Transcript: Episode Nine - Clinical Genetics: Myotonic Dystrophy
00:00:00:00 - 00:00:13:11
Speaker 1 - Sytske Lub
Hello and welcome to the Medical Genetics and Genomics podcast from the University of Glasgow.
00:00:13:13 - 00:00:34:23
Speaker 1 - Sytske Lub
I'm Sytske Lub, a 4th year medical student undertaking an SSC in Medical Genetics. And I'll be your host for this episode. This project has kindly been supervised by Dr. Saeeda Bhatti. This episode is the first clinical episode exploring triplet repeat expansion disorders, and will centre around Myotonic Dystrophy. Myotonic dystrophy refers to dystrophia myotonica or DM type 1 and 2, which are repeat expansion disorders.
00:00:34:23 - 00:00:56:02
Speaker 1 - Sytske Lub
That is, conditions caused by an expansion of a gene region which is normally known to have a small number of repeated sequences. Myotonic Dystrophy is inherited in an autosomal dominant manner, meaning only one allele with an expansion is required to cause the disease, and manifestations of the condition are usually present in every generation of the family. DM1 is the more common condition and typically presents with more severe symptoms.
00:00:56:04 - 00:01:18:13
Speaker 1 - Sytske Lub
It also suffers anticipation, that is, symptom severity increases, and age of onset decreases in subsequent generations as expanded regions tend to expand further when passed down. DM1 will be the focus of this podcast. I'm joined for this episode by Dr. Bob Ballantyne Professor Darren Monckton and Dr. Mark Hamilton. Dr. Bob Ballantyne is an alumnus of the medicine and intercalated anatomy programmes at the University of Glasgow.
00:01:18:15 - 00:01:37:23
Speaker 1 - Sytske Lub
He's currently a specialty doctor in clinical genetics, having previously been employed as a general medical practitioner and salaried GP, providing primary care and supports to care home residents. Bob acts as the clinical lead for Myotonic Dystrophy in the West of Scotland, having been in this role since 2015. He provides regular reviews of patients with DM and coordinates additional service involvement.
00:01:38:00 - 00:02:00:04
Speaker 1 - Sytske Lub
Darren Monckton is Professor of Human Genetics at the University of Glasgow. With over 30 years of experience, he currently leads an active team researching the basis and consequences of genetic instability in human disease. In particular, his team are defining the role of DNA repair and somatic expansion of CTG and CAG as major drivers of pathology in Myotonic Dystrophy and Huntington's disease, and as a novel therapeutic target.
00:02:00:06 - 00:02:36:11
Speaker 1 - Sytske Lub
Darren has won several awards, which I won't list, because there are too many to list - and has presented more than 260 invited lectures and seminars. And Dr. Mark Hamilton is a consultant clinical geneticist with a special interest in Myotonic Dystrophy. He also has oversight of the DM1 service in the West of Scotland. He published his PhD thesis on sleep disturbance, structural brain changes and neuropsychological deficits in DM1 in 2019, during which he travelled to Iowa to work with Professor Peggy Nopoulos’ group. Mark sits on the subgroup committee for the Scottish Muscle Network, which is responsible for producing and auditing evidence based national guidelines for DM1.
00:02:36:11 - 00:02:58:23
Speaker 1 - Sytske Lub
Bob, Darren, Mark, I have internally referred to as the Myotonic Dystrophy Dream Team, and it's a big welcome to you to join me on this podcast. Thank you so much for giving up your time. So, the first kind of set of questions I had to you, given your range of experiences and your length of time, especially Darren, in this field, how did you guys come to work with Myotonic Dystrophy? And why have you stayed?
00:02:59:00 - 00:03:30:00
Speaker 2 - Dr. Bob Ballantyne
Okay, I'll jump in then. So I suppose my work with Myotonic Dystrophy began when I was appointed to the specialty doctor post at the Queen Elizabeth University Hospital in Glasgow in October 2015. As you've mentioned, before that, I worked as a part time partner in general practice in Barrhead between 1999 and 2003 and as a salaried GP, working for the nursing home’s medical practice from 2003 until 2015.
00:03:30:02 - 00:03:33:16
Speaker 1 - Sytske Lub
- So Darren, considering you continued?
- That's really exciting to almost have seen it from the start of understanding the real genetic basis to where it's come along to today. Excellent. And how about yourself, Mark?
00:03:33:18 - 00:04:10:09
Speaker 3 - Professor Darren Monckton
So, I first got interested in Myotonic Dystrophy towards the end of my PhD. My PhD was in human genetics, where I was studying variation at human mini satellite sequences (that are, repeated DNA sequences), and they were the primary sequences that were being investigated or being assayed in DNA fingerprinting and DNA profiling. And although they were obviously highly informative in terms of DNA profiling, they weren't associated with any phenotypic differences in humans - they weren't associated with symptoms or anything like that
00:04:10:09 - 00:04:42:07
Speaker 3 - Professor Darren Monckton
And I kind of had an interest in human genetics and in potentially using human genetics to understand diseases. And just as I was finishing my PhD is when Myotonic Dystrophy, Fragile X, were first described as being diseases that are associated with repeated sequences. It seemed like I was kind of ideally positioned to be able to use the experience we'd gained in looking at minisatellite variation to understand the variation in Myotonic Dystrophy.
00:04:42:09 - 00:04:51:20
Speaker 1 - Sytske Lub
00:04:51:22 - 00:05:13:09
Speaker 4 - Dr Mark Hamilton
Yeah, so. Well, actually my study probably does start with a student SSC. As a medical student a long time ago, so I always probably knew that I was interested in genetics in medicine and, applied, I think, at short notice, if I remember it, to do a student SSC with, as it was, the Duncan Guthrie Institute at Yorkhill at the time.
00:05:13:11 - 00:05:36:20
Speaker 4 - Dr Mark Hamilton
And I was given a project by Cheryl Longman, who at the time was a clinical geneticist that was part of a group of clinicians, really, that had been involved in improving care a lot for people with Myotonic Dystrophy. At that time, my project was more generally about some neuromuscular conditions, but I'd stayed in touch with Cheryl because of my interest in medical genetics in general.
00:05:36:22 - 00:06:05:21
Speaker 4 - Dr Mark Hamilton
And at some point, it was suggested that given that there were, you know, this well organized clinical service, on the medical side and very established research team, particularly through Darren Monckton’s work. There was the suggestion that that maybe there was a role for a sort of clinical research post, so then embarked on a long, long period of applying for various sources of funding and lots of disappointments, but ultimately, we did we did get our funding.
00:06:05:23 - 00:06:19:05
Speaker 4 - Dr Mark Hamilton
And then I was able to complete that research post on that, that's then ultimately led to it, to the post as a as a clinical geneticist. Yeah.
00:06:19:07 - 00:06:35:09
Speaker 1 - Sytske Lub
- I really feel it might just be genetics, it might be other specialties as well, but that's how they rope you in. They start pulling you back after you've done little projects and you get, fortunately stuck. So yeah, really exciting that you’re still within fingers in this field, so to speak.
- Yeah. And actually, the whole Myotonic Dystrophy community - researchers, families, clinicians - it's a really sort-of warm community. And I think that's, that's probably been part of it as well. But you're They, you know, don't let you go really.
00:06:35:10 - 00:06:46:16
Speaker 4 - Dr Mark Hamilton
00:06:46:18 - 00:06:48:11
Speaker 4 - Dr. Mark Hamilton
But I think that's a nice thing.
00:06:48:13 - 00:07:07:23
Speaker 1 - Sytske Lub
To keep you drawn in. Excellent. So I'm going to delve a little bit into the genetics side of things now, which I know is not necessarily Bob's favourite area. He deals more with the clinical things. So Darren and Mark, the triplet repeat expansion in DM1 is quite a unique and interesting, genetic variation because it isn't actually in the non-coding region.
00:07:07:25 - 00:07:16:14
Speaker 1 - Sytske Lub
Oh, sorry – it is in the non-coding region. It's not in the coding region of the DMPK gene. So how does it come to be that this actually causes symptoms?
