Mevalonate kinase deficiency, a metabolic autoinflammatory disease

Burgh, Robert van der; Haar, Nienke Ter; Boes, Marianne; Frenkel, Joost

doi:10.1016/j.clim.2012.09.011

Cited by 133 publications

(134 citation statements)

References 67 publications

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“…Mevalonate kinase is an enzyme that is part of the mevalonate pathway. This pathway produces cholesterol and unsaturated lipid chains, known as isoprenoids (van der Burgh et al 2013). The mevalonate kinase activity is reduced in MKD patients.…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic Value of Urinary Mevalonic Acid Excretion in Patients with a Clinical Suspicion of Mevalonate Kinase Deficiency (MKD)

et al. 2015

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Objective: In patients suffering from mevalonate kinase deficiency (MKD), the reduced enzyme activity leads to an accumulation of mevalonic acid which is excreted in the urine. This study aims to evaluate the diagnostic value of urinary mevalonic acid measurement in patients with a clinical suspicion of mevalonate kinase deficiency.Methods: In this single-center, retrospective analysis, all patients in whom both measurement of mevalonic acid and genetic testing had been performed in the preceding 17 years have been included. The presence of two pathogenic MVK mutations or demonstration of decreased enzyme activity was considered to be the gold standard for the diagnosis of MKD.Results: Sixty-one patients were included in this study. Thirteen of them harbored two MVK mutations; twelve of them showed elevated levels of mevalonic acid. Forty-eight patients did not harbor any MVK mutations, yet five of them excreted increased amounts of mevalonic acid. This corresponds to a sensitivity of 92%, a specificity of 90%, a positive predictive value of 71%, and a negative predictive value of 98%. The positive likelihood ratio is 10 and the negative likelihood ratio is 0.09.Conclusion: MKD seems very unlikely in patients with a normal mevalonic acid excretion, but it cannot be excluded completely. Further, a positive urinary mevalonic acid excretion still requires MVK analysis to confirm the diagnosis of MKD. Therefore, detection of urinary mevalonic acid should not be mandatory before genetic testing. However, as long as genetic testing is not widely available and affordable, measurement of urinary mevalonic acid is a fair way to select patients for MVK gene analysis or enzyme assay.

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Section: Introductionmentioning

confidence: 99%

“…Elevated levels of urinary mevalonic acid are therefore suggestive of MKD. Examination of HIDS patients showed an increased excretion of mevalonic acid during febrile episodes, while normal levels of mevalonic acid were sometimes found between those episodes (van der Burgh et al 2013;Poll-The et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Value of Urinary Mevalonic Acid Excretion in Patients with a Clinical Suspicion of Mevalonate Kinase Deficiency (MKD)

et al. 2015

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“…Currently, there is no evidence-based treatment available for HIDS and targeted therapies are needed (van der Burgh et al, 2012). Etanercept, a TNF-α inhibitor, and anakinra, the recombinant form of the human IL-1 receptor antagonist, are reasonable alternatives in the treatment of HIDS, as these cytokines seem to play a central role in acute HIDS attacks.…”

Section: Discussionmentioning

confidence: 99%

“…If either of these treatments are not effective a switch to the other can be considered, because some patients have a good response to anti-IL1 drugs but not to etanercept, and vice versa (Caorsi et al, 2012;van der Hilst and Frenkel, 2010). Severe unresponsive cases of MA could be considered for allogeneic stem cell transplantation (van der Burgh et al, 2012). In the case here described only a partial clinical response to usual doses of anakinra (2 mg/kg/day) was initially observed, requiring step-up doses reaching 5 mg/kg/day to achieve a more controlled disease (inflammatory markers, less number of crises and severe ones with need for steroid therapy).…”

Section: Discussionmentioning

confidence: 99%

“…The disease is clinically characterized by recurrent episodes of fever and inflammation. Starting in the first year of life, patients have periodic fever episodes lasting four to six days, at variable intervals, with accompanying lymphadenopathy, hepatosplenomegaly, gastrointestinal complaints, aphthous ulcers, arthralgias, and skin rashes (Bader-Meunier et al, 2011;Korppi et al, 2011;Lierl, 2007;van der Burgh et al, 2012;van der Hilst and Frenkel, 2010). Some episodes are triggered by immunizations, stress, infection, or minor trauma (Korppi et al, 2011;van der Hilst and Frenkel, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype

