Peter Crino, MD, PhD

What else do you think about at night about TSC [tuberous sclerosis complex] before you go to sleep? 

 I spend a lot of time thinking about TS, actually. As I’ve looked back on my career and the challenges, I still think autism remains the unreachable goal in TSC, I really do. It changes the landscape and geography for patient care, for patient quality of life, independence, autonomy, and agency. It changes how we have to do surveillance screening with sedated MRIs versus nonsedated. We need to understand why it is that 40% of individuals with TSC develop autism.

In some ways, we’ve heard the concept of TSC as a linchpin disease, that it is useful to understand many other disorders [such as] diabetes, obesity, cancer, etc. I absolutely feel as though the role of the TSC1 and TSC2 genes in engendering autism is something we need to look at. Quite frankly, I think understanding that will have broad potential echoes in the greater autism community. If I think about what single disease burden over the last 25 years of care doing this has altered quality of life for patients, I have to say, I don’t think it’s epilepsy, I don’t think its kidney disease, and I don’t think it’s lung disease.

I think they’re all very serious, and they all need to be treated. But autism and TAND [TSC-associated neuropsychiatric disorders] completely changed the landscape of what a patient’s life is. I want to go after that in the next 5 to 10 years to understand, why is it that nearly 1 in 2 individuals with TSC will have something on the ASD [autism spectrum disorder] spectrum? There’s got to be something about the mTOR pathway. There’s lots of evidence that there may indeed be something about the mTOR pathway. I feel like that’s the next exciting thing, and we haven’t made major strides in that area. Therapeutics have not done much in that area, and so that to me is something I want to focus on.  

I completely agree. I think especially since moving to MGH [Massachusetts General Hospital] and taking care of adults as well as kids with TS, it was profoundly impactful to realize how important and what incredible impact, often very negative and profound, TAND is on people living with TS. 

I agree. And the autism, I think you and I have also always suggested that TS be a model for many things. Study autism and TS, and like you said, learn more about autism in the general population. It’s the same for infantile spasms, same for many other aspects of TS. I agree, there is a lot more to do. I agree with you that where we are now with our understanding and ability to care for TS has changed from when you and I started this. It is going to be great fun to see where things continue to go from here.  

 Well, Pete, thank you very much. I always like talking to you about TS any time, so this was a nice opportunity to touch base on many different aspects of it. I’d like to thank the audience for watching this 

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Elizabeth Thiele, MD, PhD, and Peter Crino, MD, PhD, provide closing remarks on the future treatment landscape of tuberous sclerosis complex.  

 

Final Thoughts on TSC Management 

 For community neurologists, what advice would you give them? I often will see a patient with TSC [tuberous sclerosis complex] who has been followed, as a neurologist, the focus is on the epilepsy, the behavior, the autism, etc. What’s the advice for community neurologists, not to feel that they have to have the burden of taking on all aspects of the care of an individual with TS, but what advice would you give? How would you approach taking care of either a child or an adult as a community neurologist? 

It’s a challenging disorder to follow, you have to keep juggling a bunch of balls in the air at the same time. Unfortunately, many neurologists, community neurologists in particular, end up being the point of service for patients with TS. They often do a fabulous job with the epilepsy, the behavior, and getting them connected for an IEP [individualized education plan], and all that sort of stuff. But they may not think about the evolution of kidney disease or progressive changes in terms of facial angiofibromas and cosmetic effects. In women, as they transition to adolescence, the appearance now and new burden, the new risk of potentially developing LAM [lymphangioleiomyomatosis], often is not acknowledged. The biggest thing I tell community neurologists, and I work with a lot of them, is that the surveillance criteria, the diagnostic criteria, not only are they published, they are on the website for the TSC Alliance. You can go and you can find them, and they’re pretty simple to follow.

They’re pretty straightforward. I also tell them that if they can’t find a center of excellence or a clinic center to go to, to feel free to have patients be seen by either nephrology or pulmonology or dermatology, so you get a multitude of opinions. It does take a village in a lot of ways. We as TSC specialists, we’re used to thinking about all the different organ systems. If you’re a community neurologist, you may not have thought about checking somebody’s glomerular filtration rate recently, or you haven’t thought about checking their pulmonary function test. It’s important to get other opinions to make sure you’re getting in front of the problems that evolve in TSC because that’s how you can stay on top of this disease. 