00:07:16:16 - 00:07:40:24
Speaker 3 - Professor Darren Monckton
We think that the primary mechanism by which the expansion causes Myotonic Dystrophy is a gain of function of the RNA. So, as you rightly pointed out, the CTG repeat isn't in the coding region so it doesn't change the sequence of the DMPK protein, but it is nonetheless in the three prime untranslated region. So it does make it into the mature messenger RNA.
00:07:41:01 - 00:08:08:19
Speaker 3 - Professor Darren Monckton
But obviously it's a CTG in the DNA, so it becomes a CUG in the RNA, and it looks like it's a direct toxic gain of function of that RNA, so that RNA appears to be able to adopt a hairpin-like secondary structure in cells. And that appears to bind, a group of proteins called the muscle-blind proteins.
00:08:08:21 - 00:08:47:15
Speaker 3 - Professor Darren Monckton
And they become sequestered by the CUG repeat so that they are no longer able to do their normal day job as well, or to have reduced capacity to do their normal day job and their normal day job, it turns out, is regulating the alternative splicing of a whole bunch of other genes. So - and I'm sure everybody's aware - genes are comprised of exons interspersed with introns and the normal splicing process removes those introns and pieces the exons together to form a mature messenger RNA.
00:08:47:17 - 00:09:08:16
Speaker 3 - Professor Darren Monckton
But for most genes, if not all, there is some alternative splicing that goes on, that not every cell at every time point uses all of the exons of a given gene. And that allows the repertoire of protein coding sequences to be increased dramatically over and above the number, the total number of genes that we have in the genome.
00:09:08:18 - 00:09:33:00
Speaker 3 - Professor Darren Monckton
So, we have in the order of 20,000 genes but there are probably millions of different splicing variants that allow greater functional diversity in the proteins that are generated. And that's normally a tightly regulated process. And then MBNL is one of the proteins that does that. So when it's not doing its job properly, lots of other genes become dysregulated.
00:09:33:02 - 00:10:12:03
Speaker 3 - Professor Darren Monckton
And I guess a nice example of that is the chloride channel gene. So that's a gene that becomes mis-spliced in patient cells because MBNL has been sequestered by the CGG RNA. It includes some cryptic exons that lead to the destruction of the chloride channel gene messenger RNA, such that patients produce no functional chloride channel protein. And we know that either humans, or mice, or goats, or horses that have mutations in the chloride channel gene have myotonia, so that's the muscle stiffness that is one of the characteristic features of Myotonic Dystrophy - from which it obviously gets part of its name.
00:10:12:05 - 00:10:37:02
Speaker 3 - Professor Darren Monckton
And again, it looks like mis-splicing of the chloride channel gene is able to reproduce that myotonia in patients who don't have a mutation in the gene but are instead mis-splicing the chloride channel gene.
00:10:37:04 - 00:10:56:10
Speaker 3 - Professor Darren Monckton
And so a patient, patients, who have a mutation, just have pure myotonia, whereas the Myotonic Dystrophy patients have the myotonia at least due in part to the chloride channel. But then they have the mis splicing hundreds of other genes. And that's probably why, again, there are so many diverse symptoms in myotonic dystrophy, because lots of other genes are being mis-spliced as well.
00:10:56:12 - 00:11:20:01
Speaker 1 - Sytske Lub
A really interesting and really complicated functional setup, I guess, for cells to be able to make lots of these different proteins and then obviously something that goes wrong, causing the array of symptoms. And Mark, when you and I had spoken, you'd show me a little bit of diagrams about the different types of symptoms and different genes related to different symptoms.
00:11:20:03 - 00:11:27:19
Speaker 1 - Sytske Lub
Could you describe a little bit about the array of symptoms people with my Myotonic Dystrophy can get and whereabouts the symptoms might come from?
00:11:27:21 - 00:11:52:04
Speaker 4 - Dr Mark Hamilton
Yeah, so again, as Darren said that, you know, the reality of what's actually going on, you know, hundreds of different proteins being made abnormally so they, you know, I guess in life the reality is probably very complex. But you can relate some of these specific genes that are being affected by the dysregulation of alternative splicing to maybe specific features that you, that you see in patients.
00:11:52:06 - 00:12:21:04
Speaker 4 - Dr Mark Hamilton
And that is very interesting for a clinical geneticist because these are genes that maybe we know in their own right from specific, single gene conditions. So I mean, the different symptoms is very broad, but some that are potentially relatable. So in heart is very interesting. So we know that proteins involved in the contractile sort of apparatus of the heart, cardiac troponin, are subject to dysregulated splicing.
00:12:21:06 - 00:13:15:16
Speaker 4 - Dr Mark Hamilton
Muscle sodium channels - so sodium channels - mutations in that same SCN5a gene can be a cause of something called Brugada syndrome that can be associated with cardiac conduction abnormalities and sudden death. And we know that people with my myotonic dystrophy have rhythm disturbances and are more prone to sort of cardiac dysrhythmias. In brain, Tau is affected by this dysregulated alternative splicing, and we, I think one of the almost underappreciated aspects of Myotonic Dystrophy is that the central nervous system is very much affected, and actually histologically you can see neurofibrillary tangles that may be attributable to Tau not quite doing its job properly. Let me see, insulin resistance as well - insulin receptors affected. So yeah, just exactly as Darren said.
00:13:15:18 - 00:13:29:15
Speaker 4 - Dr Mark Hamilton
Very - I think of if people take nothing else from talking about myotonic dystrophy, it's an appreciation that it's absolutely a multi-system condition and not just, not just a disorder of one [Sytske] Not just the muscles. [Mark] Yeah, exactly. Yeah.
00:13:29:20 - 00:13:44:01
Speaker 1 - Sytske Lub
Now, Bob, you see these patients in clinic several times a week, and I've been very fortunate to sit in some of these clinics and see the variety of symptoms that these patients present with. So, so what kind of presentations do you get? What's the sort of minimum to maximum that you tend to see?
00:13:44:03 - 00:14:17:23
Speaker 2 - Dr. Bob Ballantyne
- So as has already been alluded to, a wide variety of symptoms. I guess the commonest symptoms presented by patients who are attending the management clinics would be muscle weakness and associated issues with mobility, and problems with poor balance and therefore falls. And the muscle weakness they tend to report when it's impacting on activities of daily living or on employment.
- Yeah. It makes it obviously very difficult for being, you know, by being in the clinic to actually try and tackle some of these or as much as you can offer respiratory referral and try and get people on night-time ventilation, it might not solve problems. Also very important for patients is, Bob and I have been speaking about separately, in terms of their, well, their employment, but also their ability to drive, there are certain restrictions from the DVLA on what success you need with things like, nighttime ventilation in order to be able to continue holding a driving license.
00:14:18:00 - 00:14:51:06
Speaker 2 - Dr. Bob Ballantyne
I think the second most commonly reported issues are fatigue and daytime sleepiness. Some other symptoms which are reported are visual disturbance due to the ptosis of the, you know, the kind of low sitting position of the upper eyelid, palpitation, again, possibly reflecting the cardiac conduction disease alluded to, and problems with swallowing, again quite frequently reported.
00:14:51:08 - 00:14:59:15
Speaker 2 - Dr. Bob Ballantyne
And bowel symptoms may be one of the other more commonly reported symptoms during the management clinics.
00:14:59:17 - 00:15:16:05
Speaker 1 - Sytske Lub
A really large range, and I know we've in clinic seen patients who are very mildly affected who came to be diagnosed, say, for a family member and may just have a little bit of myotonia, a little bit of weakness, to very severely affected patients who sometimes, appeared well, quite acutely ill.
00:15:16:06 - 00:15:35:10
Speaker 1 - Sytske Lub
And recently you’ve had some things organised with that. But yeah, quite a range. And now Mark I will just pick up on one point because your PhD involved a lot of study on sleepiness and sleep studies. You had some interesting data about the prevalence of sleep apnoeas. Could you share a little bit about that?
