Diagnosis Of Mevalonate Kinase Deficiency 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.

A case report of mevalonate kinase deficiency in a 14-month-old female with fevers and lower extremity weakness

BackgroundThis case follows a 14-month-old female, who despite multiple presentations to several physicians, continued to have recurrent febrile episodes with gross motor delay. Her case revealed an often missed diagnosis of Mevalonate Kinase Deficiency, that now has an FDA approved treatment that both reduces recurrence and produces remission.Case presentationA 14-month-old female with a history of gross motor delay, frequent Upper Respiratory Tract infections, and otitis media presented to an urgent care for inconsolability and refusal to bear weight on her right leg. She had recently been treated with amoxicillin for acute otitis media and had developed a diffuse maculopapular rash, without any associated respiratory or gastrointestinal distress that persisted beyond cessation of the antibiotics. The patient presented multiple times to an urgent care over the subsequent week for fussiness, fever, anorexia, lymphadenopathy, with labs concerning for worsening anemia and elevated inflammatory markers. Subsequently, the patient was admitted to the hospital for suspected osteomyelitis versus oncologic process. X-Ray imaging of the patient’s lower extremities showed osseous abnormalities inconsistent with infection. A metabolic work-up showed elevated urine mevalonic acid, and follow-up genetic testing was positive for mutations in both copies of her mevalonate kinase gene. This led to the diagnosis of MKD.ConclusionsOften, episodic presentations require multiple perspectives to reveal the underlying cause. This case illustrates how apparent simple febrile episodes has the potential for more complexity upon further evaluation.

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

Mevalonate kinase deficiency (MKD) is an autosomal recessive inflammatory disease. Mutations in MVK gene are associated with MKD with modest genotype-phenotype correlation. In spite of recent guidelines indicating specific MVK mutations for the more severe form or the milder one, little is known about MVK variability within and between populations. The aim of this work is to provide supplementary information about MVK variability useful in the molecular diagnosis of MKD, as well as to unravel the presence of novel genes potentially involved as involved in the clinical heterogeneity of MKD phenotype. We used a population-based approach, coupled with Combined Annotation-Dependent Depletion (CADD) score, to analyze the level of genetic variability for common and putatively deleterious MVK variants. We also performed Exome screening with the Illumina Human Exome Bead Chip on 21 MKD patients to double-check our in silico findings. Haplotype block detection in different populations revealed the existence of two blocks in MVK; interestingly, the first haploblock comprises the promoter region shared with MMAB gene. Analyses of MMAB and MVK genetic variants in 21 MKD patients strengthen our observations showing a novel scenario in which the same mutations commonly associated with MKD are found coupled with different combination of MMAB rs7134594 SNP was already described as associated with HDL cholesterol level and present in the haploblock promoter region. The rs7134594 SNP is reported as an eQTL for MVK and MMAB. Hypothesizing the presence of genetic variants modulating the complex phenotypic spectrum of MKD, we suggest that future directions in screening for MKD pathogenic variants should focus both MMAB and MVK genes.

A restrospective survey of patients's journey before the diagnosis of mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is an autosomic recessive auto-inflammatory disease caused by mutations of the MVK gene. MKD being a very rare disease, numerous misdiagnoses and medical referrals may precede the right diagnosis, amplifying the burden of the disease. ObjectivesTo evaluate the patient's medical referrals between the first symptom and the diagnosis of MKD and the diagnosis delay. MethodsA questionnaire was sent to French paediatric and adult rheumatologists to retrospectively collect information from genetically confirmed patients with MKD regarding the first symptoms of the disease, the different diagnoses made previously, the treatments received, and the disease burden evaluated mainly by the number of hospitalizations. ResultsThirteen patients were analyzed. The mean age at onset was 9.5months (birth to 36months). The average diagnosis delay was 7.1years. Eleven of them were hospitalized at least 5 times before the establishment of the diagnosis. A wide variety of diseases had been suspected: systemic juvenile idiopathic arthritis, periodic fever aphtous stomatitis pharyngitis adenitis syndrome, other hereditary recurrent fever, vasculitis, connective tissue disease, inflammatory bowel disease, gastritis, infections and immunodeficiency. Before the right diagnosis, 9 patients received corticosteroids and 6 patients received non-steroidal-anti-inflammatory drugs. Half patients had received repeated antibiotics, one third had received intravenous immunoglobulin, and the others were treated with immunosuppressive drugs or hydroxychloroquine. ConclusionsMKD is a serious disease still difficult to treat, however earlier accurate medical referral and care, by increasing physicians’ awareness, is critical to improve both the disease course and quality of life.

Periodic Fever in MVK Deficiency: A Patient Initially Diagnosed With Incomplete Kawasaki Disease

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive disorder causing 1 of 2 phenotypes, hyperimmunoglobulin D syndrome and mevalonic aciduria, presenting with recurrent fever episodes, often starting in infancy, and sometimes evoked by stress or vaccinations. This autoinflammatory disease is caused by mutations encoding the mevalonate kinase (MVK) gene and is classified in the group of periodic fever syndromes. There is often a considerable delay in the diagnosis among pediatric patients with recurrent episodes of fever. We present a case of an 8-week-old girl with fever of unknown origin and a marked systemic inflammatory response. After excluding infections, a tentative diagnosis of incomplete Kawasaki syndrome was made, based on the finding of dilated coronary arteries on cardiac ultrasound and fever, and she was treated accordingly. However, the episodes of fever recurred, and alternative diagnoses were considered, which eventually led to the finding of increased excretion of mevalonic acid in urine. The diagnosis of MKD was confirmed by mutation analysis of the MVK gene. This case shows that the initial presentation of MKD can be indistinguishable from incomplete Kawasaki syndrome. When fever recurs in Kawasaki syndrome, other (auto-)inflammatory diseases must be ruled out to avoid inappropriate diagnostic procedures, ineffective interventions, and treatment delay.

