Exertion intolerance in ME vs McArdle disease?

[mango]

I randomly came across an article on McArdle disease (a genetic disorder that mainly affects skeletal muscles), and found the description of exertion intolerance both interesting and relatable.

Does anyone here know if there has been any scientific attempts to compare the exertion intolerance in McArdle disease to the one experienced by pwME? Similarities, differences, maybe some clues as to what might be going on in pwME's bodies?

People with the disease develop 'exertion intolerance', which causes pain, cramps and muscle weakness during intense muscle work [...].

McArdle's disease is one of several known glycogen metabolism disorders [...].

The symptoms are caused by not converting enough energy for muscle work. Muscle cells go into an energy crisis, causing pain, cramps, stiffness and weakness under stress, such as when running, walking, lifting or carrying.

Intense muscle work carried out without access to oxygen (anaerobic work) requires a supply of glycogen. The work produces symptoms from the muscles and can also cause palpitations, breathlessness and nausea. However, the heart muscle is not affected in McArdle's disease, only the skeletal muscles are affected.

McArdles sjukdom
https://www.socialstyrelsen.se/kuns...en/sallsynta-halsotillstand/mcardles-sjukdom/

 

[Hutan]

McArdle Disease, 2023, Khattak and Ashram

McArdle disease, also known as glycogen storage disorder (GSD) type V, is an inborn metabolic disorder characterized by a deficiency or complete absence of an enzyme called muscle glycogen phosphorylase (or myophosphorylase). This disease is inherited in an autosomal recessive pattern and mainly affects skeletal muscles. The enzyme responsible for this disease normally catalyzes reactions that cause the conversion of glycogen to glucose. The deficiency of this enzyme, in turn, results in the accumulation of glycogen in tissues. The clinical sequelae are usually systemic but the defect is limited to particular tissues in some cases. Glycolysis is only partially hindered in McArdle disease, as muscle fibers are able to convert glucose to glucose-6-phosphate (G6P) downstream of the metabolic block.[1]

Most GSDs present in childhood, however, McArdle disease is one of those that have adult-onset forms as well. Unfortunately, there have not been any established treatment options although diet therapy has been observed to be efficacious in reducing clinical manifestations. In some patients, a liver transplant becomes a viable option.

McArdle disease was first reported in 1951 by Dr. Brian McArdle from London.[2] In 1959, it was described that the enzyme responsible for the affected step was myophosphorylase.[3][4] The underlying gene for myophosphorylase (PYGM) was first discovered in 1984.[5]

 

[Hutan]

Thanks for bringing this to our attention @mango. I think it is a condition that people with ME/CFS symptoms should consider. It sounds as though the condition is under-diagnosed.

The exact prevalence of McArdle disease is not precisely known and appears to range from 1 in 50,000 to 1 in 200,000 in the United States. The variation between the prevalence according to genetic data and the prevalence according to diagnosed cases is attributable to the delay in the making of a diagnosis. One study analyzed gene frequency and next-generation sequencing data to report the true prevalence of the disease among populations. The results of that study revealed that the disease is much more common than previously thought, and has a prevalence of 1 in 7,650 (95% confidence interval (CI) 1/5,362-1/11,108). An additional method used by the same study looked at the two most common mutations and recorded a prevalence of 1 in 42,355.

There seem to be issues with histology that mean that the condition could be missed:

To support the diagnosis, muscle tissue is biopsied and examined under a microscope. The hallmark findings suggestive of McArdle disease are glycogen deposits and absence of the enzyme myophosphorylase.[21]
Glycogen deposits appear under the sarcolemmal membrane at the periphery of myofibers. The collection of glycogen between myofibrils makes the myofibers look like vacuoles. The glycogen takes up periodic acid-Schiff (PAS). The absence of glycogen accumulation in muscle biopsy should not be taken as proof for the absence of McArdle disease as the glycogen could be washed out in tissue processing.

Myophosphorylase histochemistry is easier to perform and has a good negative predictive value. Its absence is diagnostic for McArdle disease. However, providers must specifically request the testing of myophosphorylase.

There is a wide variety of presentations, including fatigue:

Clinical heterogeneity is widely seen in McArdle disease. Some patients present with very mild symptoms, such as tiredness without cramps.

I expect that some people with this disease have had a functional disease label applied to them e.g.

Seizures have been described in 4% of patients.

I recalled Rowe's use of a pressure cuff on an arm to induce PEM when I read the following:

Initial assessment in suspected cases is done using a forearm exercise test. As the process of glycogenolysis is defective, no pyruvate and subsequent lactate are produced through normal pathways. Isometric rhythmic exercises are done for one minute and the levels of lactate and ammonia before and after are compared with one another.