00:15:35:12 - 00:16:09:22
Speaker 4 - Dr Mark Hamilton
Yeah, so we know that in conditions that are associated with muscle weakness - so in normal physiology, anyone during deeper stages, particularly REM sleep, it’s normal physiology for skeletal muscles to become more relaxed. But in people with preexisting muscle conditions, that can be associated with a tendency either to, to under-breathing, so hypoventilation, where oxygen levels can get low, carbon dioxide levels can creep up, or even to obstructive events.
00:16:09:24 - 00:16:39:12
Speaker 4 - Dr Mark Hamilton
So, a sort of collapse of upper airways, and pauses in breathing during sleep can be associated with bigger desaturations. I suppose a surprise for us was just how common this sleep-disordered breathing was in our outpatient cohort. I think around half, I think slightly more than half had what would either be classified as moderate to severe sleep-disordered breathing.
00:16:39:14 - 00:17:44:13
Speaker 4 - Dr Mark Hamilton
As Bob says alongside that, a very common complaint in Myotonic Dystrophy is of excessive daytime sleepiness, and undoubtedly sleep-disordered breathing, high carbon dioxide levels, fragmentation of sleep because of these events, can contribute to daytime sleepiness. But an interesting observation is in Myotonic Dystrophy, at least for some patients, that - or as a whole - there doesn't seem to be a strong correlation between the severity of sleep disordered breathing and daytime sleepiness and indeed, one can be present without the other.
And for some patients, even effective treatment of sleep-disordered breathing with nocturnal ventilation actually doesn't lead to an improvement in sleepiness symptoms. So our thinking is that while that may be part of the puzzle, and certainly doesn't help matters, almost certainly there is also a central component, so something about these changes that are going on in the central nervous system that's also driving these fatigue and daytime somnolence symptoms. So the symptoms are certainly more complex. Yep.
00:17:44:17 - 00:18:09:01
Speaker 1 - Sytske Lub
00:18:09:02 - 00:18:30:18
Speaker 1 - Sytske Lub
So quite a big impact for these patients. Bob, this question is targeted to you because you are the man at the centre of the West of Scotland service for DM1 which is quite a unique position, especially since your background has sort of come at genetics from the sidelines, essentially.
00:18:30:20 - 00:18:37:12
Speaker 1 - Sytske Lub
So what is important in maintaining essential service for DM1? Where do you send patients?
00:18:37:14 - 00:19:01:14
Speaker 2 - Dr. Bob Ballantyne
- Yeah. Well, I mean, I think one of the first things to see is that it's important that it's an accessible service, and I think you can achieve that by providing clinics in a wide range of locations, and trying where possible to have joint clinics with other services to reduce the number of appointments that patients are being asked to attend.
- Definitely. And I haven't really scheduled a separate question on it, but I suppose, allowing people to plan their families, as carefully as they might want to, or at least be prepared. Sort of, the genetic counselling side of it is a really important feature of the job and for Bob’s job in particular, to sort of give people a chance to, like I said, either prepare for that or be able to screen against it and not have a very affected child who might be prone to a lot of suffering.
00:19:01:16 - 00:19:17:20
Speaker 2 - Dr. Bob Ballantyne
And I think those attending the management clinics should have access to support from a wide range of services, and we should aim to deliver standardised care according to nationally agreed guidelines or care recommendations.
00:19:17:22 - 00:19:46:06
Speaker 1 - Sytske Lub
Very important. And one thing we haven't touched on that I think is important to mention is as part of the DM1 phenotype, there is a level of behavioural changes and psychiatric changes in patients at times which can prevent, sorry, present as an almost avoidant personality or apathy. And there is quite often a level of learning disability or autistic spectrum disorder involved, which means that accessing, the DM1 clinics or other medical services can be quite difficult.
00:19:46:08 - 00:19:52:09
Speaker 1 - Sytske Lub
Do you have any comments on sort of what might be important for other services to remember about these DM1 patients?
00:19:52:11 - 00:20:22:18
Speaker 2 - Dr. Bob Ballantyne
Again, I think it's about awareness that that these issues are present and that, I think that, adults are not simply choosing not to attend. This is part of the condition. And I think that just needs to be taken into consideration and perhaps reflecting that and offering, you know, kind of additional appointments instead of simply removing those who are referred or who have been attending for annual surveillance.
00:20:22:20 - 00:20:28:19
Speaker 2 - Dr. Bob Ballantyne
Just ensuring that they are given a further opportunities to attend their appointments.
00:20:28:21 - 00:20:47:24
Speaker 1 - Sytske Lub
Yeah, definitely. Okay, I want to talk a little bit now about the diagnosis of DM1 and, kind of related to that, techniques that we use to study in one in the lab compared to what we actually see in clinics or request in clinics. But starting from that, I guess we need to know where patients are coming from and who might access a service.
00:20:48:01 - 00:20:56:17
Speaker 1 - Sytske Lub
So Bob and Mark are probably best placed for this, but where are these patients coming from and how do they find their way to the DM1 service?
00:20:56:19 - 00:20:59:07
Speaker 2 - Dr. Bob Ballantyne
Mark happy for me to jump [Mark] Yeah go for it, I think [Bob] in?.
00:20:59:08 - 00:21:30:18
Speaker 2 - Dr. Bob Ballantyne
Okay, so I think like we often receive referrals from members of families who are already know to the service and who have not previously undergone molecular testing and have decided at this point that it's something that they may wish to pursue. So, they may be self-refer or they may be referred by their GPs. I think often the majority of the other referrals come to me via neurology, who may themselves have received referrals from other specialties such as respiratory medicine, cardiology, anaesthetics or ophthalmology.
00:21:30:20 - 00:22:08:20
Speaker 2 - Dr. Bob Ballantyne
In addition to that, the molecular laboratory at the Queen Elizabeth University Hospital forwards to me copies of any positive molecular test results, and when I receive these I would tend to reach out to the clinician who requested the test to ensure they're aware that their management clinics are there, and to indicate that I'm happy to arrange follow up for that individual.
00:22:08:22 - 00:22:36:10
Speaker 1 - Sytske Lub
And, I know we haven't really broached it so much, but the most severe phenotype for DM1 is the congenitally affected child - a neonate with severe hypotonia of all things, rather than myotonia per, say, respiratory distress, whose lifespan is often severely limited, and they are unlikely to get past a certain age point. This is obviously quite a severe phenotype, but sometimes leads to other diagnoses of the family members coming through.
00:22:36:12 - 00:22:42:22
Speaker 1 - Sytske Lub
Mark what would you what would be your comments in terms of, patients presenting from a congenitally affected child?
00:22:42:24 - 00:23:05:23
Speaker 4 - Dr Mark Hamilton
Yeah, so that still can be - or certainly still is - a route to us identifying new families where a profoundly, severely affected, baby has been born. And it's usually written into sort of protocols in neonatal units as sort of a standard battery of tests for a - if you like - a floppy baby, that a test for Myotonic Dystrophy is done.
00:23:05:25 - 00:23:47:06
Speaker 4 - Dr Mark Hamilton
I guess that, in some ways, represents a missed opportunity if you like, because often as a result of that, we will then go on to test parents. You'll be aware that most often – although not exclusively - Congenital Myotonic Dystrophy is the result of transmission from a female affected parent. But often having done that we then do find that actually, although mild and perhaps nonspecific, there are other members of the family who have presented to various medical clinics with symptoms, or have experienced symptoms, but that they haven't been recognised as being specific for Myotonic Dystrophy.
00:23:47:08 - 00:24:22:15
Speaker 4 - Dr Mark Hamilton
So, you know, I think Bob does give the example, we do receive referrals directly or indirectly from other mainstream medical clinics. Again, with it being a multi-system condition, there are so many other physical features that can potentially present to any medical clinic, you know, early onset cataracts to the ophthalmology clinic, heart muscle involvement in conducting system disease in the cardiology clinic, respiratory issues: sleep-disordered breathing in respiratory, bowel symptom: faecal incontinence in the gastro clinic, anaesthetic complications.
