Severe phenotypic spectrum of mevalonate kinase deficiency with minimal mevalonic aciduria

Prasad, Chitra; Salvadori, M; Rupar, C. Anthony

doi:10.1016/j.ymgme.2012.10.019

Cited by 17 publications

(20 citation statements)

References 34 publications

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“…In comparison, patients suffering from the MA phenotype excreted higher levels of mevalonic acid (Poll-The et al 2000). In contrary, Prasad et al described two cases of severely affected patients with relatively low amounts of mevalonic acid excretion (Prasad et al 2012). …”

Section: Discussionmentioning

confidence: 98%

“…Several studies have described the phenomenon of elevated mevalonic acid levels in patients with MKD (Simon et al 2004;Bader-Meunier et al 2011;Poll-The et al 2000;Prietsch et al 2003;Hoffmann et al 1993;Prasad et al 2012). Hoffmann et al have shown in a series of eleven MA patients that highly elevated levels of mevalonic acid occur in urine and that the levels of mevalonic acid in urine correlated with the severity of the disease (Hoffmann et al 1993).…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

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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“…Another child developed liver disease at six months of age and was diagnosed with HIDS at 24 months of age [8]. The spectrum of symptoms seen in our patient, such as conjugated hyperbilirubinemia, thrombocytopenia, petechiae, hepatomegaly, hepatitis, and anaemia, has previously been described as the first manifestation of the severe disease mevalonate aciduria in newborns [9–11]. As HIDS and MA represent two phenotypic ends of the spectrum of MVK deficiency, it is reasonable to assume that identical symptoms can present at birth and that the neonatal symptoms in our patient were a manifestation of HIDS.…”

Section: Discussionmentioning

confidence: 78%

Neonatal Hepatitis as First Manifestation of Hyperimmunoglobulinemia D Syndrome

Linstow

Rosenfeldt

2014

Case Reports in Pediatrics

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Hyper IgD syndrome (HIDS) is a rare metabolic autoinflammatory syndrome characterised by recurrent febrile episodes, accompanied by various inflammatory symptoms. We present a case of severe HIDS in a young girl, whose symptoms started in the neonatal period with hepatomegaly, hepatitis, thrombocytopenia, and conjugated hyperbilirubinemia. From the age of five months, the child had recurrent febrile episodes, stomatitis, adenitis, and persistent hepatomegaly. The diagnosis of HIDS was established when she was three years and eight months old. This case report suggests that HIDS should be included in the differential diagnosis of neonatal hepatitis and conjugated hyperbilirubinemia.

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“…Mevalonate kinase deficiency (MKD) is a rare inborn error of metabolism caused by deficiency in the enzyme mevalonate kinase [ 1 , 2 ]. It disrupts synthesis of cholesterol and non-sterol isoprenoids [ 1 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…There are two forms of mevalonate kinase deficiency: mevalonic aciduria (MA), when residual function of the enzyme is undetectable (<1 % [ 3 ] or <0.5 % [ 8 ] according to different authors) and hyperimmunoglobulinemia D syndrome (HIDS), when residual function of the enzyme is 1.8–28 % [ 3 , 9 ] (or 1–10 % [ 8 ]). Literature reveals about 30 cases of MA, while the milder form, HIDS, is ten times more common [ 2 , 5 , 10 ]. There is evidence that phenotypes of MA and HIDS overlap; patients with the HIDS phenotype develop neurologic symptoms later in life [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Perinatal manifestation of mevalonate kinase deficiency and efficacy of anakinra

et al. 2016

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BackgroundMevalonate kinase deficiency is a metabolic autoinflammatory syndrome caused by mutations in the MVK gene, mevalonate kinase, the key enzyme in the non-sterol isoprenoid biosynthesis pathway. Two phenotypes of mevalonate kinase deficiency are known based on the level of enzymatic deficiency, mevalonic aciduria and hyperimmunoglobulinemia D syndrome, but a wide spectrum of intermediate phenotypes has been reported. Currently one of the most effective treatments is biological therapy (with interleukin-1 antagonist anakinra or tumour necrosis factor-α inhibitor etanercept).Case presentationThe patient in this case has a phenotype contributing to a severe disease that caused the symptoms to manifest very early, in the prenatal period. Mevalonate kinase deficiency was suspected on the basis of clinical (hydrops fetalis, hepatosplenomegaly, hypotonia) and laboratory signs (anaemia, intense acute phase reaction, increased urinary excretion of mevalonic acid). Mutation analysis of the MVK gene confirmed the biochemical diagnosis. Treatment with the interleukin-1 antagonist anakinra was started (minimal dose of 1 mg/kg/day) and revealed its efficacy after three days.ConclusionsOur case highlights the need for a very detailed clinical and laboratory assessment in new-borns with any suggestion of autoinflammatory disorders. It is important that patients are diagnosed as early as possible to provide better multidisciplinary follow-up and therapy when needed.

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Severe phenotypic spectrum of mevalonate kinase deficiency with minimal mevalonic aciduria

Cited by 17 publications

References 34 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)

Neonatal Hepatitis as First Manifestation of Hyperimmunoglobulinemia D Syndrome

Perinatal manifestation of mevalonate kinase deficiency and efficacy of anakinra

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