ReviewMevalonate kinase deficiency, a metabolic autoinflammatory disease
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.
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