Mark Benfield, MD: Welcome to tonight's webinar, in which we're going to talk about exploring the extrarenal manifestations of cystinosis. As a moderator, I'm Mark Benfield. I'm a pediatric nephrologist for many years with the University of Alabama at Birmingham but more recently have been in a private practice of pediatric nephrology and have had a career-long interest in cystinosis, and I'm excited to hear what all of our other folks are going to have to teach us tonight. And I'll let them introduce themselves.

Bradley Miller, MD, PhD: Great. So, I'm Brad Miller. I'm a pediatric endocrinologist at the University of Minnesota and M Health Fairview Masonic Children's Hospital. In my 21 years at the University of Minnesota, I have taken care of children with cystinosis, more on the growth and thyroid side. And we'll be talking about endocrine problems.

Reza Sadjadi, MD: I am Reza Sadjadi. I'm a neurologist at Mass General Hospital in Boston, and I have been involved in a series of clinical trial readiness studies in myopathy and dysphagia in patients, adult patients mostly, with nephropathic cystinosis, which has helped us learn a little more about the disease, and I'm excited to learn from my colleagues and you guys.

Adam Stein, MD: I'm Adam Stein. I'm an adult gastroenterologist at Northwestern in Chicago, Illinois, and I see people who have cystinosis and help with all of their gastrointestinal symptoms and signs, and we'll talk more about that in a little bit.

Mark Benfield, MD: So, let's start by talking a little bit about what cystinosis is and the disease progression of cystinosis. As you may know, cystinosis is a very rare autosomal recessive lysosomal storage disease. It involves a mutation in the cystinosin gene, and as opposed to most single-gene disorders, cystinosis has more than 100 gene variants that have been described to be associated with this disease. So not only is it very rare, there's a lot of gene variants, which make any kind of genotype–phenotype association very difficult. But when you have a gene variant of the cystinosin gene, there is a problem with the transport of cystine out of lysosomes. Proteins are pumped into the lysosome, are broken down into their amino acids, but the cystine cannot get out, so it accumulates. As it accumulates, it tends to crystallize, and those crystals injure the lysosome, the cell that the lysosome is in, and, ultimately, the organ that that cell is in. So it causes organ damage throughout your body.

It's very rare. There are only about 20 new cases per year diagnosed and only about 500 to 600 active cases in the United States. Probably only a couple thousand cases in the entire world. It's likely that this is a bit of an underestimation because of diagnosis problems, but it's a very rare disorder.

Mark Benfield, MD: It tends to present in the first year of life. The kidneys are the first and the worst organs to be involved, and it usually presents with Fanconi syndrome, with injury to the proximal tubule of the kidney, causing massive losses of fluids and electrolytes, which lead to growth failure and rickets.

The diagnosis is usually made in the scenario of Fanconi syndrome, either with a white blood cell cystine level, or now a genetic test is available, or the ophthalmologist sometimes will make the diagnosis with a slit-lamp examination that sees crystals in the cornea. As I said, the kidneys are the first and the worst organ affected, and damage starts early and occurs throughout life. Eventually, almost uniformly, patients with cystinosis will develop renal failure and ultimately require kidney transplantation.

Mark Benfield, MD: As the cystine accumulates in cells, it causes kidney damage, but it causes multiorgan damage, and one of the problems with cystinosis is that this happens slowly and almost completely silently. It doesn't cause pain. It doesn't cause anything that the patients will recognize until they have enough damage to cause organ dysfunction, and at that point, it's very difficult to do anything about treating it.

It's important to remember that this is happening throughout the body, because, even after renal failure and kidney transplant, the cystine continues to accumulate in other organs of the body and continues to cause injury. It can cause multisystem injury. In the neurologic system, there are very well-defined neurocognitive deficits. Some patients will develop intracranial hypertension. There are severe disorders with seizures and recurrent strokes and many mental health challenges.

Mark Benfield, MD: As I said, in ophthalmology, corneal crystals are very common, but if untreated, cystinosis can lead to retinal blindness. There are many GI problems that we'll talk about later with Dr Stein, but they include nausea and vomiting, stomachaches, difficulty with swallowing, dysmotility, and hepatosplenomegaly. There are a multitude of endocrine problems that Dr Miller will talk to us about, including growth failure, hypothyroidism, diabetes, and fertility issues. But the really severe problems late in life include muscle weakness and muscle atrophy that often lead to difficulty with breathing and aspiration and are the most severe of the long-term problems with cystinosis.