 I agree. I would promote the TSC Alliance. I can be an expert in tuberous sclerosis or maybe a few other things, but there are a lot of things I don’t know as much about and the right way to provide care for patients. I think having the TSC Alliance so easy to go to, to access information, to access advice, to be connected to peers; it’s an incredible network. I think that it not only improves the lives of people living with TS, but it supports those providing care to people living with TSC.  

We mentioned the turning point and where we need to go. But if you had to say what you consider the biggest unmet needs in TS, other than a cure, a cure would be great….

 What would be on your top 5 wish list?  

That’s a hard one. I think certainly something to get a better sense of the prognostic landscape for any individual. It’s very difficult for any one person to come in and tell them what the next 5 or 10 years hold. It is particularly relevant for kidney disease and lung disease, especially lung disease. So, being able to identify persons at risk with either biomarkers, blood biomarkers, tissue biomarkers, imaging biomarkers, but something that allows you to get a handle on what’s coming. As I said before, I try to lay the groundwork, but it’s all just a series of what-ifs. It would be nice to have some plans to say, “Look, we have this blood test, and it looks like you’re at pretty high risk of developing LAM or kidney disease, etc.” I think a prognostic biomarker would be huge. I think, as you mentioned earlier, the wholesale analysis of babies to identify those at risk for TSC, whether through a whole newborn screening program to assay the way we do for other types of genetic diseases, or in individuals at high risk.

As you mentioned, going forward, that early disease-modifying therapy, even in the first few days of life, and dare I say it, maybe even the third trimester, may have significant alterations in what the long-term outcome is in terms of neurocognitive development. I think that would be a game-changer. To take TSC, as opposed to a multisystem disorder plus autism, for example, to just a multisystem disorder with normal behavior and normal intellect. I think those are very different engagements in terms of patient care. No. 3, I think we’re going to have to look a little more at, even though we have good therapies right now for TSC, there are still some [adverse] effects that are difficult for patients, that limit their wide-scale deployment and their utility. Some people actually have to come off the medicines that we have because of [adverse] effects. 

I think we need a better sense of the next generation of medicines that have fewer [adverse] effects, are more tolerable, easier to dose. I would also include, do we really need to dose medications every day? Could we come at it from a cancer chemotherapeutics perspective, where we do maybe intermittent or periodic dosing? I think that would be fabulous. The final point, which is still largely aspirational, is at the end of the day, tuberous sclerosis complex is a genetic disease. There have been a number of advances in the last 5 years, certainly in the neurological disease space, where we have used gene editing to begin to alter the course of a neurologic disease. Some of them, in the case of spinal-bulbar muscular atrophy, are really serious pediatric diseases, and we’ve changed the course.

We have to think about how gene therapy might be a tractable option in TS to be able to either mitigate or indeed reverse the effects of the gene mutations and undo what nature has done in terms of gene mutations. I think that’s very aspirational, it’s almost a bit of science fiction. The truth of the matter is, in the last 5 years, we’ve made progress in gene editing, in altering human phenotypes and diseases, and improving lives.  

 I completely agree. I get that question a lot from patients because, gene therapy, they read about it in different disorders. There’s a lot of excitement now, like in Dravet syndrome with the ASO [antisense oligonucleotide] trial going on, and will those be possible in TS? I’ve had this discussion with some people in the gene therapy industries who view TS as a little different than spinal muscular atrophy. 

I think if you look at the burden of the possibilities, the various spectrum of involvement of TS as well as the years of surveillance, if you did have gene therapy, not only could you improve the lives of people living with TS, probably dramatically. But you could also probably end up saving health care dollars because you wouldn’t be doing all the MRI scans, necessarily, etc. I agree, it’s aspirational, and I think many of us hope that there will be a possibility for it someday. There clearly is with these other disorders that have trials in place that show promises, that the future is bright.  

 What you said about prognostication, I think that also would be huge. If I was counseling a young man or a young woman about family planning, who had TS, that’s a very difficult aspect of what we do. If I had TS and was mildly affected, right now no one would be able to promise me my child would be as well. Maybe, if we can do preventive therapy if we know a baby’s going to have TS, and we modify, but I think that’s also difficult. As we know, to date, the genotype-phenotype correlations we’ve all tried to hunt down and pick up so far haven’t been that clear and helpful, other than TSC2 [mutations] often being more severe than TSC1.

