The following is a summary of “Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases,” published in the October 2023 issue of Allergy & Immunology by Berner, et al.

The isoprenoid biosynthesis pathway involves phosphorylating mevalonate in two sequential steps by the enzymes MVK and PMVK to generate mevalonate pyrophosphate, which is further metabolized to produce sterol and nonsterol isoprenoids. Biallelic pathogenic variants in MVK result in the autoinflammatory metabolic disorder known as MVK deficiency. No patients with confirmed PMVK deficiency due to biallelic pathogenic variants in PMVK have been reported. For a study, researchers sought to report the first patient with functionally confirmed PMVK deficiency, providing insights into the clinical, biochemical, and immunological consequences of a homozygous missense variant in PMVK.

The study utilized whole-exome sequencing and functional cell investigations from a patient who displayed clinical and immunological features suggestive of an autoinflammatory disease.

The study identified a homozygous PMVK p.Val131Ala (NM_006556.4: c.392T>C) missense variant in the index patient. Pathogenicity was substantiated through genetic algorithms and modeling analysis, and this was further confirmed in patient cells that exhibited significantly reduced PMVK enzyme activity, primarily attributed to a near absence of PMVK protein. Clinically, the patient presented with shared and distinct features compared to patients with MVK deficiency and demonstrated a positive response to therapeutic IL-1 inhibition.

The study introduced the first documented patient with verified PMVK deficiency arising from a homozygous missense variant in PMVK, resulting in an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of systemic autoinflammatory diseases, characterized by recurrent fevers, arthritis, and cytopenia, and underscores the importance of including PMVK deficiency in the differential diagnosis and genetic testing for systemic autoinflammatory diseases.

Source: jacionline.org/article/S0091-6749(23)00809-6/fulltext