Genetics of Mevalonate Kinase Deficiency

Abstract

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.

Keywords: autoinflammatory; periodic fever syndrome; hyperimmunoglobulin D and periodic fever syndrome; mevalonic aciduria; pediatric rheumatology

Figure 1. Overview of the mevalonate pathway. Cells convert HMG‐CoA into mevalonate, which is then converted into 5‐phosphomevalonic acid by mevalonate kinase. In patients with MKD (mevalonate kinase deficiency), the pathway is blocked at this step, leading to build‐up of mevalonic acid and depletion of downstream products. 5‐Phosphomevalonic acid is converted to geranyl pyrophosphate, which serves as precursor for the isoprenoids FPP (farnesyl pyrophosphate) and GGPP (geranylgeranyl pyrophosphate), which are the substrates for protein prenylation.
Figure 2. Genetic structure of MVK and mevalonate kinase along with key variants implicated in MKD. The gene‐encoding mevalonate kinase has 11 exons, and the protein has 4 conserved functional domains including a putative ATP (adenosine triphosphate)‐binding domain and peroxisomal targeting domain. Stars denote key amino acids in mevalonate kinase function. Several well‐described genetic variants are shown: variants linked to severe MA (mevalonic aciduria) phenotype are in bold, and splice‐site variants shown to lead to exon skipping or reduced enzyme function are in italics.
Figure 3. Genotype–phenotype association in MKD. Patients with homozygous variants in MVK typically have very low enzyme activity, particularly variants associated with more severe structural consequences. Patients with significant loss of enzyme activity display markedly increased levels of urine mevalonic acid and have clinical features consistent with MA phenotype including some with RP (retinitis pigmentosa), while those with more mild defects typically manifest the HIDS (hyperimmunoglobulinemia D and periodic fever syndrome) phenotype. In contrast, patients who are carriers of heterozygous MVK variants, as well as even some with homozygous variants, have clinically silent or mild phenotypes such as DSAP (disseminated superficial actinic porokeratosis). However, there is some overlap in these categories, and even siblings with identical MVK genotypes have different clinical phenotypes.
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Schulert, Grant S(Jul 2017) Genetics of Mevalonate Kinase Deficiency. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027246]