During normal circumstances, a three-fold rise in lactate and ammonia occurs, but lactate rise is remarkably low in glycolytic and glycogenolytic disorders. The ischemic test making use of sphygmomanometer cuff is obsolete now, and there is a recent consensus upon the use of non-ischemic forearm exercise tests to avoid unfavorable outcomes like rhabdomyolysis and compartment syndrome.

This too, the typically elevated creatine kinase, was interesting. I recall the UK ME/CFS biobank study (I think) that found elevated levels of creatine kinase in (severe?) ME/CFS. Creatine kinase is elevated in people who are inactive of course, so it is a bit confounded.

A characteristic feature of McArdle disease is the chronically elevated serum creatine kinase (CK) enzyme levels.

 

[Hutan]

I have found rhabdomyolysis interesting in the context of ME/CFS before, given the symptoms of muscle pain and stiffness.

Rhabdomyolysis is an established complication of McArdle disease.[34] Acute renal failure may result from myoglobinuria after vigorous exercise. As with any patient having rhabdomyolysis, the patients with McArdle disease should be monitored for the possible complications of electrolyte abnormalities, compartment syndrome, and metabolic encephalopathy.[35]

The most frequently reported symptom remains physical activity intolerance. Other symptoms include painful muscle cramps, weakness, and fatigue. Muscle pain and stiffness sometimes can lead to painful contractures. All these symptoms are much pronounced soon after starting activity and alleviated with exercise cessation. In cases of sudden, persistent muscle contraction during high-intensity exercise, severe muscle damage can occur resulting in a massive release of muscle proteins, i.e., creatinine kinase (typical level >1,000 U/l) and myoglobin in blood, as well as myoglobinuria (excretion of myoglobin in urine) presenting as dark-colored urine. In rare instances, acute renal failure and catastrophic hyperkalemia can ensue from an episode of rhabdomyolysis (muscle breakdown).[22]

I can get a series of muscle cramps. Is that common in ME/CFS?
I have noticed I periodically get dark-coloured urine, not dark yellow, definitely more red-brown, that does not correlate with hydration levels. It occurs with generalised muscle pain and lower back pain. I'm pretty convinced that it is a symptom correlated with activity.

It was interesting to read about the idea of metabolic encephalopathy resulting from rhabdomyolysis. It's a general term:

In simple words, metabolic encephalopathy is a disorder that affects brain function. It can be temporary or permanent, depending on the severity of the damage. This condition is mainly caused by other severe health concerns. These problems affect electrolytes and blood chemicals in the body, resulting in brain cell damage. It is a severe health condition that can cause structural brain damage if not treated well.

Symptoms of metabolic encephalopathy are

• Delirium – Confused thinking and less attention span. It is a serious health concern and needs immediate attention
• Lethargy – Caused by a lack of nutrition and a high level of toxins in the body
• Muscle weakness
• Loss of memory or dementia
• Difficulty in motor tasks such as walking, eating, writing, etc., is also known as ataxia
• Illusions
• Hallucinations
• Decreased consciousness
• Mood disorders
• Breathing problems
• Mental health issues such as depression, anxiety
• Vision problems
• Seizures

Could ME/CFS, or at least some version of ME/CFS, be a condition that results in a low threshold for rhabdomyolysis and associated temporary mild metabolic encephalopathy? edit - Perhaps this is the link between the commonality of symptoms we see between ME/CFS and traumatic brain injury?

 

[Creekside]

"causes pain, cramps and muscle weakness during intense muscle work" That rules out PEM, which I think is defined as symptoms post-exertion, not during. A 24 hr delay seems common, which really rules out the 'during' part. I expect there are plenty of different causes for pain, cramps, and weakness that are unrelated to ME.

 

[Hoopoe]

Does anyone here know if there has been any scientific attempts to compare the exertion intolerance in McArdle disease to the one experienced by pwME? Similarities, differences, maybe some clues as to what might be going on in pwME's bodies?

McArdle's disease has a characteristic "second wind phenomenon" where progressive fatigue and muscle weakness appears during the first 15 minutes of exercise but then disappear. The person can then continue exercising. This is because the glycolytic energy production is impaired. In ME/CFS the impairment appears to be more in the aerobic energy production (mitochondrial respiration in this graph)



https://pubmed.ncbi.nlm.nih.gov/30363996/

I am curious about the possibility of PEM in other diseases. It would be interesting to ask doctors who deal with rare diseases if they know of other diseases with a PEM-like phenomenon.

 

[Creekside]

It would be interesting to ask doctors who deal with rare diseases if they know of other diseases with a PEM-like phenomenon.

