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

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.

Pathogenic autoantibody internalization in myositis

“…This suggests the possibility that disruption of HMGCR by autoantibodies could lead to the same pathogenic abnormalities. 28,29…”

“…This suggests the possibility that disruption of HMGCR by autoantibodies could lead to the same pathogenic abnormalities. 28,29 Upon review of all available muscle biopsies, we noted accumulations of lipids in myofibers of patients with anti-HMGCR autoantibodies (Supplementary Figures 47-49). Specifically, 90% (18/20) of muscle biopsies from anti-HMGCR-positive patients had lipid accumulation compared to 8.3% (10/110) of patients with other types of myositis (p<0.001).…”

Rare disease informs mechanism and possible treatment of statin-associated myopathy

“…In PNAS, Yogev et al. ( 4 ) report a homozygous HMGCR variant in individuals with LGMD, substantiating the connection between the drug-induced myopathy, anti-HMGCR antibodies, and a rare inherited genetic disorder, all converging on HMGCR dysfunction. They provide proof of variant pathogenicity and demonstrate that oral supplementation of mevalonolactone, a downstream metabolite of HMGCR, can alleviate symptoms in an affected individual.…”

“…In PNAS, Yogev et al. ( 4 ) utilize a combination of homozygosity mapping and exome sequencing to identify a homozygous HMGCR variant [(NM_000859.3): c.2465G>A; p.(Gly822Asp)] which segregated with LGMD in a large kindred. The onset of the disease was in the fourth decade of life with activity-induced pain progressing to muscle fatigue and weakness in a distribution typical of LGMD, and culminating with respiratory muscle involvement.…”

Effects of HMGCR deficiency on skeletal muscle development

“…Two recent reports characterize a total of 6 families with biallelic pathogenic variants in HMGCR in the setting of LGMD phenotypes, with one individual deriving therapeutic benefit from mevalonolactone administration 16,17 . However, details of the connection between pathogenic variants in HMGCR and inherited muscle disease remain unclear.…”