2. Academic Validation
  3. Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone

Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone

  • Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2217831120. doi: 10.1073/pnas.2217831120.
Yuval Yogev 1,  Zamir Shorer 2,  Arie Koifman 3,  Ohad Wormser 1,  Max Drabkin 1,  Daniel Halperin 1,  Vadim Dolgin 1,  Regina Proskorovski-Ohayon 1,  Noam Hadar 1,  Geula Davidov 4 5,  Hila Nudelman 4,  Raz Zarivach 4 5,  Ilan Shelef 6,  Yonatan Perez 1,  Ohad S Birk 1 3
Affiliations

Affiliations

  • 1 The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, 8410501 Israel.
  • 2 Department of Pediatric Neurology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410101 Israel.
  • 3 Genetics Institute, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410101 Israel.
  • 4 Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501 Israel.
  • 5 National Institute for Biotechnology in the Negev and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer Sheva, 8410501 Israel.
  • 6 Department of Radiology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410101 Israel.
PMID: 36745799 DOI: 10.1073/pnas.2217831120
Abstract

Myopathy is the main adverse effect of the widely prescribed statin drug class. Statins exert their beneficial effect by inhibiting HMG CoA-reductase, the rate-controlling Enzyme of the mevalonate pathway. The mechanism of statin myopathy is yet to be resolved, and its treatment is insufficient. Through homozygosity mapping and whole exome Sequencing, followed by functional analysis using confocal microscopy and biochemical and biophysical methods, we demonstrate that a distinct form of human limb girdle muscular disease is caused by a pathogenic homozygous loss-of-function missense mutation in HMG CoA reductase (HMGCR), encoding HMG CoA-reductase. We biochemically synthesized and purified mevalonolactone, never administered to human patients before, and establish the safety of its oral administration in mice. We then show that its oral administration is effective in treating a human patient with no significant adverse effects. Furthermore, we demonstrate that oral mevalonolactone resolved statin-induced myopathy in mice. We conclude that HMGCR mutation causes a late-onset severe progressive muscular disease, which shows similar features to statin-induced myopathy. Our findings indicate that mevalonolactone is effective both in the treatment of hereditary HMGCR myopathy and in a murine model of statin myopathy. Further large clinical trials are in place to enable the clinical use of mevalonolactone both in the rare orphan disease and in the more common statin myopathy.

Keywords

HMGCR; limb girdle muscular dystrophy; mutation; statins.

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