Ask the Mito Doc – May 2024; Q&A

Ask the Mito Doc – May 2024 Q&A



All answers today are based on personal experience of the participants. As always, please consult your personal physician prior to taking any action.

Mitochondrial Disease Primer


Melissa Walker, MD, PhD, Massachusetts General Hospital, Boston MA


Q: What is common with all Mito diseases and what are the differences?

A: Melissa Walker, MD, PhD:  There are many different signs and symptoms and medical problems that can be associated with mitochondrial disorders and diseases. These are not all of them, these are a sampling of the more commonly encountered problems, starting with the brain. I am a neurologist and it is because the brain can so commonly be affected in mitochondrial disease that neurologists like myself often choose to focus on mitochondrial disorders. Individuals may have stroke like episodes or problems with coordination that we call ataxia. They can have seizures or migraines or other headaches. Changes in their mental alertness states or developmental delay. Or movement disorders such as dystonia or involuntary movements like chorea. The special sensory systems which are closely tied to the brain are often affected in mitochondrial diseases and that can manifest as hearing loss or vision loss. Kind of keeping with the neurologist’s purview, the peripheral nervous system can be affected and that might lead to weakness or sensory changes in people who have mitochondrial disorders. We are increasingly recognizing though, that other body systems can be very much impacted, including endocrine disease. So things like hypothyroidism or diabetes is actually a very common problem for people who have Control Disorders. Also, liver disease, lung disease or kidney disease can occur. Gastrointestinal symptoms such as reflux or vomiting, diarrhea or constipation, and in the most severe form, pseudo obstruction can occur. And we know that muscles can be frequently affected in mitochondrial disorders. So if the skeletal muscle is affected, that can manifest as what we would clinically call a myopathy and would lead to potentially having weakness or fatigue or exercise intolerance. And the heart we know is a muscle as well. So difficulty with the mitochondria in the heart can cause heart disease or even abnormalities of the electrical signals the heart sends and causes things like arrhythmia. No single symptom confirms a diagnosis of a mitochondrial disorder as you can see, because almost every cell in our bodies have mitochondria, symptoms of mitochondrial dysfunction can affect almost any body part or organ. So it’s not surprising, especially after that list I just gave you, that an average mitochondrial disorder patient can have up to 16 different medical problems or conditions. But getting back to this idea of patterns and clustering of signs and symptoms, when that happens, often clinicians will recognize the pattern and describe it as what we call a syndrome. I’m going to highlight some syndromes today that are among the more common, mitochondrial disorder syndromes. We’ll start with Leigh syndrome. So Leigh syndrome is actually the most common manifestation of pediatric mitochondrial disease. It can, however, be caused by damage to one of over 80 different genes that we know of to date and any individual with any different type of damage to one of those genes can have this similar cluster of symptoms and that will include things like an abnormal brain developmental delay, movement disorders, particularly dystonia, and sometimes encephalopathy and apnea. These patients can also have myopathies and heart disease or any of these other symptoms described. But not necessarily any particular one or any particular list of them. It can be highly variable how an individual is affected with this disease. Another mitochondrial disorder that is actually one of the more common forms seen in adults, is mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, or MELAS. MELAS is a little different genetically speaking from Leigh syndrome in a couple of ways and one of them is that most people who have MELAS have the same gene change or what we call pathogenic variant or used to call mutation. People affected with this syndrome will have by definition stroke-like episodes and/or seizures. They will also often have hearing loss and diabetes quite commonly, as well as myopathy, but they also can have heart disease or endocrine conditions. Again there can be a lot of variability even between 2 people who are related who carry the same gene change.

And moving on to our 3rd and final syndrome, I’m going to contradict what I just told you that individuals will more often have a whole variety of symptoms affecting different organ systems. It does turn out that there are some mitochondrial disorders that will affect one system primarily, and almost uniquely or solely. An example of that would be Leber’s hereditary optic neuropathy, or LHON, which is also a relatively common mitochondrial disorder among the adult population. Individuals affected by LHON will typically have vision loss, but not necessarily these other symptoms that I’ve described.

The big take home point is that every mitochondrial disorder is different and this makes them very difficult for doctors and other providers to diagnose. Each patient is unique. Even within the same family. So having the same gene change and even being siblings might not mean that 2 people will have the same experience of the mitochondrial disorder.



Q: Is there any clinical research data and/or information of the benefits of taking CoQ10 no matter what type of mito you have?

