Mevalonate Kinase-Associated Diseases: Hunting for Phenotype-Genotype Correlation

Area of Science:

• Genetics
• Immunology
• Rare Diseases

Background:

• Mevalonate kinase-associated diseases (MKAD) encompass a spectrum of rare autoinflammatory conditions caused by mutations in the mevalonate kinase gene (MVK).
• These conditions range from severe systemic metabolic disorders like mevalonic aciduria to skin-limited diseases such as disseminated superficial actinic porokeratosis.

Purpose of the Study:

• To investigate genotype-phenotype correlations in MKAD.
• To determine if specific MVK variants are associated with distinct clinical subtypes or disease severity.

Main Methods:

• A comprehensive review of literature data (N=346) and patient data from a referral center (N=51) with MVK variants.
• Analysis of genotype-phenotype relationships, focusing on specific MVK mutations and their clinical manifestations.

Main Results:

• Certain genotypes, like p.(Val377Ile), were linked to milder systemic forms but also observed in severe cases.
• Specific compound heterozygous variants (p.(Ile268Thr) and p.(Val377Ile)) increased amyloidosis risk.
• Homozygous p.(Leu264Phe) or p.(Ala334Thr), and compound heterozygous p.(His20Pro)/p.(Ala334Thr) correlated with severe neurological/ocular symptoms; p.(Leu264Phe) homozygosity invariably led to cataracts.
• Porokeratosis-associated variants were specific and more likely to be frameshift mutations.

Conclusions:

• Genotype-phenotype correlations in MKAD are crucial for understanding disease variability.
• Identifying specific MVK variants can predict disease severity and guide prophylactic management strategies.
• These findings aid in the clinical management and counseling of patients with MKAD.