may be associated with ongoing inflammatory illness derived from infectious, malignant, or autoimmune conditions. It is characterized by the abrupt onset of rash with erythematous or violaceous papules or plaques along with fever and increased serum inflammatory markers. It is an uncommon condition in the pediatric population and affects mostly adults in the 3rd through 5th decade of life. We describe a case of Sweet’s Syndrome in an infant who subsequently was found to have mutations in the mevalonate kinase (MVK) gene, the underlying mutation for Hyper IgD syndrome (HIDS). This case exemplifies the phenotypic variation of mutations in MVK, and is the first described presentation of HIDS as Sweet’s Syndrome. Furthermore, this case implicates the IL-1 pathway in HIDS as the patient had rapid recovery of serum iron levels and CRP after initiation of the IL-1 receptor antagonist, anakinra.

Severe phenotypic spectrum of mevalonate kinase deficiency with minimal mevalonic aciduria

Mevalonate kinase deficiency is a rare autosomal recessively inherited organic aciduria with a complex multi-systemic phenotype. We describe two deceased patients with clinically severe mevalonate kinase (MK) deficiency confirmed by MK mutation analysis. The phenotype in our patients ranged from neonatal hydrops in the first patient to severe failure to thrive, hepatosplenomegaly, recurrent febrile episodes and lymphadenopathy in the second. Both infants excreted relatively low amounts of mevalonic acid intermittently.

Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children

Autoinflammatory diseases (AIDs) are characterized by recurrent, self-limiting systemic inflammation. Disorders include hereditary recurrent fever (HRF) syndromes such as hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). To determine the incidence of HIDS and report clinical and genetic characteristics together with the underlying MVK genotypes in German children, a prospective active surveillance was conducted in Germany during a period of 3 years. Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to two laboratories (Laboratory-ESPED, n2) performing genetic analyses. Inclusion criteria were a MVK mutation-positive patient ≤16 years of age with more than three self-limiting episodes of fever >38.5°C associated with increased inflammation markers. Clinical, epidemiological, and genetic data were assessed via questionnaires. Eight out of 16 patients were identified in Clinic-ESPED (n1) and 15 of 16 in Laboratory-ESPED (n2). Clinical and laboratory surveys overlapped in 7 of 16 cases. Incidence of HIDS was estimated to be 0.39 (95% CI: 0.22, 0.64) per 10(6) person-years. HIDS symptoms generally started in infancy with recurrent fever episodes lasting 3-12 (median, 4.5) days and recurring every 1-12 weeks. Fever was accompanied by abdominal pain, vomiting, diarrhea, cervical lymphadenopathy, and sometimes by headache, skin and joint symptoms. The patients carried 11 different MVK mutations mostly in compound heterozygosity (75%, 12 out of 16). The most frequent mutation was p.Val377Ile (81%, 13 out of 16). In Germany, the incidence of HIDS is very low with 0.39 per 10(6) person-years.

The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is a rare hereditary auto-inflammatory syndrome due to mutations in mevalonate kinase, the second enzyme of mevalonate pathway of cholesterol, and nonsterol-isoprenoids biosynthesis. The shortage of mevalonate-derived intermediates, and in particular of geranylgeranyl pyrophosphate (GGPP), has been linked with the activation of caspase-1 and thereby with the production of IL-1beta, but the true concatenation of these two events has not been clarified yet. We hypothesized that inflammasomes could mediate the activation of caspase-1 due to the shortage of GGPP. We monitored the expression of the principal proteins (NALP1, NALP3 and IPAF) of the three known inflammasomes, first in a cellular model of MKD and then in two MKD patients, after bacterial lipopolysaccharide (LPS) stimulation. In healthy subjects, alendronate alone induced the expression of NALP1 and NALP3, and then together with LPS it induced a dramatic increase in NALP3 expression. In MKD patients, NALP3 expression was higher than in untreated healthy controls. Our results, although preliminary, showed that the inhibition of the mevalonate pathway led to a hyper-expression of NALP3, suggesting a possible involvement of NALP3-inflammasome in the activation of caspase-1 consequent to GGPP decrement. This is the first time that the involvement of the inflammasome complexes was shown in MKD pathogenesis.

Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.

Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa.

To describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A low-penetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). The MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured. Mutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Her IgD values varied between normal and slightly increased, and the MK activity was in the low-normal range, while urinary mevalonate concentrations were always normal. The genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS.

Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool.

The hyper-IgD and periodic fever syndrome (HIDS) is characterized by recurrent attacks of fever, abdominal distress, and arthralgia and is caused by mevalonate kinase mutations. To ascertain the role of mevalonate kinase and the usefulness of molecular diagnosis in HIDS. Cross-sectional study. The international Nijmegen HIDS registry. 54 patients from 41 families who met the clinical criteria for HIDS. Clinical symptoms and signs, immunoglobulin concentration, leukocyte count, erythrocyte sedimentation rate, mutation analysis, and mevalonate kinase enzyme activity assay. There were two groups of patients: 41 patients with mevalonate kinase mutations (classic-type HIDS) and 13 patients without mutations (variant-type HIDS). Patients with classic-type HIDS had a lower mevalonate kinase enzyme activity, a higher IgD level, and more additional symptoms with attacks. The IgD level did not correlate with disease severity, mevalonate kinase enzyme activity, or genotype. Genetic heterogeneity exists among patients with a clinical diagnosis of HIDS.

Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is an autosomal recessive inflammatory disorder characterised by recurrent episode of fever associated with lymphadenopathy, abdominal distress, joint involvement and skin lesions. We recently demonstrated that mutations in the mevalonate kinase gene (MVK) are associated with HIDS. Direct DNA sequencing was done to screen the entire coding region of MVK in 25 unrelated patients with HIDS. Mutations were detected in the coding region of the gene including 11 missense mutations, one deletion, the absence of expression of one allele, as well as three novel polymorphisms. Seven of these mutations are novel. The large majority of the patients were compound heterozygotes for two mutations. Of these, V377I (G-->A) is the most common mutation occurring in 20 unrelated patients and was found to be associated with I268T in six patients. Mutations were associated with a decrease of mevalonate kinase (MK) (ATP:mevalonate 5-phosphotransferase, EC 2.7.I.36) enzymatic activity but not as profound as in mevalonic aciduria, a syndrome also caused by a deficient activity of MK. In HIDS the mutations are located all along the protein which is different from mevalonic aciduria where MK mutations are mainly clustered to a same region of the protein. On the basis of this study, we propose that the diagnostic screen of MVK in HIDS should be first directed on V377I and I268T mutations. Three patients are also described to illustrate the genotypic and phenotypic overlap with mevalonic aciduria.