A: Melissa Walker, MD, PhD: That is such a good question and it’s such an important one to talk about. The reason is we haven’t done the right clinical trial. Different people will tell you different reasons why we haven’t, but there’s many.  Mitochondrial diseases are rare, right? Getting enough people together to have a large enough group to say for sure something helps, that’s problem number one. And then as we just discussed, every mitochondrial disease is different. So it might be that CoQ is helpful for mitochondrial disease A caused by gene A, but to mitochondrial disease B, it doesn’t help that much, but we can’t even know yet because we don’t have enough of A or B or even A and B together to do one of these clinical trials. And 3, there are difficulties in launching any clinical trial. You have to have the money to pay the people who will study and enroll patients, you have to have the money to provide the medication that you’re testing. So where does that money come from? The other problem is with things that patients can already purchase themselves, it’s often difficult to say, Okay, I’m willing to stop my CoQ even though I know it’s helping me so that I can be in the placebo group. That’s a hard sell for patients, which is understandable. And for that reason, and because we know things like CoQ and other vitamins and supplements that we use typically are safe, we as physicians go ahead and recommend them even though we can’t prove that it’s going to help.



Q: Interested in hearing your thoughts on ACQUIRED or SECONDARY MITO diagnosis related to other gene defects that create milieu & condition metabolically that simulates primary mito diagnosis.

A: Melissa Walker, MD, PhD: So as far as how is it different, I suppose that depends on who you’re talking to and how they’re defining mitochondrial disease. In today’s discussion I was working primarily on the assumption that we’re defining mitochondrial disease as genetic mitochondrial disease. If we are, then the difference is in the cause of the damage to the mitochondria. In a genetic primary mitochondrial disease, the mitochondria are damaged because one or more of the genes that we need to make the mitochondria is damaged.

In secondary causes, it’s happening because of something else. In these circumstances, some other part of the cell or the body isn’t working properly and it in turn produces wear and tear and damage on the mitochondria. Then as far as treatment, that is both a difficult and an easy question. It’s easy unfortunately in that we don’t have targeted treatments for mitochondrial dysfunction. Many doctors will describe mitochondrial cocktails for secondary mitochondrial dysfunction. But we don’t have any proven therapies and any symptom attributable to mitochondrial dysfunction either primary or secondary, whether it would be heart disease or seizures, would be treated more or less the same way that heart disease or seizures caused by some other condition would be.



Q: Can specific medications cause muscle weakness in patients with mitochondrial disease? 

A: Melissa Walker, MD, PhD: Yes, they can. And as we discussed on the slide about contraindications, these are relative. One famous example of a medicine that can cause weak muscle damage or weakness by ways it interacts with mitochondria in any person is statins, a commonly used lipid lowering drug. So many doctors are very careful with giving statins to patients. We’re all very careful for giving statins to patients with mitochondrial disease and in some cases we won’t give it because we are concerned that it could worsen muscle weakness in a patient. That’s just one example and it’s all going to be weighing the risks and the benefits. I’ll just point out that there are medicines that you shouldn’t take if you have a specific medical problem. For example, acetaminophen shouldn’t be taken in large doses by people with severe liver disease. And that’s the case whether the liver disease is caused by an infection or a mitochondrial disorder.



Q: Do any of the amino acid depletion syndromes cause mitochondrial disease?

A: Melissa Walker, MD, PhD: I understand that question as a genetically encoded ask. So we do think that there are patterns suggestive of secondary mitochondrial dysfunction in many of these disorders and we think that because of some of the lab abnormalities we can see and also because some of the clinical symptoms look like symptoms of mitochondrial disease.



Q: I can tell my mito flare ups are triggered by my menstrual cycle. What treatments, if any, are used to control hormonal flare ups?

A: Melissa Walker, MD, PhD: The answer is probably yes. I don’t know to my knowledge of any rigorous studies looking at hormone changes and the effect on mitochondrial function in patients, but we do know kind of the opposite of that, which is some patients with mitochondrial disease can have precocious puberty, or they can have ovarian failure meaning that their ovaries are not functioning properly. We also know that hyperthyroidism can occur in mitochondrial disease. We know from basic science that typically when a cell encounters a hormone, there are changes that consume energy so it would stand to reason that could be an aggravating factor. What should we do about that? That’s going to be very case-specific and a good discussion to have with your mitochondrial expert and probably an endocrinologist.