Mark Benfield, MD: Because it's a multisystem disease, it requires multispecialty care. There has to be involvement of a transplant team, both a pediatric and eventually an adult nephrologist, ophthalmologist, neurologist, endocrinologist, gastroenterologist, geneticist. Many therapists, physical therapy, speech therapy, occupational therapy, and a list of other people. It takes a whole team of people to provide care for this multisystem disease.

Mark Benfield, MD: And our first expert is going to be Dr Sadjadi to talk to us about the myopathy in cystinosis.

Reza Sadjadi, MD: So, myopathy is considered rather later onset of complications associated with cystinosis. In brief, it can be mild, but it can also be life-threatening as it progresses. It typically begins in distal muscles in the upper and the lower extremities and progresses more proximally over time. In the meantime, patients may have some degree of difficulty swallowing. There is some association between the degree of weakness and also degree of swallowing difficulty, but it is really well possible in some patients that they may have swallowing involvement disproportionate to the degree of weakness in their hands. Similarly, patients may have breathing difficulties. This has been mainly in the pattern of breathing problems related to muscle weakness, either diaphragm and also other accessory muscles involved in breathing.

Reza Sadjadi, MD: We don't exactly know the real pathophysiology causing myopathy, although cystine accumulation and crystal accumulation in the endomysial tissue has been proposed as one of the pathomechanisms for this condition. We are not entirely sure that that only explains the myopathy, and there has been some hypotheses that the mutation itself may carry some myopathic properties leading to the complications involved in muscles.

Reza Sadjadi, MD: So, myopathy, as we discussed, starts typically more distally and progresses more proximally. It affects upper extremity more than lower extremity; it affects distal muscles more than proximal muscles. Sometimes patients don't come as their primary chief complaint as the weakness in this muscle or that muscle. They may come with having difficulty handling eye drops or pills, difficulty opening jars, buttoning. Sometimes they may not volunteer that information, and it may come with more qualitative time spent with the patient that these questions or these concerns may raise. Swallowing and breathing typically affect muscles, voluntary muscles, at least from the oropharyngeal perspective of swallowing, that we know of, get affected. And this is an area that we share a lot with our gastroenterology colleagues, and Dr Stein will touch on, I believe, too, and respiratory muscle involvement, which can be very severe and life-threatening.

These both together can actually increase risk of aspiration and unfortunately death, which has happened to many patients in the past.

Reza Sadjadi, MD: So, what nephrologists can do to play a more active role to screen for these symptoms. It's not fair to expect everybody to do the full neurological exam on each individual patient. So, the most important thing would be to know the common patterns of what gets involved. Maybe some screening questions that would be incorporated in follow-up of these patients, including, let's say, many of these patients need to use eye drops, they have difficulty using their fingers to open their eye drops; pills, handling the pills; how many times they drop things. Rather than asking specific questions about strength, it would be good to ask functional questions related to activities of daily living, mainly with the fine motor activities of the upper extremities.

Reza Sadjadi, MD: How about swallowing? What are the questions that would be helpful? Again, if you ask patients, as we did in our patients, “Do you have difficulty swallowing?” Most patients said no. But when you ask them, in the studies that we did, we ask them that “OK, does it take longer for you to finish your meal?” The answer was yes, almost most of the time. “Do you have difficulty with excessive saliva? How often do you choke on food? Have you noticed any change in your voice quality?” So, these are common questions that we ask, and there seems to be a pattern of involvement with these questions related to the quality of life, even more than activities in daily life, related to eating. And how about the respiratory involvement, and that becomes more complicated because these symptoms are also common in general population.

Reza Sadjadi, MD: Questions that we often ask about excessive daytime sleepiness or fatigue, questions that we typically associate with sleep apnea. These questions are more important than asking specifically about shortness of breath, “Do you have difficulty breathing?” So, the questions asking “Do you feel fresh when you wake up in the morning? How often do you fall asleep in front of the TV? Do you often get chest infections?” These are also very important questions. Adding all these together, maybe adding few questions related to the operations of function, swallowing function, and breathing function, can help detect probably most patients who have even mild difficulty with these domains.

Reza Sadjadi, MD: So, how about the management? So, the management is currently supportive.

