Dr. Camille Birch has a PhD in biomedical engineering and hails from the Hudson Alpha Institute for Biotechnology at Huntsville, Alabama. Hudson Alpha, only 11 years old, is one of those new biotechnology efforts that’s using sophisticated bioinformatics to understand how our genes affect our health.

Dr. Liz Worthey and Dr. Birch believed that genetic mutations in ME/CFS might be altering metabolic pathways and causing an “unstable cellular energy state” in ME/CFS. They’re using a variety of algorithms, including one called “custom network analysis”, to examine all sorts of genomic abnormalities (single nucleotide substitutions, structural variants, fusion products, expanded tandem repeats, and variants in regulatory regions). (Yes, our genome is very complex…)

The type of ME/CFS you have, they think, might depend on which metabolic pathways your genetic mutations are whacking. Boy, does it appear that they hit that nail on the head in this study.

It should be noted that the SMCI, which funded this work, did not go to them – this genetics team went to the SMCI. Dr. Birch, who has a family member with ME/CFS, checked out past ME/CFS studies, decided genetics might very well play a role, got the OK to submit her grant proposal to the SMCI – and now a new research team is working in this field.

If you tend to roll your eyes when someone talks about genetics, definitely watch this fascinating webinar.

Genetic Diseases

Dr. Birch pointed out that mutations in just one gene can cause a bogglingly wide variety of illnesses. Mutations in just one gene called lamin-A, for instance, are associated with no less that 11 diseases – many of which have no relationship to each other!

On the other end of the spectrum, all 14 subtypes of glycogen storage disease are associated with completely different genes. These genes affect glycogen synthesis, breakdown or in other ways, but all of them end up impacting energy production.

One gene and its genetically modified protein, then, could conceivably be responsible for all the different manifestations of ME/CFS, or, on the other end of the scale, a raft of mutations in different genes could be responsible for, or contribute to, what we know of as ME/CFS.

This study looked at ten patients from Dr. Younger’s cohorts, but what it lacked in size it appeared to make up in depth.

Risky Loci

First they looked at relatively common gene variants or mutations found in the general population and known to have negative effects. They have found 32 of what they called “risk loci” in ME/CFS.

It wasn’t the individual risk loci which stood out, though: it was the pattern present in them. Geneticists always like it when closely aligned genes pop up in their studies. That suggests a problem – perhaps large enough to cause disease – is showing up in one area of the body.

Birch’s sample size was small, and she needed a way to zero in on the potentially relevant genes. When she asked the program if, say, 30% of the general population has a certain variant, what was the probability that a large portion of her ME/CFS group had that variant?

The program told her that it was extremely unlikely that 5 of the 32 loci would be found at such high levels in the ME/CFS group. Bigger studies are clearly needed, but given the probability that these were real findings – that these gene mutations likely are present and possibly doing some damage in ME/CFS – she turned to those.

Three of the five, remarkably, were associated with one part of the immune system – the interleukins (IL-1, IL-12B, IL-4R). Another affects cellular energy production, and the last affects nitric oxide production – which is important in blood vessel functioning (vasodilation) and inflammation. The fact that all five – impacting energy, the immune system and possibly blood vessel functioning – fit this disease well was definitely encouraging.

Rare or Unique Variants

It got better, though, when the group searched for rare or unique gene mutations found in the ME/CFS group. Each person had an average of 14 rare or unique gene mutations. The good news is that the rare mutations, while quite variable, also made sense – hitting metabolic, immune, ion and mitochondrial pathways.

In keeping with the results of past studies, no rare mitochondrial gene variants were found. As we’ll see, though, it’s not necessary to take a two-by-four to the mitochondria to whack someone’s energy production – there are plenty of subtler ways to do that.

The fact that most of the rare gene mutations were unique to each patient presented problems. Determining which ones might be causing ME/CFS required an unusual kind of digging. It was time for Birch to get personal.

After taking notes on 60 of the 120 stories of ME/CFS presented on the Solve ME/CFS Initiative’s website, she realized that ME/CFS was more heterogeneous than she’d known. A variety of potential subsets jumped out at her – each of which could have a different molecular basis.

About 1/3rd described an infectious type onset.

About 10% never felt normal, but the problem didn’t get bad until they hit their teen to adult years. This group slowly got worse over time.

Another small group described an extremely rapid and massive onset triggered by a non-infectious event – surgery, trauma or other very stressful event.

A few people described cognitive problems so severe that they sounded like they had something like Parkinson’s.

