Elsevier

Clinical Immunology

Volume 147, Issue 3, June 2013, Pages 197-206
Clinical Immunology

Review
Mevalonate kinase deficiency, a metabolic autoinflammatory disease

https://doi.org/10.1016/j.clim.2012.09.011Get rights and content

Abstract

Mevalonate kinase deficiency is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype. In this review we discuss its pathogenesis, clinical presentation and treatment. Mutations in both copies of the MVK-gene lead to a block in the mevalonate pathway. Interleukin-1beta mediates the inflammatory phenotype. Shortage of a non-sterol isoprenoid product of the mevalonate pathway, Geranylgeranylpyrophosphate leads to aberrant activation of the small GTPase Rac1, and inflammasome activation. The clinical phenotype ranges widely, depending on the severity of the enzyme defect. All patients show recurrent fevers, lymphadenopathy and high acute phase proteins. Severely affected patients have antenatal disease onset, dysmorphic features, growth retardation, cognitive impairment and progressive ataxia. Diagnosis relies on mutation analysis of the MVK-gene. There is no evidence based therapy. IL-1 blockade is usually effective. Severe cases require allogeneic stem cell transplantation. Targeted therapies are needed.

Highlights

Mevalonate kinase deficiency impairs the synthesis of non-sterol isoprenoids. ► Abberantly activated small GTPases induce IL-1β generation by inflammasomes. ► There is no evidence based treatment for mevalonate kinase deficiency. ► Specific interventions in the metabolic pathway are being developed.

Introduction

Mevalonate kinase deficiency (MKD) is an autosomal recessive inborn error of isoprenoid biosynthesis. In contrast to most inherited metabolic diseases, the main clinical features are those of an autoinflammatory disease: episodic fever and generalized inflammation. The associated phenotypes had been recognized nearly three decades ago as the Hyper ImmunoglobulinemiaD and periodic fever Syndrome (HIDS, MIM# 260920) [1], [2] and Mevalonic Aciduria (MA, MIM# 610377) [3]. The latter was soon shown to be due to mevalonate kinase deficiency [4]. While initially, MA and HIDS were considered unrelated diseases, at the turn of the century two Dutch groups independently identified mevalonate kinase deficiency, due to mutations in MVK, as the cause of HIDS [5], [6]. The two disorders have similar inflammatory attacks with fever and a brisk acute phase response, accompanied by lymphadenopathy, hepatosplenomegaly, abdominal pain, vomiting diarrhea, arthralgia, myalgia, skin rash and mucosal ulcers. Elevation of serum IgD is a characteristic, though inconsistent finding. In addition to these features, the MA phenotype is characterized by dysmorphic features, pre- and postnatal growth retardation, ocular, and neurological involvement. Currently, the two presentations are considered the extremes of a phenotypic spectrum with a severe form, MA and a mild form, HIDS [7]. In fact, the spectrum is probably even wider, ranging from embryonically lethal to apparently healthy [8]. The pathogenesis is only partly understood and there is no evidence-based treatment available. In the following review, we will discuss current understanding of MKD pathogenesis, its clinical presentation and management.

Section snippets

Epidemiology

MKD is an autosomal recessive disease that occurs worldwide and affects both sexes equally [9], [10]. A disproportionate number of HIDS patients have been reported from the Netherlands, probably due to a founder mutation (V377I) in the Dutch population [8], [11]. The exact prevalence of MKD is unknown. Based on data from the international HIDS registry (www.hids.net) and the European Union sponsored Eurofever registry (http://www.printo.it/eurofever[10]) the number of known MKD patients

The mevalonate pathway

Mevalonate kinase (MK) is a key enzyme of the mevalonate pathway, a biosynthetic route that produces cholesterol and branched unsaturated lipid chains called non-sterol isoprenoids. The mevalonate pathway is highly regulated by several feedback mechanisms, the most important being the amount of free cholesterol available [12]. The pathway starts with the enzyme 3-Hydroxyl-3-MethylGlutaryl-Coenzyme A (HMG-CoA) reductase, which is the tightly regulated rate limiting enzyme of the mevalonate

Clinical presentation

The HIDS phenotype is characterized by early onset of febrile attacks, usually starting in infancy at a median age of 6 months and rarely after the age of 5 years [9], [48]. The attacks recur at irregular intervals of 2–8 weeks. Attacks are often unprovoked, but sometimes triggered by emotional stress, trauma, infection or, quite characteristically, by vaccinations. Fever onset is abrupt, often with shaking chills. Temperature regularly exceeds 40 °C (104 °F). Unless antipyretics are taken, fever

Diagnosis

Clinical features that should prompt testing for MKD are fever episodes recurring during at least 6 months with an onset before the age of 5 years with either strongly elevated serum IgD, attacks triggered by vaccinations or at least three of the following: cervical lymphadenopathy, abdominal pain, vomiting, diarrhea, joint pain, aphtosis, or rash [9]. Inflammatory attacks are always accompanied by a strong acute phase response, reflected by high Erythrocyte sedimentation rate (ESR), C-reactive