Reza Sadjadi, MD: And how about physical activity lessons that we have learned from other muscle diseases that we recommend that maybe it is beneficial for patients to have some degree of physical activity. Moderate degree of physical activity is often helpful, helping regenerating muscles. Swallowing difficulties, symptomatic management starts often with video fluoroscopy studies and swallow studies. These studies are helpful, one, to identify the problem, and second, if patients have some sort of exposure to their own swallowing mechanism, it is possible that they learn some tricks from the speech pathologist that are good to know how to prevent some of the accidents that can happen. For instance, holding the neck in a certain position or when to know when there’s a problem.

Reza Sadjadi, MD: So, to provide some sort of an indirect CBT, cognitive behavioral therapy, to be able to handle the situation, which can be lifesaving at times. And how about the respiratory? Do we need to measure breathing every time the patients come in? A mini PFT? Maybe, maybe not. But the screening questions, whether patients would benefit from some BiPAP or CPAP, could be helpful. Sleep evaluation could be helpful, as well as some possible respiratory sort of interventions that could strengthen some of the throat muscles that can help potentially avoid choking or get out of some minor, at least, incidents. There is some evidence and research on that that has been shown that actually it can help force and help patients push the food out if it goes the wrong way.

So with that, I think I would just connect the upper part of swallowing mechanism to the lower part of swallowing and pass the torch to Dr Stein.

Adam Stein, MD: Alright. So, we've done surveys looking at people with cystinosis and whether or not they have any gastrointestinal signs or symptoms, and pretty much everybody with cystinosis will have something going on in their gut. And it can range from the top all the way down to the bottom.

Adam Stein, MD: So, we've already heard about the swallowing difficulties, dysphagia or just the oropharyngeal motor issues that can happen, but a lot of people have just nausea, vomiting, discomfort in their upper abdomen. When they eat, they just don't feel good, leading to them not wanting to eat.

Adam Stein, MD: Reflux is very, very common, and that not only is symptomatic reflux, but also damage from acid, whether it's ulcers or just gastritis. And those ulcers can become problematic to the point where you have bleeding. And eventually, damage to the lining of the stomach and the nerves can lead to gastroparesis, meaning the stomach just doesn't empty well.

And all of these things come together in the form of needing a feeding tube, whether it's a tube that goes directly into the stomach, or what's called a G-tube or gastrostomy tube, or a tube that either bypasses the stomach and goes into the small intestine or directly into the small intestine itself.

Adam Stein, MD: A lot of people with cystinosis who have tubes use it for extra fluid and nutrition, but some people also use it to take medications since cystine-depleting therapy can be tough to take for many of our patients. Going down the GI system, the next stop is the small bowel and the connections to the liver and pancreas. And the liver can definitely be impacted; you can get elevated liver tests, so your AST, ALT, alkaline phosphatase. Your liver and spleen can be enlarged, and you can also get portal hypertension from that, meaning the blood flow back to the heart can slow down while it traverses the liver, causing backup of blood, leading to problems with varices and things like that.

Adam Stein, MD: The small intestine can be involved with bacterial overgrowth, leading to bloating and problems with peristalsis. And then the colon can be involved, the large intestine, where you can get anything from constipation to diarrhea, but you can also get bowel blockages and ulceration. We have had patients who've developed ulcerative colitis and Crohn's disease, as well.

Adam Stein, MD: So, all these things happen and are a result of several different factors. Mainly, there's 3 buckets. One is the disease itself, with cystine crystal accumulation causing damage to either the lining of the intestine, the mucosa, the nerves or muscles leading into the intestine. You can also get GI issues with the kidneys, so Fanconi and acid-based disturbances can lead to people just not feeling well and having various issues with their gastrointestinal system. And then finally, and one of the more common reasons why people have signs and symptoms, are the medications that they take. So cystine-depleting therapy, again, can cause problems with nausea, bad breath, things like that, and can also lead to ulcers and changes in pH. But then immunosuppression and other medications that they might take for their kidney disease. There's lots and lots of different things involving the GI tract that we can go through. This webinar is not designed to go into individual things since there's so many, but I'm happy to answer questions in the chat at the end. There's also a review that has been published in Pediatric Nephrology in the past year, which is a good reference that goes into all these different things as well.

Adam Stein, MD: So, with that said, really the mainstay of taking care of the GI system is to actually assess it and to talk with your patients about what's happening in their gut, which is harder than it sounds, especially when you have all sorts of other different issues that you're dealing with. And then you have a kid or a young adult who really probably doesn't want to talk about their gut. They don't want to talk about their bowel habits, or their nausea, or trouble swallowing, and things like that. But asking, keeping it part of your routine review of systems is important, and then if there is anything that comes up, or even if your patient’s doing well, involving a gastroenterologist is always a good idea because, inevitably, something will happen.