00:24:22:17 - 00:24:45:14
Speaker 4 - Dr Mark Hamilton
So, you know, having made a diagnosis, then at least people can be aware of the reproductive risks, of the reproductive options, that can be, you know, that can be offered. And obviously having a, you know, severely, profoundly unwell child is a devastating event for a family, and so. But I think things have improved in terms of awareness and ascertainment.
00:24:45:16 - 00:24:58:11
Speaker 4 - Dr Mark Hamilton
I think there's always a bit more to do, and maybe I don't know if this podcast helps with that, but for a new generation of medics coming through to be aware of Myotonic Dystrophy and the key features I think is really important. And early diagnosis can make a big impact, yep.
00:24:58:13 - 00:25:27:12
Speaker 1 - Sytske Lub
00:25:27:14 - 00:25:48:18
Speaker 1 - Sytske Lub
And Mark, so you talked about the panel that is done for the “floppy babies”. However, this obviously differs to what people might be - or how people might be – investigated in adult onset symptoms, by which I mean the techniques. And to say “analyse DNA” might be similar, but, typically speaking, how do we find out that someone has DM1 if they present as an adult?
00:25:51:09 - 00:26:18:09
Speaker 4 - Dr Mark Hamilton
So that's, I suppose that's a good point, because generally speaking we're doing - or in mainstream medicine, genetic tests are being done - much more frequently. Often they’re large gene panel tests looking at many genes at once, or even exome sequencing for children with certain presentations especially. I suppose it's important to mention because it's a repeat expansion disorder – really, currently, the only way to diagnose it is to do a targeted test.
00:26:18:11 - 00:26:49:03
Speaker 4 - Dr Mark Hamilton
In other words, to specifically request a test for Myotonic Dystrophy. It's not something that would be picked up, for example, on a current pipeline for, for exome sequencing. The methods used in the diagnostic lab, if you like, give perhaps less information or less data than those that are used in a research basis – it’s something called a triplet-primed PCR that, seeks to amplify the variant, the repeat portion of DNA.
00:26:49:05 - 00:27:19:20
Speaker 4 - Dr Mark Hamilton
And the experiment looks at it from both sides. The reason for that being, we may come on to talk a wee bit about people who have these interruptions and these sequence variations within the repeat that can, in rare instances, give an unusual result or even cause the triplet primed PCR experiment to fail altogether. So, I guess to guard against those false negatives, it's done from both sides of the repeat.
00:27:19:22 - 00:27:49:17
Speaker 4 - Dr Mark Hamilton
Results usually - so for modest sized expansions, our laboratory may report the size of the repeat but for most patients it's kind of a yes or no result. It's either no expansion is detected or an expanded, allele is detected; in most cases unless towards the smaller end of the range, the diagnostic lab won't report repeat sizes because in the, sort of, although they are of particular interest in the research domain. In terms of clinical utility, we're quite limited in what we can predict about an individual's symptoms, or the likelihood of their children being more severely affected based on repeat size.
00:27:49:19 - 00:28:14:16
Speaker 4 - Dr Mark Hamilton
So at the moment, it's not something that we seek to measure in the diagnostic lab, and it's not something that we presently report back to patients in most cases. But that maybe, yeah, contrasts a little with what Darren's group do with the samples.
00:28:14:18 - 00:28:36:22
Speaker 1 - Sytske Lub
Which nicely leads me on to asking Darren, who I appreciate I've kept quiet for the last few minutes or so - Darren, your lab obviously wants to get as accurate answers as possible. How do you get around the possible drawbacks of TP-PCR. What kind of tests - techniques is the word I'm looking for - what kind of techniques do you use to investigate DM1?
00:28:36:24 - 00:29:10:06
Speaker 3 - Professor Darren Monckton
So we use a variety of different approaches to, to try and understand what's happening at the CTG repeat. So I guess a little bit of context here is, you know, what we're trying to understand is what is the main drivers of symptomatic variation, within and between individuals and families with Myotonic Dystrophy. With the overall goal that if we understood why this disease was so variable, A: we might be able to provide more accurate prognostic information to the patients and families.
00:29:10:08 - 00:29:33:18
Speaker 3 - Professor Darren Monckton
But actually, more importantly in the longer term is, if we understand why, what's driving that variation, then that may give us clues as to how we can intervene in that process. So therapeutic opportunities. And we're really interested in what are the genetic determinants of that, that variability. And it's quite clear that a major genetic determinant is the number of repeats that an individual has.
00:29:33:22 - 00:29:52:14
Speaker 3 - Professor Darren Monckton
Again, it's very easy to say the number of repeats an individual has, but actually, turns out because of this phenomenon of somatic mosaicism, where the repeat number is changing throughout the lifetime of the individual, that there is no “one number of repeats”, or if there is a number of repeats, it's the number of repeats that that person inherited.
00:29:52:16 - 00:30:17:07
Speaker 3 - Professor Darren Monckton
So obviously in the single egg or sperm from the affected parent, there was only one number of repeats. So one of the methods that we routinely use is to try and estimate what the number of repeats was that an individual inherited. Typically the way we do that is we look in blood DNA. So, although the repeat is unstable in the blood cell lineages, it looks like it's relatively stable there compared to other tissues.
00:30:17:09 - 00:30:48:15
Speaker 3 - Professor Darren Monckton
And we use a method called small pool PCR, where essentially we dilute the DNA and we use again that same PCR, to amplify essentially single molecules. We resolve those fragments by agarose gel electrophoresis and detect them by using very sensitive, radioactively labelled probes such that we can determine repeat lengths that were present in individual cells.
00:30:48:17 - 00:31:07:01
Speaker 3 - Professor Darren Monckton
And typically, what we see in someone with Myotonic Dystrophy is that if we look in the blood, each blood cell has a different number of repeats, and we can estimate from that what is the average number of repeats - so that kind of tells us what the average size in blood - but we can also see kind of what was at the lower end of the distribution.
00:31:07:03 - 00:31:38:12
Speaker 3 - Professor Darren Monckton
And we now know that essentially that lower end of the distribution is that, is that's the best estimate for how many repeats were inherited. And it's quite clear that the number of repeats inherited is the best predictor of absolute disease severity. But then also measuring what we think it started at and then how big it is in the blood at a given time point, gives us a measure of how quickly it's changed throughout the lifetime of the individual, and it's quite clear that that's another driver of variability.
00:31:38:14 - 00:31:50:20
Speaker 3 - Professor Darren Monckton
So, individuals in who the repeat gets bigger, quicker tend to have earlier symptoms, more severe symptoms, more rapidly progressive symptoms, than patients who are expanding more slowly.
00:31:50:22 - 00:32:26:14
Speaker 1 - Sytske Lub
And that's, I suppose, a really interesting prognosticator that we may be able to look at at some point in the future. But very difficult if you've only got access to samples at certain points or if you haven't got the kind of equipment, at least in the NHS setting, to continue investigating this. Now, when it comes to your research, you’re obviously using peripheral blood samples for the majority of your DNA extractions. I suppose a lot of the condition affects, say, the central nervous system - and what makes it difficult accessing different tissues for research?
00:32:26:16 - 00:32:52:00
Speaker 3 - Professor Darren Monckton
Blood is obviously, relatively non-invasive to sample, so we can generally get blood very easily. Obviously, we're very interested in what's happening in the brain. As alluded to, there are many neurological symptoms to where the brain is clearly being directly affected. Obviously, essentially the only route to accessing those, that material, is a post mortem.
00:32:52:02 - 00:33:15:04
Speaker 3 - Professor Darren Monckton
And there has been some studies now done on postmortem brains looking at the size of the repeat - so again, it's quite clear that the number of repeats in the brain in nearly all regions of the brain is much larger, it is, than in muscle cells, much larger than was inherited. So patients are typically inheriting 1 or 200 repeats, maybe having 3 or 400 repeats in their blood, but there may be several thousands of repeats in, within the brain.
00:33:15:06 - 00:33:55:09
Speaker 3 - Professor Darren Monckton
That's even more, is seen to an even greater extent, in the muscles. So again, in the skeletal muscle typically patients – again, you have a few hundred repeats in blood, have three, four, five thousand repeats in muscle. But again, most of our data in terms of understanding that is actually very old data and stems from muscle samples that were taken before the gene was identified, where actually muscle histopathology was actually part of the diagnostic journey for those individuals.
