Activity Transcript

Alan K. Percy, MD: Welcome to this Medscape Education program. Today we're going to be discussing understanding Rett Syndrome Across the Lifespan: Current and Emerging Approaches. I'm Dr Alan Percy. I'm a child neurologist at the University of Alabama at Birmingham and been involved in studies with Rett syndrome for nearly 40 years. I'm joined today by Dr Constance Smith Hicks. Connie, can you introduce yourself?

Constance L. Smith-Hicks, MD, PhD: Thank you, Alan. I am a child neurologist as well and I'm assistant professor in the Department of Neurology at Johns Hopkins. I'm a relative newcomer to Rett syndrome, but I've been practicing in this space for the past 6 years. I also direct the Rett and Related Disorders Program at the Kennedy Krieger Institute in Baltimore, Maryland. A pleasure to be here.

Dr Percy: Our agenda today is to cover the genetics of Rett syndrome, look at the pathophysiologic consequences, discuss age related disease progression and changes in patient's needs, and then approach their current therapeutic selections and emerging therapeutics.

The background of Rett syndrome is that this is a severe and progressive neurodevelopmental disorder, which predominantly affects females that incidents about 1 in 10,000 live female births. In terms of the difference between neurodevelopmental and neurodegenerative, no pathological evidence exists to suggest that there is any loss or diminution of neuronal or neural elements.

Further, there are males who have mutations in the same gene but who present with a variety of different problems. However, some of these males, because of some changes in their developmental profile, may have 2 X chromosomes and therefore are mosaic and can have effects or demonstrate the signs and symptoms of Rett syndrome themselves.

Rett syndrome is related in 97% or so of individuals with mutations in the gene methyl-CpG binding protein or MECP2 for short. The mutations are generally arrayed in exons 3 and 4 of this gene. More recently a few mutations were identified in exon 1 and no mutations to date have been identified in exon 2. Not shown on this slide is there are individuals who are missing whole exomes or in fact the whole gene and they may represent as many as 10% of individuals as well. Now Connie will talk about diagnostic criteria.

Dr Smith-Hicks: Thank you Alan. Although Rett is tightly linked to changes in the MECP2 gene, Rett remains a clinical diagnosis, and for that we use a definitive diagnostic criterion. You'll see here that there are 4 main criteria. The first one is a partial or complete loss of acquired purposeful hand use. Second, we have partial or complete loss of acquired spoken language and the loss of language might simply be the loss of the ability to babble. Individuals can have gait abnormalities that may manifest either with them being non ambulatory or simply having impairment in their gaits.

And then more commonly associated with Rett is a stereotypical hand movement such as hand ringing, screaming, clapping, or mouthing. The supportive criteria of which there are 11 includes the breathing disturbances that occur during the awake period. And these include hyperventilation and breath holding spells, teeth grinding, also occurring in the awake period, impairment of sleep, issues with tone, peripheral vasomotor disturbances where individuals have pink hands or feet or blotchy, purple feet, scoliosis, small hands, small feet and intense eye pointing to name a few.

Use of the diagnostic criteria, it's very instrumental in distinguishing between typical and atypical Rett. Both categories require that there is a period of regression followed by recovery or stabilization. However, in the case of typical Rett, individuals need to exhibit all 4 main criteria and all exclusion criteria. The exclusion criteria would include brain injury, which may result from peri or postnatal trauma, neuro metabolic diseases, or a severe CNS infection with neurologic sequela.

Additional exclusion criteria are abnormal psychomotor development in the first 6 months of life. Now, although patients with typical Rett may exhibit supportive criteria, the supportive criteria are not a requirement for diagnoses. Atypical Rett, like typical Rett, individuals exhibit a period of regression. However, they may exhibit 2 of the 4 main criteria and 5 of the 11 supportive criteria.