Adam Stein, MD: So again, regular symptom monitoring and then monitoring the disease activity; getting routine lab tests, including liver tests; and then monitoring nutrition status. A lot of people aren't taking in reasonable nutrition, so making sure their vitamin and mineral levels are good.

Especially looking at iron, which can be a contributing factor along with the kidneys in terms of anemia; and then vitamin A, which can cause further vision changes; and then vitamin D, which is important for bones and immunity and other things.

Adam Stein, MD: And again, managing GI complications does require multiple modalities, not only talking with a gastroenterologist but even adjusting medications. You don't want their GI symptoms to be the limiting factor of why people don't take their medications. We see this with just halitosis in general, bad breath. People stop taking their medications because of that. But really working with people to adjust things so that they are getting the treatment that they need but also dealing and treating their symptoms. I will say one point on dysphagia, or trouble swallowing, one easy thing to do in clinic is have your patients eat or drink, a simple sip of water or a bite of food, and just watch them. If their swallowing looks OK, it's pretty easy to tell, great. But if their swallowing doesn't look OK, if they're doing multiple maneuvers, having to do many swallows, things like that, that's a problem. So again, some of these little techniques and tricks, they don't take too long but will be very helpful in figuring out what modalities we can utilize in terms of helping your patients out with their symptoms and treatment.

Adam Stein, MD: And with that said, I will turn it over to Dr Miller.

Bradley Miller, MD, PhD: Excellent. So cystinosis has profound impacts on the endocrine system, and I think it's important to recognize that most patients with cystinosis experience stunted growth and delayed development in maturation. As a pediatric endocrinologist, growth therapy, growth evaluation is really key. So looking at the growth chart, making sure that if they're falling off the growth chart, especially compared to where they should be based upon their midparental target height, how tall they should be, is something to look at. Kids with cystinosis need growth hormone therapy at less severe renal impairment than children with other forms of renal disease.

Next, we want to think about hypothyroidism because of the cystine damage to the thyroid, both in males and females. Primary hypogonadism in males. Both of those are the most reported endocrinopathies among adults with cystinosis, but we can also start to see them show up in kids.

Bradley Miller, MD, PhD: The majority of male patients are infertile due to damage to the testicle with primary hypogonadism and then azoospermia. And as Dr Benfield said earlier, it's that crystal damage to the tissues. Like the kidney, the testicle is being damaged from those cystine crystals. Female patients have normal fertility but are considered at high risk of pregnancy-related complications. And then there's also the risk of diabetes mellitus requiring insulin therapy.

Bradley Miller, MD, PhD: So, due to the varying reproductive health considerations, we have to think about what to do differently between males and females with cystinosis. Obviously, in males, we're going to be monitoring growth. We'll look at are the testes growing as they go through puberty to show us that they're progressing through puberty appropriately. We're assessing thyroid function, blood glucose, A1C, bone age to see if they've got adequate time to grow bone metabolism, bone health issues. We want to look at blood tests for gonadal function, which would include the gonadotropins as well as the testicular function markers.

Bradley Miller, MD, PhD: And then as boys get older, we want to consider semen analysis to help understand and evaluate their fertility, which would also be the case, obviously, for adults. And then for females, we're less concerned about their pubertal progress because they may have completely normal ovarian function, but we still want to look at growth and thyroid and risk for diabetes and bone issues. And then we do want to track to make sure that their puberty is progressing appropriately and the hormones to look at if there are concerns. AMH is a great marker of ovarian reserve to say what's their fertility potential, so there may be circumstances where you would do that for them as well.

Bradley Miller, MD, PhD: So, when we think about fertility management options, we really want to start offering and discussing it early. Male patients with cystinosis, we want to have an early discussion and counseling with the caregivers about the possibility of infertility, which is a significant concern in men with cystinosis. We may need to consider testosterone or other alternative testosterone therapies. We want to consider fertility preservation, such as sperm cryopreservation or other assisted reproductive technologies, and make sure we're referring them to the appropriate specialists, whether it's a fertility, urology, or endocrinology individual. And although cystine-depleting therapy does not negatively affect male fertility, it does not restore it, and so I think that's an important component.