I’d like to thank the audience for watching this 

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Advice to community neurologists for the optimal care of patients with tuberous sclerosis complex and future directions for TSC.  

Future of TSC Management 

The other thing you and I think about, especially you, is transition. It’s a hot topic in neurology and all medical fields, as people with disorders are transitioning into adulthood. For a disorder like tuberous sclerosis [TS] which is not just the brain, not just treating epilepsy, but many different things, how do you approach that? You say you transition people from adolescence into adulthood. What are your recommendations for the optimum way to do that for an individual with tuberous sclerosis? 

 That’s a really important question. I have been doing this for a lot of years. Whether I was ahead of the curve, I don’t know. Maybe it just worked out that way. There are a couple of fundamental points to acknowledge. No. 1 is that transition is not an event; it’s a process. It takes time to transition people. When you talk to families, you have to realize that many of them have had superlative care by pediatric neurologists, primary care pediatricians, and other pediatric specialists in a family-centered way with lots of infrastructure and support systems and resources. That’s been a wonderful experience for them, and they’ve had lots of great care.

During the transition to adulthood, adult medicine by its nature is less family oriented and more patient oriented. The idea that the individual will gain some more autonomy for their care in terms of responsibility, medications, making appointments if they’re able. If they have intellectual challenges or autism, then that’s still going to be figured out. The third issue is understanding that you’re going to have to gain the trust of the family and that you’re a new person. I have a lot of time where I just sit, and I explain, “I know this is a transition. You don’t know who I am or what I’m going to, so we’ll work together. I’ll show you that I can do this and get you through the process.” Fourth, becoming an adult means that there are other comorbid diseases that just happen in human beings that have nothing to do with tuberous sclerosis. High blood pressure, diabetes, cancer, and heart disease just happen to people, so being aware that not everything is tuberous sclerosis and that you will still need surveillance for other things.

The fifth point is the ability to understand that a critical part of this is that the caregivers are aging out. Many caregivers who were younger, enthusiastic, and energetic, as they age into their sixth, seventh and eighth decades of life, don’t have the ability anymore to care for a 40-, or 50-, or 60-year-old adult with TSC [tuberous sclerosis complex]. Other things come in, such as advanced directives, estate planning, moving to group home settings, and getting in-home health aids. 

Those are the things we talk about because a common question I get from parents about their child is, “What’s going happen to them when I’m gone? Who’s going watch out for them?” It’s a very poignant question. It’s a very important question. In my TSC center in Maryland, we have a fabulous social worker who does a lot of these engagements with patients and has these conversations. It’s a transition. We stress that it’s not, “You’re changed now.” It’s not a day thing. It takes some time. Acknowledging that we’re taking care of an adult, not a child. A 27-year-old is an adult, and they have autonomy and agency and want to be independent. I have to recognize that and acknowledge that, and then work together to get the long view of what the care is going to look like. 

 This is something that’s changed while you and I have been doing this. I remember many years ago, at an adult TSC family conference, talking to many families whose children had been followed when they were children through TSC centers. Then they aged out, and 1 woman spent 3 years trying to find a care provider for their child because these are not easy patients, with multisystem disorder, etc. With the efforts of the TS Alliance, in part, is the strength. That’s the voice of the patient community, and we have more centers in the United States with experts in the care for adults with TSC. 

That’s very important. It must be very frightening, and not only for my patients with TS but also my other patients with pediatric epilepsy. As they age, it’s a different center of family-based care. In pediatrics, it’s the parents, the patient, and the physician. But in the adult world, for some of our patients with TS, it continues to be that, depending on if they have disabilities. For others, it’s a different adult-to-adult care-provider relationship.

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Expert neurologists and epileptologists share best practices for transitioning a patient with TSC from adolescence into adulthood. 

TSC: Transitioning From Pediatric to Adult 

 A frustration that all of us in the TS [tuberous sclerosis] community still have is that there is still a lack of awareness and understanding of this order in the medical community. I know we’re all working hard to try to improve that. Even if we have the most effective treatment, it’s only going to help if we know a person has TSC [tuberous sclerosis complex]. We looked at this several years ago: What leads to the diagnosis of an individual having TSC, and what were the missed symptoms? When we looked at this, epilepsy was the most often missed symptom, which was disappointing to me. I was looking at a lot of adults who were having seizures as children. There were no MRI scans, and there was no understanding about TS.