Now in discussing supportive criteria, it becomes evident that Rett is not simply a brain-based disorder with neurodevelopment and neuropsychiatric phenotype, but it is in fact a multisystem disorder which may manifest with long QT, about 7% of patients with Rett syndrome, involvement of the lung with respiratory manifestations, GI manifestation, which could include feeding abnormalities, swallowing difficulties, constipation and reflux, and muscular skeletal abnormalities.

In addition to scoliosis, we often see bone density concerns. Our approach to treatment at this time is primarily symptomatic care for epilepsy, sleep, and behavioral issues are primarily the standard interventions that are used in care. Therapies are a mainstay of treatment. Communication specialist, be it a speech language pathologist or an augmented communication specialist, occupational therapist, and physical therapist support patients in the need for their fine motor and gross motor care.

Individuals with Rett all require individualized educational plans to support them in their both cognitive and adaptive functioning. And given the multisystem nature of the disorder, referral to specialist care is essential. We'll see that managing a Rett syndrome is a multidisciplinary team-based approach with a patient at the center and therapists are an integral part of the team.

Other physicians include gastroenterologists, orthopedists, we may have a gynecologist, bone health specialists, psychiatrists to name a few. Alan, given the use, the comprehensive use of symptomatic care, how does this impact the longevity of patients with Rett?

Dr Percy: The longevity of Rett syndrome is very interesting. From the initial description of Andy Rett's group, when that group was surveyed after 25 or 30 years, only 1 woman was alive still from the original group of 23 or 25 individuals. However, with more attention paid to this disorder and better overall care, the survival has definitely improved, such that greater than 50% of in individuals now live to age 50.

However, the changes in survival over age may be varied by the availability of care, by the differences in approaches to their management and by the differences in the basic underlying problems that are associated with Rett syndrome. But nevertheless, survival is fairly prolonged such that care must be diligently provided by other individuals, because the individuals, if they reach age 50 or more, their parents are considerably older and therefore need additional help and guiding their children.

The clinical manifestations of an aging person have been looked at in a couple of studies that are published and one that we have done through our own natural history study. Scoliosis is something that occurs in 80 to 85% of individuals by menarche. Epilepsy has been demonstrated in over 90% of the girls or individuals with Rett syndrome. Although, at any given time, about 40 or 45% require continued medication.

As Connie mentioned, constipation is a very significant problem, as are elements of GE reflux, gastric emptying, or even gallbladder dysfunction. Nutrition is a constant problem for many patients and osteoporosis, or osteopenia more commonly is a frequent association in girls with Rett syndrome. The existence of non-traumatic fractures is much higher in this population than in a general population.

One chemical, carnitine, which is a normal constituent of our bodies, has been found to be associated with a variety of systemic and neurologic problems and levels have been found to be low in individuals with Rett syndrome. Dental problems, particularly a poor alignment of teeth, can be commonly find. And in addition, as aging occurs, mobility is more and more difficult, particularly as there is a change in muscle tone from being relatively low during early years to increase tone and rigidity and appearances of dystonia, which are unusual positions in specific joints, particularly the ankles or the wrists or even at the head and neck.

The second study I've done more recently covers pretty much the same elements. Girls or women lose the ability to walk in some percentage. And although this says 10%, in our own studies we find still 30 or 40% of girls or women with Rett syndrome can walk.

The issue of mutation in terms of severity or mildness of the mutation can affect the long-term outcome and therefore individuals with milder neurological issues may have a better outcome and more ease of care during their aging years. Bradykinesia, dystonia, and Parkinsonism are common, and we're seen in 20% of this population. In our population we have seen a much higher incidence of dystonia. The stereotypical movements do persist through life, although they may become less aggressive as aging, but they still are persistent problems.

How does age impact these symptoms? Mobility is a problem due to the rigidity and dystonia, but also anxiety. These girls tend to be incredibly anxious and fearful of falling, so that affects some mobility. We discussed stereotypies. Epilepsy continues to be a problem and requires constant oversight, as does nutrition with calcium and vitamin D being crucial for bone health.