Bradley Miller, MD, PhD: For women, we still need to have routine discussion and counseling on fertility and reproductive health and contraception, but it's more focused on the risks for pregnancy. So, we need careful consideration and planning for pregnancy, particularly around their renal function, medication changes, and the risk for preeclampsia.

And then for thyroid, because of the increased risk of hypothyroidism in cystinosis, we want to make sure that women who are thinking about being pregnant or are pregnant are getting adequate thyroid therapy because it's really important in the development of the baby's brain. We have to adjust medications when women are pregnant, and we also have to make sure they're seeing the right specialists for fertility, endocrinology, urology, or OB-GYN, depending upon the circumstance.

Bradley Miller, MD, PhD: And then there's an unknown risk of cystinosis disease progression during pregnancy while patients are not taking their cystine-depleting therapy. Pregnancy outcomes do depend on renal function, and pregnancy is not recommended within the first year of renal transplantation. So, those are some of the things that we talk about with our adolescents and younger patients with cystinosis as well as those that are transitioning into adulthood. And with that, I'd like to transition back to Dr Benfield.

Mark Benfield, MD: So, now we want to have just a brief panel discussion with our specialists.

I want to start with a question for the panel. In your opinion, what do you think is the #1 thing a nephrologist should remember about the extrarenal complications that you manage? And we'll start with Dr Sadjadi.

Reza Sadjadi, MD: Great question. I think from my perspective, I briefly touched on this. I think the patients, especially when the symptoms are mild and in the slowly progressive disease, they may adapt really well to the symptoms and adjust. They may not have a lot of complaints, or they may not be aware of their deficits. But these deficits, especially something related to swallowing, for instance, or muscle weakness or respiratory weakness, can potentially be dangerous. And who knows, maybe an earlier intervention can prevent a lot of further complications. So, I think it would be important to have some sort of screening for early symptoms and making a referral early on, or making patients more aware, not necessarily making them anxious, but more aware of potential implications and options.

I think I would emphasize the role of, I saw that neurologists were not popular in the list of like patient referral, here at least. But I think speech pathology and pulmonology referrals, I think, early on would be more appropriate. Neurologists typically will say that “OK, examine the patient. You have this deficit,” but they don't do much. But the speech pathology and pulmonology, I highly recommend.

Mark Benfield, MD: OK. What about you, Dr Stein; what are your thoughts?

Adam Stein, MD: I think the biggest thing is, and I'm going to sound like a broken record, I'm going to say this quite a few times, but don't go in alone and try to treat your patients’ GI symptoms. Find a gastroenterologist who's willing to work with you and learn. Chances are there’s really probably not any in your area that are too familiar with cystinosis. But trying to find one and then sending your patients to them so you don't have to be the one managing their GERD, their bad breath, their problems swallowing, diarrhea, constipation, whatever it is.

I don't manage dialysis. I would hope that nobody would expect me to do so, nor would I expect a nephrologist to manage the gut, but we're certainly here to help. The other thing is, it's really hard to get people, especially kids, to talk about their gut. And, you know, we do this all day every day, and we're pretty good at getting information out of people. So if your patient’s not willing to talk about their GI system, it's OK, just send them over to a friendly GI.

Mark Benfield, MD: Great. Alright. Dr Miller, what about you?

Bradley Miller, MD, PhD: I have one for pediatric nephrologists and one for adult. And so, on the pediatric side, I think it's important to think about growth, and, if part of your nephrology practice doesn't involve growth hormone treatment, feel free to involve the pediatric endocrinologist in that realm. And then for both the pediatric and the adult teams, I think thyroid is an important thing and an easy thing to be monitoring and replacing if there's a problem. But the fertility is really a huge impact on patients. And so how you approach it, that you approach it, is really important that it's talked about. And if you don't feel comfortable talking about it, definitely get them to an endocrinologist or someone else who will have that conversation.

Mark Benfield, MD: Great. I want to talk a little bit about what you guys think is the best practices that you have found helpful in working with, collaborating with the nephrologist. I think you talked about it a little bit, but expand on what problems we should be screening for, when we should send them to see you. What are the best practices that you've seen that we either do well or that we need to do a little better? How about starting with you, Dr Stein?

Adam Stein, MD: I think the biggest thing, again, beyond partnering with the gastroenterologist to help with all their gut stuff, is the feeding tube aspect of cystinosis. Feeding tubes, for some people, are essential to get nutrition, to get their medication, things like that. They're pretty straightforward to manage, but the problem is most people are going to have an issue with their tube throughout its lifespan. And the worst thing is seeing somebody who's had a feeding tube for 10 years and it's never been replaced, and it just looks disgusting.