Another group described really severe pain.

Another group had really severe orthostatic intolerance.

She needed some more information, though, and asked each person an additional 32 questions (!) that would help the researchers guide their analysis. She’s basically doing a precision genetic analysis – examining each person’s story in detail – and using that information to better understand their genetic results. Included were some open-ended questions which allowed the participants to just tell it like it is in their own rich detail.

She’s now analyzing that data, but even without it the preliminary genetic analysis provided some intriguing possibilities. Every one of those ten patients had genetic issues in three pretty darn exciting categories.

The Webinar

Energy Metabolism

The first was energy metabolism, a subject that’s getting more and more attention all the time. Another nice pattern formed when she found that three of the patients had a potentially very damaging and rare gene mutation that affected the AMPK energy sensing pathway – which studies have suggested may be compromised in both ME/CFS and fibromyalgia.

None of the genes have been associated with a disease before – which, in my book, counts as a plus. Intriguingly, these genes are closely related – one tells AMPK to ramp up, another to ramp down, and another has an intermediate role. That close relationship suggests that different kinds of damage to AMPK could result in the same kind of fatiguing problems.

AMPK ensures that proper ATP levels are present in our cells. As ATP declines during exercise, for instance, AMPK ensures that more ATP is produced.

Way back in 2003, Dr. Grahame Hardie (“Management of cellular energy by AMPK”) suggested that AMPK problems were present in ME/CFS at a MERUK Workshop talk. AMPK should get activated in our muscle cells during exercise, but more recently, when Julia Newton in the U.K. whacked the muscle cells from ME/CFS patients with exercise, AMPK didn’t respond…

In type II diabetes, AMPK activation issues produce “metabolically inflexible” muscles that have trouble switching between glucose and fatty acid metabolism. Researchers refer to the reduced skeletal muscle mitochondrial capacity that results as “mitochondrial overload”.

Interestingly, if AMPK is a problem, a wide variety of treatments may be able to help (see blog above).

Iron Metabolism

They found rare and damaging mutations in two people with ME/CFS in iron-metabolizing genes that could cause trouble transferring iron from the liver or in iron recovery. Because iron carries oxygen to our cells – which then use the oxygen to produce energy – it’s no surprise that iron deficiency diseases such as anemia can cause enormous fatigue.

If an anemia is present in ME/CFS, though, it’s a very different kind of anemia than what we’re used to. Birch brought up the interesting possibility that if anemia is present in ME/CFS – it’s not present in the blood – it’s present in the tissues.

That was an interesting possibility. Throw in another admittedly very preliminary (and not genetic) report from an ongoing study at Ian Lipkin’s research center – and the iron issue gets even more interesting. Instead of examining the makeup of the genes we are born with, Lipkin is examining which genes are active.

In a possible tie-in, Lipkin found that several genes associated with iron metabolism were less active in ME/CFS patients. The differences were modest, but because they showed up in one pathway (that pattern thing again), Lipkin thought the ultimate impact could be significant.

In fact, Lipkin stated that, based on their “very early” data, they could predict that lesions in four parts of the iron intake pathway into the cell could be present. Not getting iron (and oxygen) into the cell could, of course, put quite a damper on energy production and wreak havoc with the resulting oxidative stress. Problems with that pathway could spell trouble in two potentially very important aspects of ME/CFS: oxidative phosphorylation (ATP production) and oxidative stress.

Glycogen Storage Disease?

So far, Birch had found rare and damaging mutations that could very well impact energy production in five out of ten patients in that study. Would the trend continue? Would we be so lucky? Rather remarkably, we were. In fact, Birch actually saved the best for last. In what she described as another surprise, mutations in glycogen storage genes showed up in two people.

Both mutations are very, very rarely found in the general population. One gene codes for an enzyme called enolase 3, which is associated with a glycogen storage disease (GSD 13) which, interestingly enough, shows up in adults (check), is characterized by severe muscle pain post exercise (PEM; check), and is associated with an intolerance of exercise (double check!). It’s one of two GSD’s associated with “exercise intolerance”.

Birch was very calm, but I was about jumping out of my seat when she described a genetic disease with adult onset, severe muscle pain after exercise, and exercise intolerance.

The plot thickened further when she reported that GSD 13 is thought to be very (VERY) rare – as in present in only two families thus far. She noted that that fact is almost irrelevant, because, if no one is testing for this disease (it requires a muscle biopsy) – and few doctors probably are – it’s going to be rare no matter how many people are affected. It’s not uncommon at all to later find that “rare diseases” aren’t so rare after all.