The other thing that’s been exciting over the past 20 years is the emergence of all these TSC clinics and programs. You and I several years ago discussed the role of TSC clinics and the concern if you don’t have access to a clinic? How do you view TS care? Obviously, we both direct TSC clinics. How would you advise either our colleagues who don’t have access to a clinic or patients who don’t have easy access to a clinic? What advice would you give them? 

It’s a very challenging question. It comes down to access to health care. That applies to both urban and rural areas. Lots of individuals have been evaluated for seizures, and TSC has never even been on the differential diagnosis. Sadly, I’ve seen more patients than I care to who have been evaluated. I even had scans of their organs and never had a diagnosis made. No one closed the loop. It’s a sad thing. We really have to push the awareness. The Tuberous Sclerosis Alliance has done a huge job to build awareness. For patients, it’s important to be your own advocate and realize that knowledge is power. The ability to explain to your physician, “I have this genetic disease, and these are the features.” Go to the website, print the diagnostic criteria, print the surveillance criteria, and say, “This is what I need to have done.

At the end of the day, that’s very important. The nice thing about the TS Alliance is that if you’re a patient in the United States, Canada, or even worldwide, you can access the alliance and say, “I need some help. Is there anyone who can help me?” You and I and a lot of our colleagues do tele-evaluations and review records for patients. That’s the other way to do this. Finally, figuring out a network now that the pandemic has taught us all how to do telemedicine visits. The future of a telenetwork to connect people from around the globe with TSC is going to be the way of the future. That’s the way we’re going to get in underserved areas around the world. That’s the way we’re going to get the message out. Even in the United States, lots of people in designated rural areas are never evaluated for TSC. It’s unfortunate because it leads to patient morbidity. 

You and I have been very involved with the TS Alliance, and now you’re chairman of the board. Working with that organization—I was on the board for 12 years—taught me how important that type of that organization is for patients and families living with these disorders. TS Alliance is also very important for our colleagues in the medical field because it is a source of information. Not everyone can be an expert about everything, and there might be a neurologist who has 1 or 2 patients with TS, and that’s a resource to easily go to. With your role with the TS Alliance, where do you view it leading to further research and further awareness of TSC?

We’re at an inflection point, for sure. In TSC, we’ve done what many rare-disease organizations have not been able to do but still aspire to. We’ve gone from a group of patients that this diagnosis was around in the late 1800s. We have a century’s worth of clinical experience. In rapid fire over several years, we identified the causative genes for this disorder. In a bedside-to-bench strategy, we immediately did lots of funded research—some by the National Institutes of Health, some by the Department of Defense, some by the TS Alliance—and tried to understand what these genes do. What pathways do they function in? Amazingly, we were able to come up with actionable areas that we could treat with existing medications and rapidly proceeded to clinical trials. And then wow, here we are with FDA approval. 

That’s a remarkable story of bedside to bench and back to bedside. That’s all great, but we haven’t cured tuberous sclerosis. This disease is still here, and people still are suffering with epilepsy in tandem kidney disease. The next generation, the inflection point, is taking where we are, expanding on our knowledge, looking at more patients through a natural-history database, looking at tissue samples from patients in a biorepository, and using a preclinical consortium, which has existing mouse models to test in a very high throughput way different compounds that might affect the features of TSC with an eye toward eliminating autism, tuberous sclerosis, epilepsy, and lung disease in 5 to 10 years. Those are the goals in the next 10 years that we need to be aiming for. 

 I completely agree. You and I have known each other for over 20 years, and I’m thinking of the journey and the things we’ve learned. I’m thinking about how there are still unmet needs, there’s still a lot going on, and there’s a lot of more work to do. 

Elizabeth Thiele, MD, PhD, and Peter Crino, MD, PhD, comment on unmet needs and challenges in treating tuberous sclerosis complex. 

Peter Crino, MD, PhD

Articles

Final Thoughts on TSC Management

Future of TSC Management

TSC: Transitioning From Pediatric to Adult

Unmet Needs in TSC Management