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Mitochondrial disease
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Mitochondrial disease

Dr Andrew Schaefer discusses diagnosis and treatment of mitochondrial disease.
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Hi, Andy. Perhaps you could just introduce yourself to everybody. Thanks, Will. So I’m Dr. Andrew Schaefer. I’m one of the consultant neurologists at the Royal Victoria Infirmary in Newcastle. And I’m also the adult clinical lead for the NHS highly specialised services for rare mitochondrial disorders at Newcastle. Thank you. Perhaps I can start by asking you, how common are mitochondrial diseases? So as a whole, because there are a lot of them, they are a lot commoner than people think. As individual entities, they’re very rare. So when we look at the prevalence altogether, and the prevalence of patients with clinical mitochondrial disease, with clear clinical features, we’re talking a number of one in 8,000.
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In addition to that, there’s 1 in 4,000 patients who carry these mutations, who are at risk of presenting. So that’s the kind of figure that might present to a GP surgery. And so if we assume that the average GP surgery has about 2000 patients, then there’s a good 50-50 chance that there’ll be a patient within that group with mitochondrial disease. And the additional thing to consider is that because of the inheritance patterns, if you’ve got one mitochondrial patient, there’s a very good chance you will actually be looking after several patients either with mitochondrial disease or who might develop mitochondrial disease. Thank you. In the case of Susan, she had a 3243 A to G mitochondrial disease variant.
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Do other mitochondrial diseases present similarly to this? So the answer to that is yes they can. There’s a huge variation in the way mitochondrial diseases can present. So what I will often say to patients when I see them in the clinic is that often, the way it’s best to think about mitochondrial diseases is that it’s a huge umbrella term. And underneath that umbrella are literally hundreds of different diseases. And I say that because patients will often gravitate towards the internet to seek information, and they may come away with information that’s just not relevant to them, which is important. But in general terms, certain things like diabetes and deafness are much more common in mitochondrial disease.
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They are, of course, common in the general population, but often one of the keys is to note that those are recurring either at a young age, prematurely, or perhaps in the case of diabetes, but it appears like type two diabetes, but is presenting in somebody with a low BMI instead of a high BMI. So there are unusual features which might make people take note of those. And then of course, when we’re talking about the mitochondrial DNA itself the maternal inheritance pattern is something that might give a clue as well to this being mitochondrial disease.
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Now because there are a variety of different symptoms that could occur, I don’t want to go through the whole list, but things like ptosis, ophthalmoplegia, proximal myopathy, ataxia, cardiomyopathy, renal problems. All of these sort of things. If those seem to be clustering within a family, particularly down the maternal line, that would be something that would make you think about mitochondrial disease. But one of the difficult things is that there is impaired penetrance of a lot of these mitochondrial DNA mutations, because of something called heteroplasmy, where you can have different proportions of the mutated DNA in any tissue. So in this lady’s family, you might have a mother who develops diabetes and some deafness later on in life.
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She might have a brother who’s actually had a stroke like episode, which is a seizure driven phenomenon, at 18 years of age. She might have a maternal aunt who actually has renal failure and a transplant that, not unreasonably, was assumed to be due to diabetes. But when you actually look at her diabetic control, it was fine. And therefore, that’s odd, why would that have happened? So you can have similar things, but there’s a wide spectrum. But it’s often picking up on this clustering of unusual features. What do you think are the main challenges to diagnosing mitochondrial disease? And are these problems shared by other rare diseases?
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So I think one of the main challenges, particularly when we’re talking about primary care, is recognising them. Because as we touched on earlier, a lot of the problems that these patients can develop are actually, in their own right, very common. Deafness, diabetes, patients complaining of weakness. So that’s one of the problems is identifying those things as unusual. And as we said, the clustering of those features, perhaps them occurring prematurely or in a much more severe way than you might expect, are clues. And also the maternal inheritance pattern, albeit you have to remember that may be very patchy, because of what I discussed before about heteroplasmy.
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I think a lot of other rare diseases, they share the problem of recognition because they’re rare, and we can’t know everything. Even the best specialist doesn’t know everything, especially about areas outside of their area of expertise. And so as a GP, we can’t expect GPs to know every feature. And so it is, to a degree, pattern recognition. And with the other genetic disorders, usually they have a more homogeneous clinical course. There’s usually a more typical presentation. And there’s usually a limited number of genes that will cause that disorder. Many of them are monogenetic, so that makes things easier if you are screening for them. Finally, for patients affected by these conditions, what are the benefits of an accurate diagnosis?
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So I think there are a lot of benefits. And I think it’s very important for us to recognise that, because sometimes, with rare genetic disorders where there isn’t currently a cure for the vast majority of them, that can lead us to think that we shouldn’t be pursuing those and trying as hard to find the answers. I don’t think that’s correct. I think for many of these patients, when they come to clinic, they’re hugely relieved to have a diagnosis because they’ve been dealing with uncertainty up to that point. It allows us to give them as much information as possible, and correct information about the disorder.
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And that’s one of the benefits, as well, that we can direct those patients through to specialist centres, where experts have had the chance to see a rare group of conditions commonly, because they all come from all over the country. To centres like those, arranged by the highly specialised services. And that means those doctors know more about it and can give the right information. It also means that we, through the knowledge about those conditions, know what the complications are. So in the case of this young lady, we would be recommending yearly diabetic screening. Because of course if you pick up diabetes early, you avoid the complications. So that’s a treatment in its own right.
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We would recommend yearly cardiac screening, because these patients would be at risk of cardiomyopathy, and they sometimes have things like Wolff-Parkinson-White syndrome. And again, if you pick up a cardiomyopathy early, because it could remain asymptomatic for many years, you’re treating it at the right time. And you can help to prevent that going on to develop into something more serious. So there are huge implications for the patient’s health by picking these things up early, as well. And you can give relevant advice, you can make sure that doctors at the hospital, or the anaesthetist if there’s an operation planned, knows what to look out for, what to avoid.
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In a certain condition, polymerase gamma, we avoid sodium valproate as an antiepileptic drug, because we know it can cause fulminant hepatic failure. That would be something, you wouldn’t have that information unless you’d made the diagnosis. So there are all these sort of features that are very important. And perhaps the last thing to touch on is we would be able to tell them about the inheritance pattern. In this lady’s case, if this had come from grandmother to mother to her, or to her brother, the family may well have recognised it themselves and think it’s a dominant condition. The importance of that is, number one that, say if she had a brother, he might believe that his children were at risk.
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And we’d be able to reassure him that they weren’t. And for her, with advances in reproductive options, we would be able to chat about her risks of passing this on, and what her options were to try and reduce those risks, if she wanted to go down that path. And so that’s quite a long winded answer to your question, but that’s because there are so many things that we can do to help these patients. So I think it is very important to make that diagnosis. Thank you very much. Thank you, thank you, Will.

Watch the video where Dr Evans interviews Dr Andrew Schaefer, a mitochondrial disease expert. Dr Schaefer is Consultant Neurologist and Adult Clinical Lead at Wellcome Centre for Mitochondrial Research in Newcastle.

What do you think are the key messages in Dr Schaefer’s interview? Please add your comments and reactions to the discussion area.

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Genomic Scenarios in Primary Care

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