00:33:55:11 - 00:34:20:08
Speaker 3 - Professor Darren Monckton
And at a time when most of those biopsies were open biopsies, literally, they used a scalpel to cut out a big chunk of essentially meat – muscle – and yeah, there was a lot of material there from which DNA could be extracted. They could do the histopathology and everything can be done. Nowadays, obviously, muscle biopsies are not part of routine diagnostics.
00:34:20:10 - 00:34:40:18
Speaker 3 - Professor Darren Monckton
Again, we can just go straight to the blood DNA once they have a clinical suspected diagnosis, then you would just go straight to, the genetic test, which is great. Obviously saves that muscle biopsy, but it means we don't have any additional material left over for research. So any muscle now would have to be taken specifically for research purposes.
00:34:40:20 - 00:35:07:02
Speaker 3 - Professor Darren Monckton
And again, obviously taking an open biopsy is highly invasive, so you have to have a very, very good reason why you're going to do that. So most biopsies now are done really for looking at RNA, and they're using needle biopsies which again, obviously is much better for the patient in terms of much less invasive, much less painful - but it results in a much lower amount of biological material.
00:35:07:04 - 00:35:34:19
Speaker 3 - Professor Darren Monckton
And actually, again, the techniques for looking at the DNA in blood, two, three hundred, 500, a thousand repeats, that's within the range that we can PCR amplify. So even starting from relatively small amounts of blood DNA, we can still have lots of DNA for analysis. Whereas in muscle, where the repeats are three, four, five thousand repeats, that's actually very challenging for PCR, and often we can’t use PCR.
00:35:34:21 - 00:35:59:04
Speaker 3 - Professor Darren Monckton
So actually the techniques you would need to use to really examine what's going on in the muscle would require much larger amounts of DNA, which again, we just don't physically get from needle biopsy. So we, as we've - the last few years really started to realise is that that somatic expansion is really important, we kind of realize we don't really know enough about what's going on in muscle. We would like to understand that much better, and actually getting the appropriate samples now becomes a real challenge.
00:36:05:15 - 00:36:31:15
Speaker 1 - Sytske Lub
Yeah, becomes really difficult. And that balance between not putting your patient through a really invasive procedure, even for the sake of research, versus what you learn I suppose, is a very difficult balance for research proposals to address. Yeah. An important and interesting point. Now Mark, you’d mentioned earlier, I think it was yourself who’d mentioned earlier, about variant repeats - interruptions within the expansion of CTG.
00:36:31:17 - 00:36:46:23
Speaker 1 - Sytske Lub
So this is a phenomenon that affects only a very small proportion of DM1 patients, however it can have quite a big effect on the phenotype of the condition. So I guess I'll start with Bob. What is the importance of variant repeats in your clinic?
00:36:47:00 - 00:37:20:05
Speaker 2 - Dr. Bob Ballantyne
Of course. It's important for a couple of different reasons. I think, again, important as Mark had mentioned earlier, it's being aware that if they are present that the standard laboratory probably where they're testing may return a false positive test result. And if there is a generally a high clinical index of suspicion that the individual is affected, then you need to, you know, kind of explore further testing.
00:37:20:07 - 00:37:46:07
Speaker 2 - Dr. Bob Ballantyne
I think the other kind of main implication for the management clinic is probably for the support of the genetic counselling that we would give through the management clinics. And again, as we have alluded to, generally associated with, with a milder phenotype. So, has an impact on the counselling provided.
00:37:46:09 - 00:37:50:08
Speaker 3 - Professor Darren Monckton
Bob, you said a false positive there - I think you meant a false negative.
00:37:50:10 - 00:37:52:24
Speaker 2 - Dr. Bob Ballantyne
Oh yes. Sorry, Darren. Yes, thank you. That's great.
00:37:52:26 - 00:38:24:09
Speaker 1 - Sytske Lub
Thank you for correcting that Darren, that had come to my mind but I'd let it, slip through. So a result can come back as negative, but a patient present with a very clear family history, or a reasonably clear family history and clear symptoms, that may prompt further investigation. And indeed there’s some individuals in Darren's lab who very kindly receive some of these samples with potential variant repeats, to try and identify an expansion, which may obviously be then heritable for future generations of that family.
00:38:24:11 - 00:38:34:15
Speaker 1 - Sytske Lub
And now I think it was yourself, Mark, who I’d spoken to, about the genetic counselling side of variant repeats, or it might have been Bob - you might have to correct me.
00:38:34:17 - 00:38:36:09
Speaker 4 - Dr Mark Hamilton
Possibly both.
00:38:36:11 - 00:38:59:10
Speaker 1 - Sytske Lub
Possibly both! Good thing I’ve been asking the same sort of questions. Wonderful. So, you said it influences the genetic counselling in a way, I suppose. And the question is what advice would you give to a patient who might have a milder phenotype, might be expecting milder phenotypes to carry on through the family? Is there a risk of these patients having congenitally affected child, I suppose is my question.
00:38:59:12 - 00:39:24:04
Speaker 4 - Dr Mark Hamilton
Yeah, so I mean that's definitely something we're continuing to learn more about. So I guess just to very briefly explain what we're talking about is within that CTG repeat array, interruptions with different sequence – so it’s commonly, common interruptions are CCG interruptions, and sometimes even in particular patterns like a hexamer of CCG CTG repeated over and over. We know, oh gosh, Darren, current thinking: 4%, 7% - that sort of range of patients?
00:39:30:24 - 00:39:32:07
Speaker 3 - Professor Darren Monckton
Probably 5 to 10%, probably.
00:39:32:09 - 00:39:59:19
Speaker 4 - Dr Mark Hamilton
Five to 10, okay. They have these interruptions and there’s evidence, certainly, that the presence of these interruptions can be associated with a later age of onset of symptoms, milder symptoms or less progression of symptoms overall, and even, I guess what we think is at least a major contributor to that, is a stabilisation of that somatic instability that Darren has talked about.
00:39:59:21 - 00:40:28:14
Speaker 4 - Dr Mark Hamilton
So the ongoing expansion of the repeat over time in individual cells. There's also evidence, at least in some families, to suggest that these interruptions can be more stable on transmission as well. So thereby reducing the effect or even entirely negating the effect of genetic anticipation. But I think it's, like I said, it’s something we’re certainly continuing to learn more about.
00:40:28:16 - 00:41:00:20
Speaker 4 - Dr Mark Hamilton
It's likely that – I’m sure Darren can talk more about – that the particular structure of the variant repeat interruptions. And I think although we can talk in general terms about having variant repeats seeming to be a good thing and seeming to maybe mean that your symptoms will be milder, and your risk of an affected, severely affected child, it's perhaps less, I think there are certainly examples that prevent us talking in absolute terms, and the recommendations would still be for an individual to have all the health checks that would be recommended for someone with Myotonic Dystrophy.
00:41:00:22 - 00:41:26:19
Speaker 4 - Dr Mark Hamilton
And there’s certainly at least one helpful case that we've, you know, where we’ve published data from together, you know, to suggest that certainly there can still be expansions or considerable changes in size even of repeats with interruptions on transmission. So, yes, I think it's been our practice, and again, we've got the advantage of our links with Darren’s lab where we can characterize these interruptions. That’s certainly not something that's open to every diagnostic lab.
00:41:26:21 - 00:41:42:05
Speaker 4 - Dr Mark Hamilton
But we tend to acknowledge them to patients, acknowledge what the evidence says, but wouldn't talk in absolute terms about being reassuring about these things. So I think – is that fair Darren?
00:41:42:07 - 00:41:42:22
Speaker 3 - Professor Darren Monckton
- Ye
- Yeah. So we've obviously done a lot of work on characterizing the structure of the variant repeats in different individuals, and again, we're using a lot of new sequencing technologies particularly long range sequencing now to try and understand what is, not just the presence of variant repeats in individuals, but what exactly is the structure, and understand better exactly how that does relate to the presentation of symptoms.