I think it would also be interesting to ask alternative practitioners, particularly of the ancient practices, whether they were familiar with the phenomenon. Since they didn't have blood tests and RNA scans, they would have focused on patient's descriptions of symptoms, and "consistently, 24 hrs after I do something strenuous, I abruptly feel weak and can't think clearly" seems like a fairly clear symptom, and something worth recording.

 

[duncan]

I am curious about the possibility of PEM in other diseases. It would be interesting to ask doctors who deal with rare diseases if they know of other diseases with a PEM-like phenomenon.

As I think you know, channelopathies might qualify.

 

[Hutan]

"causes pain, cramps and muscle weakness during intense muscle work" That rules out PEM, which I think is defined as symptoms post-exertion, not during. A 24 hr delay seems common, which really rules out the 'during' part. I expect there are plenty of different causes for pain, cramps, and weakness that are unrelated to ME.

These are different things. I think many people with ME/CFS can at times experience symptoms during muscle work, but also experience the constellation of symptoms at a later time that is PEM.

 

[Trish]

I agree, Hutan. I certainly experience increasing pain and weakness in muscles during activity which I would define as fatiguability, or exertion intolerance. I also experience PEM later if the activity was beyond my current limit. It's not either/or, we can have both.

 

[NelliePledge]

Yep both definitely happen for me. Both physical and cognitive. As well as getting physically drained mostly linked to orthostatic issues standing for say 10 minutes will do it or sitting for a meal out. I experience cognitive issues during activity eg if I’m socialising with family or on a phone call with friends eg word finding, losing thread or if I’m online visual triggers like large bold text or large images causing brain freeze. not just waking up the following day after feeling normal during an activity with worse functioning.

 

[Shadrach Loom]

Another hard yes.

For me, exercise intolerance pains are specific to the limbs used, and feel more like muscular-skeletal damage, while PEM pain is an all-over neuropathic fizzing, accompanied by that poisoned feeling. Very different, but both feel core to this illness.

 

[Hutan]

Can we definitely rule out rhabdomyolysis as part of the delayed response that is PEM? It seems to fit, for me, with the dark urine and kidney ache and all.

Nontraumatic causes of rhabdomyolysis can be from a mismatch between oxygen supply and demand, electrolyte changes, and metabolic abnormalities.

I wonder if testing for metabolites has actually been done enough when people really do have the full-on PEM experience with pain and extreme exhaustion, rather than just after a short exercise challenge, often immediately after? Has there been careful tracking of changes in creatinine phosphokinase (CPK) before and during PEM?

If it was rhabdomyolysis, would we expect to see more people with ME/CFS heading into hospital with life-threatening organ damage? and a lot more muscle wasting?

It's a question I'd like to poke into sometime. Maybe people here have thoughts?

 

[obeat]

https://www.atsjournals.org/doi/full/10.1513/AnnalsATS.201701-014FR

A review of exercise testing in metabolic myopathies.

 

[Hutan]

That interesting review covers McArdle disease and mitochondrial myopathies

On mitochondrial myopathies:

Cardiopulmonary exercise testing in mitochondrial myopathy usually shows a significantly reduced peak work rate and peak V." role="presentation" style="display: inline; line-height: normal; font-size: 16px; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative;">V.V.o2 (52–55) (Figure 3B). In contrast to defects of glycogenolysis and glycolysis, mitochondrial myopathies show early lactic acidosis during exercise, as there is increased reliance on anaerobic metabolism to produce ATP (52, 55) (Figure 3C). Anaerobic metabolism is a very inefficient process for ATP generation and yields only 2 ATP per glucose moiety compared with at least 30 ATP with oxidative phosphorylation (56). The early lactic acidosis is reflected in an early gas exchange lactic acidosis threshold, and in one study the values seen for the lactic acidosis threshold were in the range commonly seen in patients with heart failure (52). The degree of depression of the lactic acidosis threshold in mitochondrial myopathy is related to the severity of involvement of the electron transport chain (57). Although the absolute value of lactate achieved at peak exercise is not always greater than in normal subjects (55), the respiratory exchange ratio appears to be significantly higher than normal (53). The very high respiratory exchange ratio is likely to reflect a very rapid rate of lactate accumulation and consequent high rate of bicarbonate buffering.

I note the last point about higher than normal respiratory exchange rates in exercise tests in people with mitochondrial myopathies. We've seen the RERs of people with ME/CFS reported as normal in many CPET studies (that is, around 1.1). However, I think we've seen at least one member who has reported their RER being higher than that. Perhaps a high RER is a useful diagnostic clue for mitochondrial myopathies.