Fatigue and Exercise Intolerance as Initial Manifestations of a Nonsyndromic Mitochondrial Disorder Due to the Variant m.3243A>G, 2022, Finsterer

Abstract
Objectives. Fatigue and exercise intolerance have been only rarely reported as initial- and sole-onset manifestations of a mitochondrial disorder (MID). We present a patient with nonsyndromic MID with fatigue and exercise intolerance as its initial manifestations of the disease.

Case Report. A 39 yo female experienced fatigue since age 18 and exercise intolerance since age 21. Later on, she developed Hashimoto thyroiditis, recurrent diffuse headache, and double vision upon exercise. Clinical exam revealed short stature, bilateral ptosis, partially reduced tendon reflexes, and hypertrophic calves. Serum lactate was elevated, and the lactate stress test was abnormal. Workup for suspected MID revealed ragged-red fibers and NADH-deficient muscle fibers, and biochemical investigations revealed a mild complex-I defect. mtDNA sequencing revealed the variant m.3243A>G with a heteroplasmy rate of 70% in the muscle.

Conclusions. This case shows that the initial manifestation of a MID can be fatigue and exercise intolerance. MIDs due to the m.3243A>G variant may have a slowly progressive course and only delayed multisystem involvement. The variant m.3243A>G may not only manifest as syndromic MID, particularly MELAS but also as nonsyndromic phenotype. MIDs should be considered as differentials of chronic fatigue even if no other phenotypic manifestation of a MID is present.

Open access, https://www.hindawi.com/journals/crinm/2022/7846852/

 

Interesting case. They say:
Fatigue may be present already without any physical activity or only in association with physical exercise. The latter is also known as exercise intolerance or exhaustibility.

That does not immediately sound like exercise intolerance as understood in the context of ME. It is a pity that it is not described in more detail.

I recently came to write this sentence:
The term ME/CFS has become recognised as useful in defining a group of people with chronic disabling symptoms of unknown origin, including fatigue and often pain, with a characteristic form of exertion intolerance, manifest as what is known as post-exertional malaise.

The point being that exertion intolerance can mean a variety of things and that in ME it has a specific meaning linked to PEM.

 

Yes, I agree.

 

There's a massive difference between exercise and exertion intolerance, like the difference between losing $1,000 and losing $100,000. Not being to jog freely is a whole different level of impairment from barely being able to walk across a room and all the implications this has. It's impossible to know what researchers actually mean, since it's almost universally confused.

It's going to be hard to make any progress while that block in basic communication stands. It's not even currently possible to resolve this since the recognized "experts" are biased to not see the difference, and don't even understand what we are telling them, placing it in invalid boxes.

Maybe they mean the same thing. Maybe the patients mean that but the researchers don't get that and mean something else. This is about as confusing as a barter system, how much butter is a goat worth and all that confusion? We need scientific measurement and we are at the whimsical level of everyone has their own definition and how many butts of beer to a haystack.

 

In genetic mitochondrial disease all mitochondria will be affected but in ME it is most likely that the mitochondrial dysfunction, whether it is in the mitochondria themselves or slightly further down the line, is only in some cells of the body.

It could explain the differences. Of course, I do not think PEM is a specific symptom but a shorthand for individual consequence of some damaging process caused by exertion. Like MS makes people crippled but that is just an outcome of the disease.

 

If I remember rightly it is actually only a proportion in many mitochondrial problems because the cells form a mosaic of abnormal and normal ones.

 

Interesting. I love genetics, it is like quantum theory, they show that science is not nearly done with explaining the universe.

 

The technical term for a situation where a person has two mitochondrial genomes, one normal and the other with a disease causing mutation, is heteroplasmy. Heteroplasmy can vary between tissues.

For this reason I suspect that mitochondrial disorders are underdiagnosed.