00:41:42:24 - 00:42:01:18
Speaker 1 - Sytske Lub
Definitely a point to learn more about. Darren, what is your - I suppose your research has mostly been about somatic instability and expansion at the moment – but what is your research’s experience of variant repeats and can this possibly be something that might be useful in therapeutics? Or biomarkers?
00:42:01:20 - 00:42:26:22
Speaker 3 - Professor Darren Monckton
00:42:26:24 - 00:42:49:16
Speaker 3 - Professor Darren Monckton
And it's quite clear now that, yes, essentially the more variant repeats a person has, the bigger the impact on somatic instability, and the bigger the impact on the presentation of the disease. With the caveat as Mark absolutely indicated there, that's still there is additional variation on top of that that we cannot fully explain, but exactly in terms it's a major modifier.
00:42:49:18 - 00:43:15:19
Speaker 3 - Professor Darren Monckton
So that still leads to complications that we can't say with certainty - prognosis for any one individual. But what I think it has really helped us to do is get a much better picture of the role of somatic expansion in disease. So we clearly know that repeats are getting bigger, that more repeats makes things worse. But it's quite difficult to say do you actually need somatic expansion?
00:43:15:21 - 00:43:37:08
Speaker 3 - Professor Darren Monckton
And you know, how much is that really contributing to the overall progression of the disease? And I think the fact that, you know, we have some individuals with expanded alleles with variant repeats that are not just more mildly affected - there are some individuals who appear to have so many variant repeats that they have essentially no overt symptoms.
00:43:37:10 - 00:44:07:09
Speaker 3 - Professor Darren Monckton
Some of them typically have some mild signs, but they have no overt symptoms, and it appears that, you know, that the repeat is particularly stable in those individuals. That kind of really is, I think, strongly telling us, that somatic expansion is really an important driver of the disease process. So if we could replicate that degree of somatic instability in other individuals, then that we think would be highly therapeutically beneficial.
00:44:07:11 - 00:44:40:15
Speaker 3 - Professor Darren Monckton
Again, obviously, trying to artificially introduce variant repeats is something that people are thinking about. You know, gene editing approaches might be something that could potentially be used there, but again, that's kind of a way off. So we're much more involved in understanding how the repeats expands, what are the enzymes, proteins that are mediating that - and we know a lot about that now from our work and lots of other work in terms of the role of DNA mismatch repair proteins in driving somatic expansion.
00:44:40:17 - 00:45:15:15
Speaker 3 - Professor Darren Monckton
And that's really great from a perspective that those enzymes are working to generate expansion, so it's not failure to undergo DNA repair - it’s an active DNA repair process – so from a pharmacological intervention perspective, identifying drugs that stop those enzymes working should be therapeutically beneficial in a number of companies. Now, researchers are engaged in trying to identify either small molecules around sense oligonucleotides or siRNAs that will inhibit those proteins and potentially have therapeutic, benefit.
00:45:15:18 - 00:45:34:23
Speaker 3 - Professor Darren Monckton
And again, what's really attractive about that is that we can we think the same thing is happening not just in Myotonic Dystrophy, but in Huntington's disease, a bunch of spinal cerebellar ataxias, fragile X syndrome, a whole bunch of other disorders that share a similar genetic mechanism. So there's a lot of excitement now that potentially one drug might treat multiple disorders.
00:45:35:00 - 00:45:40:16
Speaker 3 - Professor Darren Monckton
And that would be obviously an amazing - if we can get a drug that does, hits, multiple diseases.
00:45:40:18 - 00:46:00:19
Speaker 1 - Sytske Lub
A very exciting time in the research side of things. So that definitely, to find not only, identifying that, there must be some kind of common mechanism, but actually identifying the key players in that, that may then be therapeutic targets, which hopefully, if successful, will be able to find a way into Bob's clinic and provide some relief of symptoms for these patients.
00:46:00:21 - 00:46:28:24
Speaker 1 - Sytske Lub
And kind of coming off the back of that, I suppose. Darren, you definitely have the most experience with Myotonic Dystrophy, but definitely Mark and Robert's. Robert? Sorry, I got dead formal for a moment. Mark and Bob, feel free to comment with things that are salient I suppose, more to the clinical side of things. But from the last 30 years till now, what have been the key moments of change and, direction shifts for Myotonic Dystrophy?
00:46:29:01 - 00:47:00:01
Speaker 3 - Professor Darren Monckton
- Yeah. Well, I think that well, I think that goes right back actually to that initial discovery of the mutation. So the identification of the CTG repeat that did one thing which was obviously give the prospect for molecular diagnosis. And again, that's clearly, again has huge impact, it provides information to patients and families that again, I think, enables them to understand that they really do have a disease. Particularly again, in some cases with Myotonic Dystrophy, actually, where the symptoms are, maybe appear, relatively mild and nonspecific, to know that there really is a clear explanation for the constellation of symptoms that people are presenting with.
- Yeah. So, I guess even just looking a bit more historically, I think, you know, on the clinical side, probably the first big milestone that was a little bit before my time, you know. One time people with myotonic dystrophy might have been seeing, you know, various specialists and, you know, District General Hospitals sort of seeing, maybe under the care of a neurologist, but seeing different medical specialists for different things that I think one great piece of progress was the, just the establishment of the myotonic dystrophy specialist clinics, because I think prior to that there was a lot of preventable harm coming to patients.
00:47:00:03 - 00:47:23:13
Speaker 3 - Professor Darren Monckton
And then again, as Mark has already alluded to, the ability to make informed reproductive choices is clearly, I think, was a key step that was kind of, facilitated by the initial identification of the gene. And then the other thing was, again, coming back to that, reproductive choices, you know – the concept of anticipation and again, wasn’t widely believed until the Myotonic Dystrophy Mutation was identified.
00:47:23:15 - 00:47:45:08
Speaker 3 - Professor Darren Monckton
And so now it seems blindingly obvious that the disease nearly always gets worse in successive generations. But that wasn't widely accepted until the mutation was identified, and now it's clear that it is the case. And we have a molecular explanation for it – the number of repeats is increasing from one generation to the next.
00:47:45:10 - 00:48:17:23
Speaker 3 - Professor Darren Monckton
So having a molecular explanation for anticipation, I think has been critical. Obviously, on top of that, then, is understanding the disease process. So as we talked about earlier on, the idea that to gain a function of an RNA molecule, again, very easy, now widely accepted that that's the mechanism again, took a long time to get to that point. Was more than five, nearly ten years before it became clear that it really was a gain of function of the RNA.
00:48:18:00 - 00:48:57:04
Speaker 3 - Professor Darren Monckton
And that's because no other disease had had such a mechanism before. This was the first disease in which it was clearly shown that it was a toxic gain of function of the RNA. And again, that obviously in and of itself then presents therapeutic challenges, but also therapeutic opportunities. And again, very exciting, what's happening now in terms of some of the strategies to ameliorate the presence of the toxic RNA are in clinical trials now, and some quite exciting data, preliminary at the moment, but at least what appears to be very exciting, preliminary data coming out from some of those trials.
00:48:57:06 - 00:49:15:22
Speaker 3 - Professor Darren Monckton
And that's to me, that's what we've been doing for the last 20 or 30 years, is trying to get to that point where our knowledge at the molecular level can lead to new, life changing therapies. We're not quite there yet, but it looks like we are very close, hopefully [Sytske] to approaching it.
00:49:15:24 - 00:49:40:06
Speaker 1 - Sytske Lub
It's fascinating. It's a really good example of the evolution of sort of the research process, and just genetics in general and finding new techniques and being able to roll that out and seeing it rolled out successfully within a national health system. So, yeah, very fascinating. And I know, Mark, you and I had spoken a little bit about one – a couple – of particular, medicines that may be coming on the horizon.
00:49:40:08 - 00:49:46:06
Speaker 1 - Sytske Lub
Would you like to give a little bit more insight about things that are looking more promising than the rest?
