Treatment and Symptom Management for Rett Syndrome

An expert discusses the current treatment landscape of Rett syndrome including the goals of treatment and implications for utilization management strategies with the disease.

David Lieberman, MD, PhD: Goals of treatment at present are to reduce symptom severity. The way we do that is by tackling each symptom in and of itself, for the most part. When the patient has constipation, we give them osmotic laxatives or stimulant laxatives. When they have gastroesophageal reflux, you might give them proton pump inhibitors. We treat their seizures with antiepileptic medications. If they have problems with sleep, we give them medications that help to induce and prolong sleep. The average patient can be on 5 to 10 medications [to treat] all these various symptoms. Importantly, we don’t have any drugs available at present that treat the core symptoms of Rett syndrome. Although I can help a patient’s constipation, I can’t think of a drug to give a patient to improve their communication or their hand use, or reduce their stereotypies or help them walk. Those core features aren’t amenable to current treatments. Fortunately, there have been several recent trials in Rett syndrome using pharmaceutical compounds. Perhaps now [there will be] gene therapy approaches [where] we might see improvements in some of these core features.

My experience with preauthorization and prior authorization for medicine in Rett is actually like [that for] my other neurology patients. I think there’s been an increase in the number of times you have to get preauthorization for medication, even if it’s just a dose change, and it delays treatment. I’ve had patients who needed a refill and the pharmacy reaches out [to say] there’s a problem with preauthorization, and the patient doesn’t get their anti-epileptic medication for several days, for example. Then the patient presents in status epilepticus to the emergency [department]. I don’t know what the payers are doing to make things a little bit more complicated to get these prior authorizations, because these are often medications that are very important for the health of the patient, and delays in getting those to the patient puts the patient’s health at risk. This is a situation that we see, at least in neurology, both in a Rett patient population and those…without Rett. I think a certain question with payers will be coming up in the next few months, as there is a compound called trofinetide that has been forwarded by Acadia Pharmaceuticals and Neuren Pharmaceuticals…for approval from the FDA for treatment of Rett syndrome. It would be the first disease-specific intervention for this disorder. I think they’ll be meeting in March. We’ll have to see what the FDA says and then how this medication might be [made] available to patients with the disorder.

The role of genetic testing in Rett is a couple-fold. There are some disorders that look like Rett syndrome that we’ve now kind of pulled out of the Rett syndrome group, and they’re their own independent disorders. That includes CDKL5 [disorder], which is the early-onset seizure variety of Rett syndrome. This is where the girls could have infantile spasms as an early presentation or epileptic seizures. And there’s a FOXG1 mutation that is now just identified as a FOXG1 syndrome that has microcephaly and early developmental delay, so there can still be some regression, but the development was not normal in the first 6 months of life. It is helpful to do the genetic testing. Also, there are over 200 mutations identified in Rett patients. Among those, there are about 8 more common mutations, 4 being milder and 4 being more severe, and there’s some utility in [it] because they’re so common that we can try to say which type of symptom might be more prevalent with one specific genotype versus another. There can be some rough approximations of that that might be helpful in prognosis. The fact is that 2 girls with the same exact mutation in the MECP2 gene can still present with variable severity, in part because there might be differences in X inactivation. There are 2 copies of MECP2 in girls and only 1 in boys. In girls, there’s a healthy copy expressed in some cells and a mutant copy expressed in some cells; it’s the balance between the 2. It’s usually 50/50, but it could be skewed one way or the other. You could have a higher percentage of cells expressing the mutant MECP2 and that would present with a more severe phenotype, whereas…the [X-chromosome] inactivation favors the wild-type copy [and] would have a milder phenotype. Genetics can be very helpful for management.

Transcript edited for clarity.

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