Patient care

The goals of management in MKD are normal participation in activities of daily life, reduction of inflammatory symptoms, prevention of long-term sequelae, and supportive care for disabilities. There are no evidence-based management guidelines. Patients are followed on a regular basis to check for disease activity, complications and drug (side) effects. It has been shown in other inflammatory disorders that persistently elevated serum amyloid A protein levels are associated with progressive

Prognosis

The prognosis of MKD depends on the severity of the defect. Most MKD patients have fewer attacks with age. Some HIDS patients even attain spontaneous complete disease remission. In contrast, severely affected (MA) patients risk death from a systemic inflammatory response syndrome early in life with up to 40% reportedly dying in infancy [27]. With the advent of allogeneic stem cell transplantation for this population and improved supportive care, these figures are likely to improve.

Conclusion

Mevalonate kinase deficiency is a rare autoinflammatory disease due to an inborn error of metabolism. Depending on the specific genetic defect and inherent enzyme deficiency, the clinical expression ranges from stillbirth to apparent full health. Severely affected patients have neurological involvement in addition to inflammation. The pathogenesis of the inflammation in MKD is gradually being elucidated and interleukin-1β appears to be a major effector. There is no evidence based therapy,

Conflict of interest statement

The author(s) declare that there are no conflicts of interest.

References (70)

  • S.M. Houten et al.

    Regulation of isoprenoid/cholesterol biosynthesis in cells from mevalonate kinase-deficient patients

    J. Biol. Chem.

    (Feb 21 2003)
  • A. Marcuzzi et al.

    Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes

    Int. Immunopharmacol.

    (2010 Jun)
  • L.M. Kuijk et al.

    HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB-dependent caspase-1 activation

    Blood

    (Nov 1 2008)
  • J. Harris et al.

    Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation

    J. Biol. Chem.

    (Mar 18 2011)
  • J. Lee et al.

    Autophagy suppresses interleukin-1beta (IL-1beta) signaling by activation of p62 degradation via lysosomal and proteasomal pathways

    J. Biol. Chem.

    (Feb 3 2012)
  • E.J. Bodar et al.

    Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome

    Blood

    (Mar 15 2007)
  • J.D. Gillmore et al.

    Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein

    Lancet

    (Jul 7 2001)
  • S. Chaudhury et al.

    Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria

    Am. J. Transplant.

    (Mar 8 2012)
  • A.M. Prieur et al.

    Nosologic aspects of systemic forms of very-early-onset juvenile arthritis. Apropos of 17 cases

    Sem. Hop.

    (Jan 26 1984)
  • G. Hoffmann et al.

    Mevalonic aciduria—an inborn error of cholesterol and nonsterol isoprene biosynthesis

    N. Engl. J. Med.

    (Jun 19 1986)
  • S.M. Houten et al.

    Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome

    Nat. Genet.

    (Jun 1999)
  • J.P. Drenth et al.

    Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. international hyper-IgD study group

    Nat. Genet.

    (Jun 1999)
  • A. Simon et al.

    Mevalonate kinase deficiency: evidence for a phenotypic continuum

    Neurology

    (Mar 23 2004)
  • S.M. Houten et al.

    Carrier frequency of the V377I (1129G>A) MVK mutation, associated with hyper-IgD and periodic fever syndrome, in the Netherlands

    Eur. J. Hum. Genet.

    (Feb 2003)
  • J.C. van der Hilst et al.

    Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome

    Medicine (Baltimore)

    (Nov 2008)
  • N. Toplak et al.

    An international registry on autoinflammatory diseases: the Eurofever experience

    Ann. Rheum. Dis.

    (Jul 2012)
  • A.C. Bulua et al.

    Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS)

    J. Exp. Med.

    (Mar 14 2011)
  • L. Henneman et al.

    Compromised geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency

    J. Inherit. Metab. Dis.

    (Oct 2010)
  • S.J. McTaggart

    Isoprenylated proteins

    Cell. Mol. Life Sci.

    (Feb 2006)
  • R.J. Lutz et al.

    Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina

    Proc. Natl. Acad. Sci. U. S. A.

    (Apr 1 1992)
  • S.M. Houten et al.

    Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome

    Hum. Mol. Genet.

    (Dec 1 2002)
  • L. Cuisset et al.

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

    Eur. J. Hum. Genet.

    (Apr 2001)
  • S.H. Mandey et al.

    Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency

    Hum. Mutat.

    (Aug 2006)
  • B.T. Poll-The et al.

    Mevalonic aciduria in 12 unrelated patients with hyperimmunoglobulinaemia D and periodic fever syndrome

    J. Inherit. Metab. Dis.

    (Jun 2000)
  • G.F. Hoffmann et al.

    Clinical and biochemical phenotype in 11 patients with mevalonic aciduria

    Pediatrics

    (May 1993)
  • Cited by (0)

    View full text