00:49:46:08 - 00:50:23:08
Speaker 4 - Dr Mark Hamilton
00:50:23:10 - 00:50:56:20
Speaker 4 - Dr Mark Hamilton
So things like, you know, arrhythmias potentially treatable by pacemaker, respiratory infections potentially preventable by vaccination, anaesthetic complications. So that I think, actually, even just bringing the patient cohorts together, learning more about good management of the disease has, you know, in itself has been a big, a big milestone of progress. And it's the people who came before us in Glasgow that were involved in a lot of that.
00:50:56:22 - 00:51:43:15
Speaker 4 - Dr Mark Hamilton
For the new therapeutics - absolutely. And I think alongside all this, molecular research has really identified different points in the pathway and in the disease process that seem to lend themselves, to, yeah, to targeted therapies. So this idea of the toxic messenger RNA - so there are molecules called antisense oligonucleotides, which are synthetic nucleic acids, that can be designed to be complementary, and to, so to stick through that sort of complementary binding that nucleic acids do, to stick to specific messenger RNAs. They've been used historically and in the laboratory for sort of knockdown experiments where you wanted to reduce expression of a particular gene.
00:51:43:21 - 00:52:08:22
Speaker 4 - Dr Mark Hamilton
But having bound, what they then do is target that messenger RNA to be broken down within the nucleus. So I think for a long time people have recognized that that seems a very attractive strategy for Myotonic Dystrophy. One of the first attempts to come to clinical trial in humans directed - I guess it's important to acknowledge that these molecules don’t cross the blood brain barrier, so if they're administered peripherally, they won't do anything for the central nervous system involvement - but the first, I suppose, target was muscle.
00:52:08:24 - 00:52:39:15
Speaker 4 - Dr Mark Hamilton
And I guess although there was a lot of positives to be taken from that first trial, one of the disappointments, I suppose, was that the penetration or the ability of the drug to get into muscle, was less than hoped and less than was aspired to achieve the correction of splicing in the therapeutic effect.
00:52:39:17 - 00:53:03:14
Speaker 4 - Dr Mark Hamilton
There are a number of pharmaceutical companies that have come up with various strategies to try to overcome that and improve delivery, and I think one that we talked about was sort of hitching the, oligonucleotide onto a monoclonal antibody that then binds to the muscle transferrin receptor and gets brought into the cell by the usual mechanism for iron.
00:53:03:16 - 00:53:25:18
Speaker 4 - Dr Mark Hamilton
And that seems to be, again, not peer reviewed, but there are data coming out from the pharmaceutical company that suggests that that is now looking very promising indeed. So, yes, I think and you know various other molecules at different stages of development targeting other aspects of the pathway.
00:53:25:24 - 00:53:47:18
Speaker 4 - Dr Mark Hamilton
But it seems that, yeah, targeting that toxic messenger RNA seems to be where there’s particular purchase, at the moment. And it’s - Darren and I were recently at a meeting overseas where, you know, suddenly there was representation from a number of different pharmaceutical companies. So clearly, I think, you know, a sign that things are really happening. Yeah.
00:53:47:20 - 00:53:49:00
Speaker 1 - Sytske Lub
Things are picking up.
00:53:49:02 - 00:53:49:18
Speaker 4 - Dr Mark Hamilton
- Yeah.
- Yeah.
00:53:49:20 - 00:54:14:18
Speaker 1 - Sytske Lub
And, Bob, you came into this, into genetics - into specialty doctors in genetics - I’ve said from the sidelines before, but just from a slightly different angle. So you've really seen the last, I can't count, nine years, 8 or 9 years? Of Myotonic Dystrophy practice. Would you say things have changed in the actual management of DM at the moment?
00:54:14:20 - 00:54:48:15
Speaker 2 - Dr. Bob Ballantyne
I think, yes. I think in terms of the way the kind of management has been delivered in, in Scotland, that began as Mark said, you know, before I came in to post. That was probably from the mid 2000s, I think from around 2007, maybe around about then. But I think sort of generally, I think there's been a bit of a kind of increase in development and implementation of management guidelines.
00:54:48:17 - 00:55:16:05
Speaker 2 - Dr. Bob Ballantyne
We had the kind of consensus care recommendations for two, 2 or 3 years ago, and they're continuing to be added to. So recommendations for not just Type 1 Myotonic Dystrophy but Type 2, and for Congenital Onset Myotonic Dystrophy as well. And that kind of whole library of guidelines is continuing to be developed and to, you know, come into clinical practice.
00:55:16:07 - 00:55:31:03
Speaker 2 - Dr. Bob Ballantyne
So I suppose, yes, through the kind of increased development and implementation of the guidelines, the biggest change that I've been aware of during the last 8 to 9 years or so.
00:55:31:05 - 00:55:53:09
Speaker 1 - Sytske Lub
So, I suppose guidelines are really important for achieving that standardised care as best as possible throughout the nation, so, very important. And I suppose the one other thing that I'd seen while being in clinic was that there's now a patient registry that is accumulating data about patients, for audit purposes, for research purposes, which will obviously aid things in the future, maybe less so in actual clinical practice.
00:55:53:11 - 00:55:56:09
Speaker 1 - Sytske Lub
But, definitely from the research point of view.
00:55:56:11 - 00:55:57:04
Speaker 2 - Dr. Bob Ballantyne
00:55:57:06 - 00:56:14:08
Speaker 1 - Sytske Lub
- Darren, I know we’d spoken a little bit about these potential novel therapeutic targets, but - and just on a very much sort of lab based level – where is the research in Myotonic Dystrophy in your lab going at the moment? What kind of things are you looking at?
- Yeah. I think it's really important to consider, it's something that's often forgotten, the actual, not just the accessibility of the tissues that are affected by certain conditions that you're trying to study, but the natural history of the disease, in terms of how long it takes to develop and not to forget that actually, yes, if you want a complete picture, ideally, you’d need to follow a large cohort of patients.
00:56:14:10 - 00:56:46:19
Speaker 3 - Professor Darren Monckton
So, we're looking at a variety of things. So we're still, again, trying to understand again what is the relationship between the number of repeats inherited, how quickly that's changing, and particularly the role of the variant repeats in driving not just age of onset but the spectrum of different symptoms in different organ systems. Trying to understand that better. And really now trying to focus on what are the non DMPK modifiers of that.
00:56:46:21 - 00:57:03:18
Speaker 3 - Professor Darren Monckton
So we know the repeats are really important, but what other genes are important in that? So again we've got a lot of work now done in related disorders. So in Huntington's disease now we've got a big list of genes that are modifying Huntington's disease. Some of those we think are modifying through the repeats, and we expect those to overlap with Myotonic Dystrophy.
00:57:03:20 - 00:57:36:15
Speaker 3 - Professor Darren Monckton
And we're kind of doing some candidate gene studies in the Myotonic Dystrophy population to try and better address them again. But ideally getting towards the position where again, we can do an unbiased genome wide association study for modifiers of both genetic instability and overall DM1 symptoms. That's where we'd like to get to, but that's going to require a much larger international collaborative projects to get the large numbers of well-characterised patients that we would need to be able to do those kind of next-level genetic studies.
00:57:36:17 - 00:58:06:00
Speaker 3 - Professor Darren Monckton
What we're going to do in the meanwhile is again, trying to understand even better how the number of a repeats is changing throughout the lifetime of the individual. To understand again how that's contributing towards disease severity. But again, also anticipating that, as I've alluded to, various drug companies and various other entities are trying to develop drugs that should slow the rate of expansion. In the context of a clinical trial, we'd like to show that they really do slow the rate of expansion of the number of repeats.
00:58:06:02 - 00:58:25:01
Speaker 3 - Professor Darren Monckton
So we're doing quite a lot with seeing how the number of repeats changes over a relatively short time period. So we know over five, ten years, we can see clear differences in the number of repeats, but any clinical trial is likely to be done over a matter of months or, you know, very low number of years, ideally less than one year.