“Hyper-IgD syndrome” or “mevalonate kinase deficiency”: an old syndrome needing a new name?

In the recent paper by Stabile et al. [1], the authors evaluate a group of patients suffering from a rare metabolic disease, called mevalonate kinase deficiency (MKD), previously known as Hyper-IgD syndrome (HIDs). The latter name was due to the fact that some patients displayed, among other symptoms, increased levels of circulating IgD during febrile flares. Stabile and colleagues re-evaluated 305 children with recurrent fevers, drawing out 10 patients based on the presence of inflammatory signs and elevated IgD levels. They found that IgD levels did not correlate with disease severity. This is one of the several works showing that IgD levels in this syndrome are not specific as diagnostic marker [2, 3]; the diagnosis of MKD should be based on other, more specific, markers (for a review of a possible diagnostic algorithm, see [4]. Here, we propose to re-evaluate the christening of this syndrome, for both the names HIDs and MKD. As we stated above, IgD levels should not be considered strictly a marker of this specific disease, rather an indication of a generic inflammatory state, due to the fact that around one out of five patients has normal IgD levels [2, 3]. So, we suggest that the use of HIDs name is obsolete, while MKD definition could suit better to the description of the disease. However, the role of mevalonate kinase in the pathogenesis of the disease could be questioned. A critical factor in the diagnosis of MKD is the level of mevalonic acid excreted in urine during fevers as well the presence of mutation in MVK gene (12q24). To our knowledge, there is no robust correlation between MK activity and the severity of the phenotype (see also [5]. To give an example, the more frequent mutation in MVK gene, causing MKD, is the Val377Ile: the phenotype is not constant and some individuals are completely asymptomatic while others are affected but still homozygous for this mutation. Stabile and coauthors found five patients (out of 10) with a novel SNP in heterozygosis, a substitution of a Ser to a Asn at position 52 (S52N). We evaluated ‘‘in silico’’ the potential for damaging effects using PolyPhen2 software [5]: S52N has potentially no effect on MK activity. Based on the literature findings and our own experience in the genetics of MKD, we suggest that the role of MK in MKD should be re-evaluated. Are other novel genes, previously overlooked, involved in the modulation of the clinical phenotype? The hereditary pattern of the disease correlates with the transmission pattern of MK mutations but not in a complete monogenic way. We could hypothesize the presence of other mechanisms, still linked to MVK gene. For example, could MK intronic sequences regulate through miRNA other genes and thus mutations linked to MKD could influences other genes? To answer this question, we performed a ‘‘in silico’’ search (using TargetScan and PolymiRTS softwares) looking for SNPs at 3’UTR of MVK gene able to change the affinity for the miRNA: we identified seven SNPs potential targets for miRNA (Table 1). So, when performing MKD genetic diagnosis, the 3’UTR region containing the potential targets for miRNA should be considered as possibly involved in the regulation mechanisms of MVK expression. This is just an example of different mechanisms possibly overlooked due to the main focus only on MVK gene. The search of novel pathogenic mechanism aimed at better understanding/diagnose this F. Celsi (&) A. Tommasini S. Crovella Institute for Maternal and Child Health, IRCCS ‘‘Burlo Garofolo’’, Trieste, Italy e-mail: celsi@burlo.trieste.it

Utility of denaturing high performance liquid chromatography (DHPLC) for the diagnosis of mevalonate kinase deficiency in periodic fevers of autoinflammatory nature suspicion

We developed a genetic investigation using denaturing high performance liquid chromatography (DHPLC), in order to identify polymorphisms of the gene MVK in patients with autoinflammatory syndrome suspicion. We evaluated 19 patients affected by recurrent fevers and other clinical manifestations usually found in autoinflammatory syndromes and not correlated with infections or autoimmune disease and 10 healthy controls. IgD level was measured in all patients. Molecular testing was performed in DNA extracted from PBMC and MVK gene was analysed either with DHPLC or with automatic sequencer. Primers for PCR amplifications, amplicon lengths and PCR conditions were designed in our laboratory. IgD level was normal in 14 patients. Healthy controls did not show any alteration of the DHPLC-profiles and of the DNA sequences. Twelve patients had at least one altered DHPLC-profile and these data have been confirmed by sequencing. In particular we detected the polymorphisms c.78+61A>G, S52N, S135S, D170D, c.632-18A>G, c.885+24G>A already described in the database INFEVERS. With DHPLC we got the results in shorter time (10 hours/patient) and with lower cost (40 euro/patient) in comparison to direct sequencing (25 hours and 150 euro/patient). High IgD levels do not represent an essential marker for diagnosis of MKD, as already reported in literature. DHPLC is a rapid low cost technique in order to screen mutations in patients with MKD suspicion. Twelve patients carried at the same time D170D and c.632-18A>G: such event suggests that these SNPs could be in linkage disequilibrium and that such polymorphisms could predispose to MKD.