So again, just like the gut, don't go in it alone. If they have a feeding tube, getting them to somebody to see, to help manage the feeding tube, replace it from time to time, things like that, I think will go pretty far, not only with your patients, but with you and your team.

Mark Benfield, MD: Great. How about Dr Miller?

Bradley Miller, MD, PhD: As a pediatric endocrinologist, again, growth and thyroid and puberty are our main focuses. I think most nephrologists aren't comfortable with the puberty assessment, not something they do typically, and it's a huge part of how kids are growing. So, making sure that we're connected with the team once we're there. The collaborative approaches, I think these days it's a little easier with the electronic medical record if you can't get directly in front of somebody. But man, that phone call really is the best way to connect with folks to say “This is the problem I'm worried about, and can you see him sooner rather than the twelfth of never.”

And then in the adult population, I think it can be a bigger challenge because endocrinologists are frequently not involved in thyroid issues and bone issues. Many of those things are taken care of by the internal medicine team. So again, trying to make sure that what you're connecting with is something that is in the alley of things that they're going to be wanting to participate in.

Mark Benfield, MD: Great. How about you, got any thoughts, Dr Sadjadi?

Reza Sadjadi, MD: They’ve left me with very few answers, but I can tell you more from a neurology perspective. Every disease that we see in neurology is rare or ultra-rare. So, I think it would be very difficult to have to expect nephrologists or any other specialist to remember everything about every rare disease.

Highlighting the importance of having some of the efforts that I think Dr Miller and Dr Stein both have worked on in terms of having guidelines, I think that would be helpful in terms of knowing what are the options and what is feasible to do and what's not feasible to do. You're seeing a patient in a clinical setting; nobody can help you to do like the full exam and full evaluation of everything, so any efficient way of screening patients, communicating with them, and to be able to utilize the resources. I think at least from my experience, from the diseases that we deal with, I think that would be something that would be helpful in the nephrology world, too, for ultra-rare diseases.

Mark Benfield, MD: Dr Miller, at what age do you generally suggest that we begin discussing the impacts of cystinosis on fertility? What’s the right age to begin talking to families and patients about that?

Bradley Miller, MD, PhD: So, I think it's really important that you talk about it when kids are even infants or toddlers to just make parents aware of it. They will not remember it, 100%. So as kids get closer to puberty and we're talking about how kids are going through that process, it's another point where it reminds you to start talking to the parents about it. And when a child becomes an age where you'd be talking about puberty to them, I think it's important to begin the conversation of how puberty might be affected and how fertility might be affected. And then as they're transitioning into the adult world, we keep trying to hit it multiple times during puberty, but most of the time, kids are like don't want to talk about it, don't want to do anything about it, but when they're 17 or 18 and getting ready to go off to college, it's suddenly on their radar when it wasn't before.

So if you're meeting a new adult patient, I think it's part of that conversation as well to be like “What things have you guys discussed? What options are you aware of?” And in men, because of some of the damage to the vas deferens that may be irreversible, there may be limited options for treatment. And so, I think that's an important thing that we talk about of like “Here are things that we could do, but unfortunately, here are other things that may not be successful,” and talking about that with the families.

Mark Benfield, MD: Is there a general age that you think, if cryopreservation is something the family is interested in, is there an age that we got to get that done or it's going to be too late?

Bradley Miller, MD, PhD: Probably the teen years where you're starting to make sperm, probably 13, 14, 15, somewhere in that range depending upon the child. And with cystinosis, puberty may be delayed, and so that's some of the things that we want to think about as well. So right in that age, but if they're not showing any signs of puberty, it's too early. So, I think that's part of the equation.

Mark Benfield, MD: Right. Alright, another question that's here for Dr Stein is how do we manage the constant nausea and vomiting?

Adam Stein, MD: That's a huge challenge, and I don't think there's a one-size-fits-all solution. I think part of it is looking at medications and seeing what medications might be causing nausea and trying to titrate those medications. And then the other is looking at the esophagus and stomach in terms of how it's functioning, making sure that you understand if the stomach isn't emptying well, getting a gastric emptying test to look for gastroparesis, which can happen in cystinosis. But ultimately, it's tough. It's one of the tougher things to deal with, but part of it is medication.