Health maintenance and medical assessments are essential for these females, as for any other woman in an aging population, and including, as Connie mentioned, a need for gynecologic assessment and breast examination. GI issues continue to be a problem throughout life with a perhaps greater emphasis on bladder dysfunction, but the elements of gastric emptying, reflux, and constipation are a continuing problem. And finally, importance of therapies, socialization, do not end with the end of schooling, but it is very difficult to find programs for adults and therefore extra effort must be taken in support for the families to address these important needs.

The International Rett Syndrome Foundation, together with investigators in the natural history study, did develop a set of guidelines for assessing Rett syndrome. I'm not going to go through this entire list, but importantly there are general issues, gastrointestinal, nutritional, respiratory, neurologic, cardiologic, and we haven't really discussed that, but there is increased incidence of or prevalence of QTC abnormalities, generally increasing with age. And overall, about 20% of individuals may have prolongation of the QTC interval. Regular ECGs on an annual basis and annual checkups should be performed and if there is an abnormality, then the individual should be referred to a cardiologist.

Skin health is important, particularly with the prevalence of hand mouthing or with bracing that may produce pressure sores or with immobility which may also produce pressure sores and these need to be observed. Are there additional assessments of treating conditions for the aging patient. And Connie will discuss some of this.

Dr Smith-Hicks: Some of which you have touched on, Alan, I think it's important to remember that individuals with Rett syndrome can have anything that any other aging individual can have. And so certainly gynecological assessments, breast assessments, examination, and colonoscopies, those sorts of assessments are critical. But it's also important to take into consideration the family history and any other diagnosis that may travel in that family.

But speaking specifically to the treatments of symptoms, one of the things that is apparent is that many of these symptoms persist across the lifespan. Our approach to treatment in an aging population is going to be very similar to approach to treatment in the younger individuals with Rett. For example, there are no specific agents for the treatment of epilepsy that is no agents that are used and shown to be effective for all patients with Rett syndrome. Some of the common anti-convulsants that are used are Lamotrigine, sodium valproate, or oxcarbazepine. Topiramate is also beneficial in some individuals.

For the management of mood in anxiety, the SSRIs, serotonin reuptake inhibitors, benefits have been seen with Escitalopram. I would recommend against the use of clonazepam for managing anxiety, especially in individuals who have intractable epilepsy and may require benzos as an abortive, targeting GI reflux: H2 blockers. Constipation, again a very critical issue, require in many cases laxatives or milk of magnesia or senna to ensure that stools are passed easily.

Sleep is a common problem in individuals with Rett syndrome. Melatonin is very effective for treating issues with sleep onset. And depending on the age of the individual, you may go anywhere between 1 and 10 milligrams about 30 minutes prior to bedtime. Trazodone is beneficial again in this population that requires that we look for drug-drug interaction, especially if atypical antipsychotics are being used, given the risk for QTC prolongation.

We heard that bone health is a common problem in Rett, in part due to disuse. Many of our individuals are non-ambulatory and do not stand or walk. And so, it's very critical that good levels of vitamin D and calcium are maintained. Daily uses of a vitamin D on the order of 2000 IUs. We recommend routine checking of vitamin D and calcium to ensure that the levels sit in the mid-range. And therapies, PTOT, assistive communication, are essential across the lifespan essential to help with managing tone, essential to help with bone strength. And often parents will share that their child is irritable because they're not able to communicate. And so augmented communication is critical for the supporting patients across the lifespan. And as Alan said earlier, services are required even past age 21. It's often difficult to get them, but they are an essential component to the care for individuals with Rett.

Mobility as in gait trainer and standing frame. Again, critical to help manage tone, mobility, and bone density issues. Now we have shared that Rett is a multisystem neurodevelopmental disorder with a significant impact. We expected that there is going to be significant quality of life challenges for both the patient and the caregiver. And from the natural history study that Alan led, the data indicates that the physical quality of life of the parent was higher than the mental quality of life, initially when the child was first diagnosed. And that makes quite a good sense to me, because often parents will tell you that getting a diagnosis of Rett syndrome is very challenging. As the child ages, the parents then develop better coping strategies. Although their mental quality of life improves, they get older, and consequently, their physical quality of life declines.

