Article
Phosphomevalonate kinase deficiency expands the genetic spectrum of systemicautoinflammatory diseases
Search Medline for
Authors
-
Juergen Brunner
- Department Kinder- und Jugendheilkunde, Medizinische Universität Innsbruck, Innsbruck; Danube Private University, Krems
-
Jakob Berner
- Anna Children’s Cancer Research Institute (CCRI), Wien
-
Cheryl van de Wetering
- Anna Children’s Cancer Research Institute (CCRI), Wien
-
Raul Jimenez Heredia
- Anna Children’s Cancer Research Institute (CCRI), Wien
-
Christina Rashkova
- Anna Children’s Cancer Research Institute (CCRI), Wien
-
Sacha Ferdinandusse
- Amsterdam UMC location University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam
-
Janet Koster
- Amsterdam UMC location University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam
-
Johannes Weiss
- Department Kinder- und Jugendheilkunde, Medizinische Universität Innsbruck, Innsbruck
-
Alexandra Frohne
- Anna Children’s Cancer Research Institute (CCRI), Wien
-
Sarah Giuliani
- Anna Children’s Cancer Research Institute (CCRI), Wien
-
Hans R. Waterham
- Amsterdam UMC location University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam
-
Irinka Castanon
- Anna Children’s Cancer Research Institute (CCRI), Wien
-
Kaan Boztug
- Anna Children’s Cancer Research Institute (CCRI), Wien; St. Anna Children’s Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Wien; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Wien
| Published: | September 18, 2024 |
|---|
Outline
Text
Introduction: In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in 2 subsequent enzyme steps by MVK and PMVK to generate mevalonate pyrophosphate that is further metabolized to produce sterol and nonsterol isoprenoids. Biallelic pathogenic variants in MVK result in the autoinflammatory metabolic disorder MVK deficiency. So far, however, no patients with proven PMVK deficiency due to biallelic pathogenic variants in PMVK have been reported. This study reports the first patient with functionally confirmed PMVK deficiency, including the clinical, biochemical, and immunological consequences of a homozygous missense variant in PMVK.
Methods: The investigators performed whole-exome sequencing and functional studies in cells from a patient who, on clinical and immunological evaluation, was suspected of an autoinflammatory disease.
Results: The investigators identified a homozygous PMVK p.Val131Ala (NM_006556.4: c.392T>C) missense variant in the index patient. Pathogenicity was supported by genetic algorithms and modeling analysis and confirmed in patient cells that revealed markedly reduced PMVK enzyme activity due to a virtually complete absence of PMVK protein. Clinically, the patient showed various similarities as well as distinct features compared to patients with MVK deficiency and responded well to therapeutic IL-1 inhibition.
Conclusion: This study reported the first patient with proven PMVK deficiency due to a homozygous missense variant in PMVK, leading to an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of systemic autoinflammatory diseases, characterized by recurrent fevers, arthritis, and cytopenia and thus should be included in the differential diagnosis and genetic testing for systemic autoinflammatory diseases.
References
- 1.
- Berner J, van de Wetering C, Jimenez Heredia R, Rashkova C, Ferdinandusse S, Koster J, Weiss JG, Frohne A, Giuliani S, Waterham HR, Castanon I, Brunner J, Boztug K. Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases. J Allergy Clin Immunol. 2023 Oct;152(4):1025-31.e2. DOI: 10.1016/j.jaci.2023.06.013
