Video
Rett Syndrome Diagnosis and Disease Progression
An expert explains how Rett syndrome is diagnosed, how commonly it is misdiagnosed, disease progression, and which providers are best positioned to manage a Rett Syndrome patient.
David Lieberman, MD, PhD: The typical age [of diagnosis] is around 3 years old. Right now, we base it on a clinical diagnosis. That means we review the developmental history, and [determine] if they have the regression in hand function, regression in communication, the hand stereotypies, the repetitive hand movements, and the problems with their ambulation or the absence of ambulation. Those 4 features define classic Rett syndrome. You can also have atypical Rett syndrome, where you have at least 2 of those 4 with some clear evidence of regression, but you may not have all 4 features. There are some criteria that you could use to help support the diagnosis of atypical Rett syndrome.
The genetic mutation in MECP2 is found in 90% to 95% of patients with classic Rett syndrome, but only in 40% to 70% of patients with atypical Rett syndrome. You can have Rett syndrome without an MECP2 mutation. Based on current analysis, there still could be a problem with the MECP2 gene, perhaps in an intronic region that regulates gene function. We don’t have a clear way to ascertain that right now. There are also patients with a genetic change in MECP2 who don’t meet criteria for either classic Rett syndrome or atypical Rett syndrome. We refer to that group as [having] MECP2-related disorder. Those patients could look just the same as Rett patients, [but] they may not undergo a regression in skills, they just may never have developed good hand function, for example. They don’t regress in that skill; they just never developed it. The genetic diagnosis is not necessary at this point. [But depending] on what kind of treatment trials are coming, the genetic diagnosis may be needed. [So we] try to get that in all our patients.
The question is if there can be a delay in diagnosis or misdiagnosis for our Rett patients. Yes, there are some disorders that could look similar to Rett syndrome, including cerebral palsy or Angelman syndrome. Some of our milder patients have a lot of autistic features. Right now, the current recommendations for genetic testing in autism are for a chromosomal microarray in a fragile X [syndrome] screen. It’s not MECP2 gene testing, but that is recommended for females with intellectual disability. You could miss the MECP2 genetic change in some patients with autism who may not [meet] all the criteria for classic Rett syndrome.
The question is, who helps to manage the diagnosis of Rett syndrome? Is it a single clinician? Is it the primary care provider? Or are there sub-specialists involved? There is some variability based on regions in the country or regions in the world. The predominant group that manages Rett syndrome are child neurologists, as it presents in childhood initially. They’re the group that [usually] makes the diagnosis, although geneticists make the diagnosis in many cases. Developmental pediatricians might make the diagnosis because they also will be following the same kids because of their developmental regression. We try managing some of the symptoms within the Rett clinic ourselves, but we often refer to specialists predominantly in gastroenterology and in orthopedics because of the prevalence of some of those associated disorders. For example, our GI clinicians help manage our constipation, which is very frequent, gastroesophageal reflux, and swallowing dysfunction. In our orthopedics clinic, they monitor for hip stability. They monitor for scoliosis and kyphosis, which can develop in these patients. It’s kind of a team approach. In some cases where there’s not a local neurologist, I think that the pediatricians can do a good job. We have some guidelines, published in 2020, that could help the pediatrician know what features to monitor for on a routine basis. We can still serve as consultants for those pediatricians if they don’t have a local pediatric neurologist to help them out.
Transcript edited for clarity.