Feeding is a common source of decline in the quality of life, both physical and mental, for the patients. And we find that the caregiver quality of life in Rett syndrome is very to the care caregiver, quality of life and other chronic disorders that have significant impact on the personal and home life of the patients. At this point the question is really are there any targeted FDA approved treatments for Rett syndrome? And the answer is no, not yet. However, there is significant work being done in both genetic and pharmacological space to really target this on that need.

We can see here that there are potential targets that act at the level of mutations in the MECP2 gene. And there are also potential targets that act downstream of the gene itself. Some of those are pharmacological agents that target neurotransmitter signaling and others target growth factor receptor signaling. Now Alan, you have been involved in work done with IGF1 analog. Can you tell us a little bit more about that?

Dr. Percy: The first agent, which has gone through phase 3 trial, it's called trofinetide. That is an analog of the IGF1 growth factor, which with a methylation allows it to be taken as an oral agent as described in the right side of the slide. This study involved more than 180 individuals, evenly split between the agent and placebo. The women or girls had to be 15 to 20 years of age, had to have a body weight of 12 kilograms or more, and had to have typical features of Rett syndrome with a mutation in the MECP2 gene.

The severity scales were required. They had to fall within a certain range, and they had to have a stable pattern of seizures and medication for the prior 2 weeks. The primary outcome measures were the RSBQ, which is the Rett syndrome behavioral quotient, is a caregiver-based measure, and the CGII, which is a clinician score. That's a clinical global impression of improvement at age 12 weeks.

The results of the study show that in both instances, both the caregiver and the physician rating scales, there was significant improvement in the drug vs the placebo group at 12 weeks, which was the end of the double-blind phase of the study. Ongoing or open label studies were conducted for the rest of the year and that has now ended, and an even longer open label study is currently ongoing.

On the other hand, there were side effects associated with the drug, principally with diarrhea. The majority of those were mild and moderate and generally easily managed with medications to control the diarrhea. Vomiting was also increased but not as much as diarrhea and the other features were only slightly different from the placebo group. All in all, this seemed to be an effective agent and application is made by the company to FDA for approval. Next slide is for Connie.

Dr Smith-Hicks: Blarcamesine is both a sigma-1 receptor agonist and it modulates the muscarinic receptors. It plays important roles in calcium homeostasis and mitochondrial functioning and it's present in multiple brain regions. Pre-clinical studies have shown in the MECP2 mice that there have been some improvements in the atypical hind limb classing, which we think is analogous to hand ringing, and there's also been some improvement in motor function.

This has led to clinical trials in Rett syndrome. There are 2 ongoing trials. One is a phase 2/3 double-blind placebo-controlled study. It's called Excellence. It's a dose escalation study that looks at safety, tolerability, and efficacy. And this particular study is being done in 5 to 17. A similar phase 3 trial called Avatar is being done in older populations and currently there are no results from either of these.

An additional study was recently completed. That is a study of oral ketamine. Ketamine is a modulator of the NMDA receptor. And this phase 2 study was a sequential ascending dose study that looked at safety, tolerability, and effectiveness. Oral ketamine in girls with Rett syndrome, we're still awaiting results from those studies.

To conclude, what we have shared is that Rett is a severe developmental multisystem disorder resulting from mutations in MECP2. It's a clinical diagnosis and it's based on definitive clinical criteria. We've also discussed that the management of Rett syndrome currently is symptomatic. Although there are no specific targeted treatments at this time for Rett syndrome, there is significant work being done looking at targeted pharmacological treatments.

Dr Percy: Thank you very much for your attendance.

This transcript has not been copyedited.