00:58:25:03 - 00:58:56:19
Speaker 3 - Professor Darren Monckton
So being able to come up with techniques that are sensitive enough to see how the number of repeats changes over such very short time periods is quite challenging, not just in Myotonic Dystrophy, actually, but in the other disorders as well. Actually, it's quite possible that Myotonic Dystrophy really might actually present something of a sweet spot, in terms of how quickly the repeats are changing in blood could be a very good disorder from that perspective, in terms of providing a patient population in which the repeats are changing rapidly enough in an accessible tissue, such as blood.
00:58:56:21 - 00:59:21:07
Speaker 3 - Professor Darren Monckton
Again, we've talked a little bit about the challenges of accessing muscle, which is not ideal, is obviously relatively invasive, but it's not impossible. Whereas obviously sampling the brain in Myotonic Dystrophy living patients or in Huntington's disease living patients, obviously is a complete no go. Whereas at least in Myotonic Dystrophy we can get some of those tissues that are being directly affected.
00:59:21:09 - 00:59:38:00
Speaker 3 - Professor Darren Monckton
Again, that's not to obviously ignore the fact that there are major neurological symptoms in DM1 as well, but at least some of the tissues that are being clearly affected are accessible for the purposes of a clinical trial, which is encouraging. Again, we're trying to understand how we might do that.
00:59:38:02 - 00:59:58:05
Speaker 1 - Sytske Lub
00:59:58:07 - 01:00:25:11
Speaker 1 - Sytske Lub
Sort of from birth till death. So that's at which point you've missed the time window for things like introducing a therapeutic measure. And or you wouldn’t be able to organize it in the first place due to the logistics of it. So a very challenging, I suppose, set of disorders then, thinking about triplet repeat disorders in general, which often share similar characteristics, challenging to design trials for and a challenge which I'm sure you'll embrace in your - well I suppose you’re not designing the drug trials - but in helping get to that point
01:00:25:13 - 01:00:56:12
Speaker 1 - Sytske Lub
My last question, in terms of things changing, in terms of the future, will probably be what the clinical management could improve with. What we would want from a service - I know we've mentioned about developing guidelines and standardised audits, but just from your experience, Bob, what would make your care - not saying that your care is bad – but what would make things even more ideal for patients? What would safety net these patients better? Who come to your clinic.
01:00:56:14 - 01:01:25:09
Speaker 2 - Dr. Bob Ballantyne
Yeah, I guess what I would like to see is an increased awareness about Myotonic Dystrophy, you know, just among health care practitioners, but also amongst the social care practitioners. And I think we need to also raise awareness of what resources are available to support those with Myotonic Dystrophy. And I think, what, would follow from that kind of would be an enhanced multi-disciplinary approach in delivering the care, I think, to individuals.
01:01:31:14 - 01:01:53:19
Speaker 1 - Sytske Lub
Very important points. My last question to all of you, I suppose if you have any – no worries if not – this podcast is mostly directed towards young trainees, medical students and the like. Do you have any words of wisdom, any advice, for young people who may be interested in genetics or who might encounter genetic conditions in practice?
01:01:53:21 - 01:02:10:21
Speaker 3 - Professor Darren Monckton
Well, we've talked a little bit about the idea that there are potentially going to be some life transforming therapies available in the next few years. I think we're all really hoping that that is going to be the case, and I think we're all pretty positive that that is likely to happen. That might not be next year, might be five years, but it will come.
01:02:10:23 - 01:02:32:05
Speaker 3 - Professor Darren Monckton
But it's not gonna be done by then. That's that's not going to be: “That’s it, no more needs for genetics”, we all go home and put our feet up. It's clearly going to be massive implications for the delivery. And again, you know, typical course at the moment is that each patient is seen once a year in a multidisciplinary clinic trying to address all of those different things.
01:02:32:07 - 01:02:54:03
Speaker 3 - Professor Darren Monckton
The guys have done a fantastic job in getting those procedures in place to provide the best possible management. Even in the context of a therapy that, again, it's certainly these first generation therapies, if the ones that are in trial at the moment go through – those are injections, probably again going to be every month, every two months, even if it's every quarter of a year, that's four visits per year.
01:02:54:05 - 01:03:17:08
Speaker 3 - Professor Darren Monckton
Whereas at the moment that service is dealing with one visit per year. And before we get into the costs and delivery, there's going to be some implications there. And again, we're going to need to know: are those drugs working? Again, some really fantastic story: now obviously with Spinal Muscular Atrophy the treatment available for that condition is clearly majorly life changing treatment there for that condition.
01:03:17:10 - 01:03:35:24
Speaker 3 - Professor Darren Monckton
But again, that's a lifelong treatment. Very expensive drugs. Patients need to be carefully monitored to know, you know, which, again, when now there are competing drugs, and again, which drug is working best? How are we going to measure that? How are we going to make sure that the right patient gets the right drug? There's going to be a lot for people to do.
01:03:35:26 - 01:03:47:05
Speaker 3 - Professor Darren Monckton
So anybody who's thinking “oh, genetics is done”, that's time to, to try and to find something else that's not yet done. You know this is not going to be done for a long time yet.
01:03:47:07 - 01:03:58:22
Speaker 1 - Sytske Lub
- So then the news from you is, come and join us at genetics. And don't wipe us out just yet. We, we are desperately needed. Fabulous. Mark?
- Yeah. So, I mean, I think whatever specialty people choose, I think genetics and genomics is going to be absolutely unavoidable in the future of medicine. We’re inundated with test requests and email queries every day now. So I think I mean, if people are listening to the podcast, they're probably already making the right moves. But I think whatever you choose, arming yourself with a basic working knowledge of genetics and genomics is going to be important.
01:03:58:24 - 01:04:30:16
Speaker 4 - Dr Mark Hamilton
01:04:30:18 - 01:04:55:07
Speaker 4 - Dr Mark Hamilton
And for those that are interested in the specialty. Absolutely. I love my job. My only complaint is being too busy. And I think anyone choosing a specialty I suppose, just remember, it's a long road. You know, I didn't get my training post first time around. I didn't get my research funding first time round. But if it's if it's a passion and it feels like the right fit for you, then do keep at it.
01:04:55:09 - 01:05:20:01
Speaker 4 - Dr Mark Hamilton
And we, you know, we do need good people and I, you know, I think approaching medicine from a genetic perspective does actually give you a very holistic view of medicine, both for the individual and even families. And really, no part of your medical training up until you come to work in genetics is wasted because it's all potentially relevant.
01:05:20:03 - 01:05:23:24
Speaker 4 - Dr Mark Hamilton
So yeah, I agree. Come join us.
01:05:24:01 - 01:05:27:23
Speaker 1 - Sytske Lub
- And, Bob, any parting words?
- More “come join us at genetics and” [Bob] absolutely [Sytske] “find it interesting.” I think that's great parting words. Fabulous. So thank you so much Bob, Darren and Mark, for your really interesting insights into Myotonic Dystrophy. More information about the condition can be found in the blog, which will be accompanying this podcast, where you can also read more about our esteemed guests.
01:05:28:00 - 01:05:52:04
Speaker 2 - Dr. Bob Ballantyne
Oh, gosh. I'm very reassured to hear that it seems as though, with the advances in the therapeutics, that I certainly would be out of a job by the sounds of it, for quite some time. So I think it's a, it's a fascinating condition. And from my perspective, it's been incredibly interesting learning about the genetics.
01:05:52:06 - 01:06:20:17
Speaker 2 - Dr. Bob Ballantyne
I, you know, I came into this having not studied genetics since about the time the gene was being discovered. So that is – but it's been really enjoyable being able to kind of expand my knowledge through the clinics and learning alongside my colleagues as well. I think it's a fascinating condition, to be involved in providing the care to.
01:06:20:19 - 01:06:39:07
Speaker 1 - Sytske Lub
01:06:39:09 - 01:06:40:17
Speaker 1 - Sytske Lub
Thank you very much.
01:06:40:19 - 01:06:42:06
Speaker 4 - Dr Mark Hamilton
Thank you for having us.
01:06:42:08 - 01:07:01:03
Speaker 2 - Dr. Bob Ballantyne
Thank you.