Mitochondrial disease clinical manifestations: An overview

https://bcmj.org/articles/mitochondrial-disease-clinical-manifestations-overview

This has some comments on adult-onset mitochondrial disease which is relevant to ME/CFS in my opinion. The authors say that:

Mitochondrial diseases are heterogeneous and multifaceted, and can present at any age. Clinical features may range from an acute life-threatening metabolic derangement to intermittent or episodic crises with partial recovery to a more gradual progressive neurodevelopmental decline or regression.

Adult-onset mitochondrial disease often presents in subtle ways.

Adult-onset mitochondrial disease is typically a progressive multisystem disorder.

Although adults with mitochondrial disease may present with findings that are characteristic of a typical syndrome, more commonly they do not.

Mitochondrial disease often involves the following systems: central nervous system, peripheral nervous system (peripheral neuropathy), vision and hearing, skeletal muscle problems, heart, gastrointestinal system, endocrine system.

The relevance to ME/CFS is that a portion of people being diagnosed with ME/CFS may actually have difficult to diagnose mitochondrial disease (or a similar metabolic disease that affecting energy production).

Assuming that ME/CFS causes problems with energy production through a different mechanism than a genetic defect (which currently seems like a reasonable hypothesis), it could intensify the negative effects of subtle or subclinical defects in energy production.

 

In this study, the authors reported that "those with ME/CFS have fewer mildly deleterious [mitochondrial DNA] variants than controls". One of the possible interpretations of this is that those with deleterious mtDNA variants are more likely to be removed from the category of ME/CFS (for example by developing sufficiently obvious problems to receive a different diagnosis (ME/CFS is still often a diagnosis of exclusion), or by becoming too ill to participate in these kinds of studies, or by dying early). What kind of important information do we lose due to the exclusionary nature of a ME/CFS diagnosis?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393470/

Another interpretation is that somehow mildly deleterious [mitochondrial DNA] variants protect against ME/CFS and it's hard to see how that would work. It doesn't seem to pass the common sense test.

That patients and controls differed in this regard does seem like evidence that mtDNA has something to do with the illness.

 

Yes, well this is something I’ve been wanting to write about for a while but I find it hard to engage in this topic (outside of the emotional support forum).

However I’m glad you brought this up.

Ever since I read more about mitochondrial disease, and metabolic diseases in general, I have been thinking about the relevance to ME/CFS, but in particular to people with ME/CFS who have quite severe organ involvement (so they tend to be those on the more severe end of the ME scale as well).

One thing my doctor said when he talked about my heart, is he said “this does not happen in ME”. He isn’t someone who is dismissive of ME. There are some people with ME who are told they have progressive ME, because they end up on ventilators or oxygen being unable to breathe (respiratory failure), or have heart failure, kidney failure or intestinal failure being unable to eat. They are told both by the ME community, and by ME doctors, that this is caused by ME or is progressive ME. It may be the case. But equally, it may not be.

And, well..there is no doubt in my mind that if a patient presented with exercise intolerance (PEM), fatigue, pain, peripheral neuropathy, and with organ failures such as these, and were to see a doctor who specialises in genetic & mitochondrial diseases, they would (or should) be investigated for these diseases. In many cases, organ failures such as these are red flags for genetic diseases. Certainly sudden heart failure in the context of multi systemic disease must be investigated for mitochondrial disease, for example. Yet I’ve also seen posts on social media of people saying people with severe ME dying of heart failure is a common thing. It concerns me that everything is being put down to ME, both by patients and by doctors, but without yet having the knowledge or biomarkers to do so.

Some people may say why does it matter what you have? It matters a great deal, not only for things like surgery and anaesthesia, but also to make sure someone is given preventative help, and to try to prolong life as much as possible.

For example, heart failure in context of multi system illness:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783139/

“Mitochondrial cardiomyopathy: pathophysiology, diagnosis and management”

“A high degree of suspicion is important when considering a diagnosis of mitochondrial disease. Clinicians should consider possible mitochondrial cardiomyopathy in any patient who presents with signs of acute heart failure and multisystemic involvement without a clear explanation, and the patient should be referred to a geneticist or other specialist who is familiar with diagnosing mitochondrial disease.”

I have another paper about GI involvement which I’ll post below.

 

https://openaccess.sgul.ac.uk/id/eprint/107121/1/Mitochondrial Myopathy Review 19.11.12-1.doc

“Unexplained gastrointestinal symptoms: Think mitochondrial myopathy”

I came across this paper a while ago and saved it. It’s a series of case studies from the UK, about families which had mitochondrial disease. In one family, despite all three children having severe symptoms (and all three of them dying at a young age), one of the children was noted to have had “depression”. In addition, “anorexia nervosa” and “bulimia” were considered. “Munchausens syndrome” is mentioned in one of the child’s notes! By the time the first 2 children had died, the 3rd child was then put on “anorexia watch”. It is only later on, that MNGIE - a mitochondrial disease affecting the stomach, leading to GI dysmotility, gastroparesis, weight loss & not being able to eat properly, was found. It is very likely this disease would have affected all 3 of them. MNGIE itself is very rare, but stomach problems affect a lot of people with other mitochondrial diseases. (I find this case study informative because all of the children also had quite severe and obvious neurological signs as well, and they still weren’t taken seriously).

Some quotes from the paper: (my bolding)

“The prevalence of medically unexplained symptoms (MUS) in outpatients is common and ranges between 25% and 75%. Comorbid psychiatric disorders are frequent in such patients, who present major challenges to conventional medical management, are commonly frequent attenders and may have misattributed psychiatric conditions. MUS can, however, only be diagnosed when organic disease has been excluded. Gastrointestinal involvement is common in patients with mtDNA disease, affecting up to 15%, yet symptoms are frequently overlooked as they may be non-specific such as abdominal pain, chronic constipation or vomiting. Other manifestations include severe gut dysmotility and profound weight loss, which may be among the principal presentations of mitochondrial disease, as in MNGIE. Importantly, mitochondrial disease can be easily mistaken for anorexia nervosa. Indeed the misdiagnosis of organic disease as ‘anorexia nervosa’ is well recognised in the literature.”

…

Discussion

Our case series highlights two important but poorly recognised aspects of mitochondrial DNA disease: the clinical and the genetic. All patients had clinical evidence of multisystem disease that is characteristic of patients with more complex mitochondrial defects. This is an important clinical signal, because it means that such patients can present to any of many specialists, who are likely to be unfamiliar with mitochondrial myopathies (…)..most will assume that myopathic symptoms predominate in patients with a mitochondrial myopathy and tend to ignore ‘non-specific features’ such as tiredness, easy fatigability, systemic symptoms, or diabetes. It is notable for example that patient AB’s concerns were his gastrointestinal symptoms and neurogenic pain, which were potentially treatable symptoms, but which may not be given a high priority in a general muscle clinic. Like a coin, a medical condition always has two sides: what is familiar to one group of specialists may be obscure to another.

Mitochondrial myopathies should be part of the differential diagnosis for anorexia nervosa and also for medically unexplained gastrointestinal symptoms. We conclude by proposing a checklist of investigations that may be helpful in establishing a diagnosis of mitochondrial disease. The checklist cannot be comprehensive, but should increase awareness that apparently rare mitochondrial disorders can account for common symptoms. The key component is the alert physician, whether in primary or secondary care: when the clinical picture cannot readily be explained and does not quite fit (such as unaccountable weight loss in someone with irritable bowel syndrome), mitochondrial myopathy should be considered.

The true prevalence of mitochondrial myopathies may well be masked by failing to consider the diagnosis, which in turn limits the research that could potentially ameliorate outcomes for these patients.”