And then part of it is just understanding the anatomy in terms of how it's working or, in fact, not working. And then finally, if nausea is significant, working with your gastroenterologist and potentially a neurologist to look for more nerve-type, central-type, nausea. And if needed, this is where a feeding tube might come into play, either directly into the stomach or bypassing the stomach. Feeding tubes tend to be looked at very negatively, especially in kids, but we've got good feeding tubes now that are low profile. You can't tell if people have one or not, and it can really take the burden of trying to get medications and nutrition down, to potentially help relieve some of the nausea by using the feeding tube. But it's tough, and there unfortunately isn't a one-size-fits-all answer to that.

Mark Benfield, MD: So, Dr Sadjadi, another question that's out there is at what stage are patients typically sent to see you with the myopathy, and is that the right stage? Do you wish you had seen them sooner?

Reza Sadjadi, MD: It's a very good question, and sometimes it's difficult to detect when symptoms start. The question, for us, is that when did everything start, or when did the patient become symptomatic enough to see us? Then we can do something about it. I think the answer is in the function. Does it impair patients’ function, whether pediatric or adult, mostly adult? If there is notable, sort of, effect on activities of daily living and quality of life related to weakness, then it may be worth visiting, seeing patients earlier. But the sooner is not always the better, especially when you're dealing with a lot of other complications.

I understand that there are a lot of nutritional issues that could also cause neuropathic or myopathic complications earlier on, and I would sort of wait until the patient is slightly more mature, I would say. Having said that, most of the patients I have seen in my work, which is mostly clinical trial readiness study and research, were adults, so the younger patients that I've seen were 16 years old. But talking to families, they always talk about some other complications and including like change in the voice, maybe difficulty swallowing. That is a more complicated topic than what we see in adults. Adults are easier targets in terms of figuring out what is wrong with the muscle or which muscle, and in pediatric, that becomes a little bit more complicated. But I think just looking from like adult experience, given that there are things that we can do, I think I would just emphasize or put more emphasis on patients who are having symptoms that are affecting their quality of life or activities of daily living.

Mark Benfield, MD: Do you think there's a benefit in having our patients see physical therapy or have some organized exercise routine even before they have symptoms?

Reza Sadjadi, MD: That's a great question. Unless you have like a study looking into that and assessing that in like a systematic manner, it would be very difficult to say. But so our colleagues in Europe, and even here, there is this sort of belief in musculoskeletal and neuromuscular medicine that there is like a bone health correlated or related to the muscle health. And these patients have other complications of endocrinopathy, GI issues, malabsorption, etc.

Obviously, the sooner you start training the mitochondria to behave better in the muscles, the better the outcome presumably they would have. Now, can I say that by 100% confidence? No, because we don't have a study to look into that. But that is what we tell other patients with myopathy, so like a congenital myopathy, even in those conditions, we don't have like a systematic study to say “Well, you did exercise this much and this much, you have lower risk of fracture or lower risk of disease progression.” But overall, we believe that that's the case. So at least if not for muscle purposes, for bone health and other complications, it would be beneficial to have some degree of physical activity as early as possible.

Mark Benfield, MD: As a general question to all of you, is there something specific that you would recommend that we do to prepare our patients and families to come and see you? Is there something you wish that they knew or had been prepared for before we refer them?

Bradley Miller, MD, PhD: I'll start by saying, you know, if they're worried about growth, then preparing the growth hormone discussion. If they're at least introducing the reason why they're coming to see us, is really helpful to sort of predicate, so they know what they're coming for.

Mark Benfield, MD: OK.

Adam Stein, MD: I would flip it around, and I think, at least in the GI world, you need to prepare the gastroenterologist more so than the patient or their family. My worst fear is you send somebody to a specialist and then the specialist looks at them and they say “Well, I don't know why you're here. Why are you here?” So, you know, talking to your friendly gastroenterologist ahead of time. People make fun of me because I say, you know, give them, give them a phone call. It's probably more efficient. But if you call the specialist ahead of time and just say “Hey, this is what's going on, this is what I'm worried about,” it'll make the visit much more fruitful.

You can warn your patients and families that we're going to ask some leading questions that they may not want to talk about, about their poop and things like that. But let us know what's been going on and what you need help with.

Mark Benfield, MD: Any other thoughts?

Well, I think this has been a very fruitful discussion.

Reza Sadjadi, MD: Thank you.

Bradley Miller, MD, PhD: Thank you.