Reddit - Interesting posts on Reddit, including what some doctors say about ME/CFS

It may be difficult because, as Trish says, there is so much muddled thinking everywhere.
But the first thing I would say is that 'the literature' on MCAS and hEDS is by and large fringe pseudoscience put about by physicians who make a living out of giving people these labels.

MCAS may be a useful term for a very small number of people with rare abnormalities of tryptase or something but 95-98% of people given this label either just have allergies, or their problems are nothing to do with mast cells. I am pretty sure that the term is not useful. Virtually all the literature comes from a Dr Afrin, who I find very unimpressive.

The situation for hEDS I have explained I think. I haven't seen any hEDS diagnostic criteria but I think if there are any they are almost certainly made up by the same fringe physicians. An EDS diagnosis has nothing to do with fatigue or generalised unexplained pain or any of the things we are familiar with in ME/CFS.

It is vanishingly unlikely that someone should actually have both EDS and a genetic mast cell disorder - the chances would be about one in a million. OK that may mean there are fifty people in the UK who do have both but I very much doubt they would have any symptoms resembling ME/CFS. These two diagnoses are always given together by physicians who make things up I am afraid. I have to call a spade a spade.

I can understand that people feel that they get support from doctors who make these diagnoses. I can understand the sense of being validated. But to me it is all a scam. For me a diagnosis of ME/CFS is validation enough simply on the basis that it describes a disabling illness that large numbers of people report, with not the slightest indication that it is, on their part, made up.

I think it quite likely that 80-90% of people diagnosed with 'hEDS' simply have ME/CFS and mobile joints (which are quite normal in themselves).

 

Apologies for just popping in --

not able to participate in the discussion but the question about what could doctors do to help people with ME/CFS asking for help when there is no treatment reminded me of a forum discussion (members only) :

"As long as there is no treatment for ME, what can doctors do to improve patients' quality of life?" --

Think there are some sensible suggestions that negate the idea that patients asking for help urge doctors to do pseudo-medicine.

 

I think part of our problem with ME is that some medical professionals think exactly this way about ME and effectively want to shut down the ME/CFS diagnosis.

It’s a real challenge for everyone.

 

@Yann04 In case you haven't seen this yet Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome (2024, Preprint: Research Square)

Spoiler: Abridged passage with highlights

To identify genetic causes for hEDS, a genetic registry was developed at the Medical University of South Carolina (MUSC). Within this registry, a four generation family was identified that presented with autosomal dominant hEDS. Eleven family members were enrolled for genetic analysis, of whom five met the clinical diagnostic criteria for hEDS and three were coded as probable due to age and clinical history at time of analyses. Whole exome sequencing (WES) of the proband (IV-1) and a second cousin (IV-4) was performed. Following variant filtering, four rare and potentially damaging variants were shared between the affected individuals (IV-1 and IV-4). PCR amplification and targeted sequencing of all enrolled family members identified only one of these variants with a perfect phenotype-genotype segregation throughout the pedigree. This variant, located in the Kallikrein serine-protease gene KLK15 (chr19:50825890-C-T), was also found in affected members of a second family. The single nucleotide polymorphism (SNP) results in a missense change (KLK15 p. Gly226Asp), is rare in the population with a minor allele frequency (MAF) of 0.002 (gnomAD v2.1.1), and is predicted to be damaging with CADD and DANN scores of 24 and 0.998, respectively. To determine relevance to connective tissue biology, RT-PCR was performed and confirmed KLK15 mRNA expression in glandular and connective tissues isolated from human and mouse biopsies.

KLK15 is part of a contiguous cluster with 14 other members of the Kallikrein gene family on chromosome 19q13.33. Given the known involvement of Kallikreins in regulating one another through activation cascades, and their shared expression patterns in connective tissues, we evaluated the genetic burden of the entire KLK family of genes in a larger hEDS cohort. WES was performed on 197 clinically diagnosed, unrelated hEDS patients and filtered for KLK variants with MAFs less than 0.01 (<1%) in gnomAD. A total of 76 variants were identified, with 48 being unique in the cohort and 65 patients having at least one rare variant in a KLK gene (32.8%). A gene-based burden test was used to evaluate enrichment of rare variants in individual KLK genes and the entire contiguous gene cluster in hEDS patients. Significant enrichment for qualifying variants was observed in 11 of the 15 KLK genes with p-value <0.05 as well for the entire KLK gene cluster (considered as whole, p = 2.28×10−14); thus supporting a broad role for Kallikrein genes in hEDS.

Exploring the molecular consequences of Kallikrein variants will not only uncover mechanisms of normal connective tissue development and disease but also shed light on the comorbidities commonly associated with hEDS. Notably, Kallikreins are known to interact with substrates in the extracellular matrix, influencing the connective tissue environment in both homeostasis and disease. This class of genes also plays roles in blood pressure regulation and immune cell function, potentially contributing to various comorbidities such as postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome, which are frequently observed in hEDS patients. Relatedly, it is curious that there is a tight interaction between Kallikreins and in the innate immune system, specifically the complement system. Kallikreins can cleave complement 3 (C3) and 5 (C5) directly, leading to the generation of C3a and C5a16 , which are potent anaphylatoxins that enhance inflammation upstream of mast cell activation.

Given the autosomal dominant mode of inheritance and the variability of phenotypes associated with hEDS, it is likely that KLK gene variants, such as KLK15 G226D, function primarily in a dominant-negative manner. However, given the known synergistic hierarchy of Kallikreins, where they auto-activate and catalyze the activation of downstream Kallikrein enzymes, even subtle changes in expression levels due to loss-of-function alleles may have damaging effects. While we implicate KLK variants in hEDS, they represent just one aspect of the genetic landscape.

 

I just stumbled across this and sent it too my mum five minutes ago haha — cheers

 

The trouble with that report is that it is only two families and the knock out mice had defects in multiple organ systems - i.e. not hEDS. But a partial functional variant might produce just hypermobility.

What needs to be remembered is that genetically based EDS has, as far as I know, nothing whatever to do with the sort of fatigue and pain you get in ME/CFS. Therehave always been some families with what look like monogenic pedigrees and some other genes have been found like tenasoin variants I think, but as far as I know none of this is relevant to our discussions here.

 

Probably not the right thread for it, but they did look at 197 unrelated hEDS patients a found a third has this kind of variant.

 

True, but pwME also have to be prepared for them to say, "All we can recommend is pacing."

Some recently diagnosed pwME will find it hard to accept that almost nothing is known about the cause of their symptoms or how to treat them, and go off looking elsewhere. But there are doctors who're good at explaining, for instance, that single studies rarely add up to evidence—I was way too impressed by papers like this when I was first diagnosed, until one of the GPs at our practice grinned and explained that if he wanted to claim eating celery causes chickenpox, he could probably find published research to back it up.

We need more people like him, who'll approach it with good humour and understand that most recently diagnosed people aren't equipped to assess research credibility. It doesn't mean they're stupid; it's natural for them to look for answers, and working out who and what to believe is quite a learning curve.

 

Yup, like when I tried educating my M.E doctor and Virologist about the hypercoagulation theory for M.E and was warned not to become their guinea pig for their pet theories. They were very kind about it because they have seen many desperate patients in their careers.