A major adverse effect of statins is myopathy (known since 1980). Now genetics have shed light on this association. Two independent teams have recently discovered that recessive mutations in HMGCR cause a severe form of muscular disease in humans.
A 🧵 for genetics lovers.
HMGCR codes for HMG CoA reductase which converts HMG-CoA to mevalonate, a rate limiting step in the cholesterol synthesis. Statins act by inhibiting HMG-CoA reductase.
en.wikipedia.org/wiki/HMG-CoA_reductase
Statins were discovered in 1970s by a Japanese scientist, Akiro Endo. The statins are, according to WSJ, "the first in a class of medicines that today brings $25 billion a year to pharmaceutical companies."
en.wikipedia.org/wiki/Akira_Endo_(biochemist)
And yet, Endo derived no financial benefit from his discovery. Michael S. Brown and Joseph Goldstein, who got Nobel prize for cholesterol related work, famously said "The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo"
I strongly recommend reading this fascinating WSJ article on Endo's story: "How One Scientist Intrigued by Molds Found First Statin". You'll be amused by the way the article ends.
wsj.com/articles/SB113677121574341250
Okay, coming back to our main topic, it turns out that the very first human, an 18 yr old female, who received statin developed severe myopathy to the point she was unable to walk. The drug was discontinued, and the woman recovered fully.
Then Endo and his colleague (Akira Yamamoto) continued testing statins (in secret!) in lower doses in other patients and achieved a 27% drop in blood cholesterol. And they even published those results (in 1980).
pubmed.ncbi.nlm.nih.gov/7362699/
Then as the statins were used widely across the world, it has been well recognized that myopathy is a common adverse effect, seen in ~30% of the users. But the mechanism underlying remained elusive.
More than four decades later, now two independent group of researchers have encountered patients with a rare muscular disease that turned out to be caused by biallelic mutations in HMGCR.
The first group of scientists, from Israel, published in the PNAS their work on the genetic investigation of a consanguineous Bedouin kindred where multiple individuals suffered from a severe limb girdle muscle disease.
pnas.org/doi/10.1073/pnas.2217831120
The disease manifested in the 4th decade of life starting as a mild to moderate pain and fatigue in proximal and axial muscles, then progressing to severe weakness, often involving respiratory muscles, requiring wheel chair and assisted ventilation.
Exome sequencing pinpointed the genetic cause: a homozygous missense mutation within a highly conserved region of HMGCR gene that severely reduced the affinity of the enzyme HMG CoA reductase to its substrate HMG CoA.
Note that these biallelic mutations only reduce the function of the enzyme. Complete deficiency of this enzyme is incompatible with life (homozygous KO is embryonically lethal in mice).
Likewise, a second group of scientists, from the USA, published in the AJHG a few days ago their work on the genetic investigation of nine individuals from unrelated families who all suffered from a limb-girdle like muscular dystrophy.
cell.com/ajhg/pdfExtended/S0002-9297(23)00130-1
The patients had a very similar features as those from the Israeli study: gradually worsening proximal and axial muscle weakness leading to loss of ambulation and respiratory insufficiency, except that here disease onset was earlier ranging from childhood to adolescence.
Through exome sequencing, the authors identified compound heterozygous missense variants in all the patients except one who, the authors speculate, might be a homozygous for a missense variant due to uniparental disomy.
All of the identified missense variants were located within conserved residues clustering within protein domains critical for enzyme activity. In vitro assays confirmed defective enzyme activity at varying levels of severity.
But what is amazing about these discoveries is that scientists have not only established the precise cause of statin associated myopathy but might have also found the treatment for it.
Going back to the Israeli study, the authors didn't stop at just diagnosing the genetic cause but went one step further and ran n=1 clinical trial.
If the HMG CoA reductase deficiency is hurting muscles, then can externally supplementing mevalonic acid (which the enzyme is supposed to help make) will reverse the symptoms?
The Israeli scientists received approval for the trial from the Israeli ministry of health under the compassionate treatment procedure and treated one of their patients with weekly oral dose of mevalonalactone.
The doctors noticed improvement in muscle function as early as day 21. While previously the patient was unable to do any of these tasks, now she can raise herself sideways from sitting position, fully abduct her arm, extend her knees and
feed her grand child, stand with assistance and breathe without ventilation. A supplementary video from the paper recorded 4mon after treatment showing that the pt was able to abduct her arm fully which wasn't able to before the treatment.
The authors also modeled statin associated myopathy in mice and demonstrate that mevalonolactone supplementation reverses statin induced myopathy.
The authors are currently extending the treatment to other patients and envision that mevalonolactone might become a standard treatment for statin-induced myopathy in the future. If this happens, all those who will benefit will owe it to these rare disease patients.