Santos¹,

Aróstegui²,

Brito³

et al. 2014

Gene

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Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM# 260920) is a rare recessively-inherited autoinflammatory condition caused by mutations in the MVK gene, which encodes for mevalonate kinase, an essential enzyme in the isoprenoid pathway. HIDS is clinically characterized by recurrent episodes of fever and inflammation. Here we report on the case of a 2 year-old Portuguese boy with recurrent episodes of fever, malaise, massive cervical lymphadenopathy and hepatosplenomegaly since the age of 12 months. Rash, arthralgia, abdominal pain and diarrhea were also seen occasionally. During attacks a vigorous acute-phase response was detected, including elevated erythrocyte sedimentation rate, C-reactive protein, serum amyloid A and leukocytosis. Clinical and laboratory improvement was seen between attacks. Despite normal serum IgD level, HIDS was clinically suspected. Mutational MVK analysis revealed the homozygous genotype with the novel p.Arg277Gly (p.R277G) mutation, while the healthy non-consanguineous parents were heterozygous. Short nonsteroidal anti-inflammatory drugs and corticosteroid courses were given during attacks with poor benefits, whereas anakinra showed positive responses only at high doses. The p.R277G mutation here described is a novel missense MVK mutation, and it has been detected in this case with a severe HIDS phenotype. Further studies are needed to evaluate a co-relation genotype, enzyme activity and phenotype, and to define the best therapeutic strategies.

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Genetics of Mevalonate Kinase Deficiency

Schulert

2017

Encyclopedia of Life Sciences

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Mevalonate kinase deficiency (MKD) represents a spectrum of clinical phenotypes that result from genetic variants in the MVK gene encoding mevalonate kinase. This spectrum ranges from the autoinflammatory disorder hyper‐IgD and periodic fever syndrome (HIDS) on the mild to the severe metabolic disorder mevalonic aciduria (MA). Homozygous variants in MVK lead to loss of enzyme function, and severity of clinical phenotype is linked to degree of residual enzyme activity. However, the disease has variable genotype/phenotype correlation, and additional modifier genes may exist to alter the clinical presentation. In addition, MVK variants have recently been associated with expanded phenotypes including retinitis pigmentosa, disseminated superficial actinic porokeratosis and inflammatory bowel disease. Further genetic and pathophysiological understanding of MKD is needed to better predict clinical course and direct management. Key Concepts MKD is a metabolic autoinflammatory disorder linked to variants in MVK , encoding mevalonate kinase. MKD is an autosomal recessive condition with variants leading to loss of enzyme function. Severely affected MKD patients have minimal mevalonate kinase activity and present with MA. Patients with some residual enzyme activity lack metabolic and central nervous system features and manifest HIDS. While there is significant genotype–phenotype association in MKD, there is a broad range of clinical features. In addition, there are reports of asymptomatic patients despite biallelic variants and patients with heterozygous variants and HIDS. There may exist modifier genes which impact the clinical features of MKD such as risk for complications including macrophage activation syndrome. MVK variants have recently been linked to additional disorders including retinitis pigmentosa (RP) and disseminated superficial actinic porokeratosis (DSAP). Further genetic and pathophysiologic understanding of MKD is needed to improve patient diagnosis and management.

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Mevalonate kinase deficiency, a metabolic autoinflammatory disease

Cited by 133 publications

References 67 publications

Diagnostic Value of Urinary Mevalonic Acid Excretion in Patients with a Clinical Suspicion of Mevalonate Kinase Deficiency (MKD)

Diagnostic Value of Urinary Mevalonic Acid Excretion in Patients with a Clinical Suspicion of Mevalonate Kinase Deficiency (MKD)

Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype

Genetics of Mevalonate Kinase Deficiency

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