If the mutation causes severe muscle pain after exercise and exercise intolerance, one wonders how many people with FM or ME/CFS may have been misdiagnosed? Will GSD 13 be like craniocervical instability – a rare condition or disease with a difficult diagnosis – which doctors just haven’t been testing for?

Of all the GSD’s, GSD 13 is clearly potentially the most relevant for ME/CFS. Most of the other GSD’s produce in young children low blood glucose levels, enlarged livers, swollen bellies, heat intolerance, slowed growth and muscle cramping/pain after exercise.

GSD 13 – which is not even mentioned in some medical websites, including the Association for Glycogen Storage Diseases (lol) and the Cleveland Clinic (but is in Wikipedia – go figure) – does not cause hypoglycemia, enlarged livers, swollen bellies, etc., but is one of only two GSD’s that causes “exercise intolerance” and “an increasing intensity of muscle pain over the decades” (check!).

It “appears” to be extremely rare. The website on which the most GSD 13 information is found states under epidemiology – 3 patients (!). The clinical pool is obviously very small, but the website states that muscle strength is usually normal, episodic elevations of serum creatinine kinase can occur, which are reduced and can be normal with rest, and that episodic rhabdomyolysis may occur. (Rhabdomyolysis is a serious event which occurs when muscle fibers rapidly break down and release so much muscle detritus into the blood that kidney failure can result.) Beyond that, it appears that we know little about the disease.

Lastly, another patient had a mutation in another gene associated with a glycogen enzyme (glucosidase alpha neutral C) that could impact glycogen storage, but not much is known about that enzyme or gene.

I don’t know if I particularly want the answer to be a rare genetic disease (lol) but I certainly want answers. Whether or not GSD 13 is present in ME/CFS, the potentialglycogen storage issue, as well as the AMPK and iron issues appear to open up more possibilities.

Conclusion

It’s important to note that Birch is not hunting for rare AMPK or ion metabolism or glycogen metabolism gene mutations – they are simply the ones that are popping up. They popped up in 7 of the 10 patients.

So far, ME/CFS is looking more like a glycogen storage type disease than anything else: rare, different gene mutations have popped up that could produce problems with energy production in different ways.

Of course, we don’t know if these gene mutations are having an effect or if they’re present in other ME/CFS patients. The body is complex with many redundancies. Just because you have a rare and potentially damaging gene mutation doesn’t mean it’s impacting your health, and, indeed, Dr. Birch warned that the study is quite small and that as more patients are added and they dig deeper molecularly, some of these avenues may not pan out.

Dr. Birch emphasized their desire to collaborate with others and stated they were actively talking to other ME/CFS researchers as well as geneticists outside the ME/CFS world – and then mentioned two. She said she spoke to Nancy Klimas at the last NIH conference and to a UK researcher involved in a very large genetic study.

That’s just the tip of the iceberg in this evolving field. Avindra Nath at the NIH should certainly know about this research – he’s doing muscle biopsies – possibly right now – and genetics work; Ron Tompkins of the Open Medicine Foundation’s Collaborative ME/CFS Research Center at Harvard will be doing the deepest dig in ME/CFS patient’s muscles yet; Ian Lipkin would probably love to hear of more evidence of iron metabolism issues; Allan Light in Utah has been involved in several genetic studies and a family study is underway at the Bateman Horne Center. Of course, there’s Ron Davis at Stanford – our in-house genetics expert – who is overseeing a personalizied approach to the genome in studies of families with ME/CFS, as well as other genetic studies with the Open Medicine Foundation’s help.

When contacted, Ron Tompkins said his team would be assessing glycogen issues in the muscle biopsies they’re doing.

The group’s findings were presented at a clinical genetics conference recently and were “received really well”. The presenter said the frustrated doctors (they are frustrated, too) were quite eager to get some potential answers for this disease.

Pilot Studies Work!

The Ramsay awards are designed to open up new areas of inquiry and provide researchers with the ability to gather the data needed to get major NIH grants. No data – no big grants! Grant packages like the Ramsay Awards are small, but potentially very powerful. They’ve historically played an important role in our continuing efforts to understand ME/CFS. Jarred Younger is just one researcher who got his feet wet in ME/CFS using pilot study grants. (He recently received another large NIH grant.)

This study is another win for the SMCI’s Ramsay Awards and for the SMCI’s newest research director, Sadie Whittaker. In her first round of Ramsay Awards, she chose well with this one.

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