Only one month at 100mg. It seems like she had no response during titration—probably 25, 50, 75 and then 100mg. It seems a little strange that she had no response until she hit exactly 100mg—but life is strange.
Preprint Spironolactone for ME/CFS in a Patient Homozygous for rs5522 (I180V): A Case Report, 2026, Donnellan et al
- Thread starter forestglip
- Start date
Only one month at 100mg. It seems like she had no response during titration—probably 25, 50, 75 and then 100mg. It seems a little strange that she had no response until she hit exactly 100mg—but life is strange.
jnmaciuch
Senior Member (Voting Rights)
Preferential capture is a biochemical principle that has to do with receptor binding affinity to a ligand. It is a real phenomenon but the basis for invoking it here with such confidence and claiming that it causes cells to be functionally "starved" of GR activity is...entirely unsubstantiated.
Firstly, the mutation does not occur in the ligand binding domain (LBD) of the protein, it's all the way on the other end. There are instances where mutations in other parts of the protein can change the shape of the LBD, but even more likely this mutation affects something that matters after cortisol already binds like nuclear localization. The conclusion from this 2024 preprint was basically that we know this mutation affects enhances the downstream effect of cortisol binding to the MR but we don't know why. And the effect it would have on intracellular GR activity is even less known
Long story short: as far as anecdotal evidence goes it's theoretically plausible that this person's health is affected by this mutation and that the drug did something to counteract it, I just don't think the biological explanation for why can be trusted
Utsikt
Senior Member (Voting Rights)
Thank you!
It also seems a bit weird to me to place the entire illness on one fairly common mutation. Wasn’t it 11 % or something?
11 or 12% is the frequency of the allele. Everyone has two alleles. So out of all the alleles in a population (twice the population), how many are C? That's the allele frequency.
The proportion of people who have two copies of the minor allele is fairly rare - around 1%.
Online calculator for seeing the expected genotype frequencies based on a given allele frequency: https://scienceprimer.com/hardy-weinberg-equilibrium-calculator
jnmaciuch
Senior Member (Voting Rights)
Even a common mutation could be relevant if the mutation worsens a problem that is already under strain from the disease state. That might explain things like how two people end up with very similar disease presentation, except one has debilitating OI as a primary symptom and the other doesn't. But yeah, I don't have faith it would explain the entirety of the illness