1st analysis of global Rett prevalence may help in trial planning

Study sets new estimate of 7.1 cases per 100,000 females worldwide

Joana Vindeirinho, PhD avatar

by Joana Vindeirinho, PhD |

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The global prevalence of Rett syndrome is estimated to be 7.1 cases per 100,000 female individuals, according to the first known meta-analysis ever done to estimate the number of girls and women worldwide with the rare neurodevelopmental disorder.

This finding “may facilitate planning of therapeutic trials in this disease, especially for target sample size and accrual times,” the researchers wrote, noting that “one of the rate-limiting factors in the development of new pharmacologic therapies for RTT [Rett syndrome] is the low prevalence of the disease.”

For the meta-analysis, the team used 10 pooled studies that included more than 9 million women and 673 people with Rett syndrome. These studies showed individual estimates compatible with a prevalence range of about 5 to 10 cases per 100,000 female individuals.

“This is the first systematic review and meta-analysis of [Rett syndrome] that reports pooled prevalence of RTT in the general female population,” the researchers wrote.

The study, “Global prevalence of Rett syndrome: systematic review and meta-analysis,” was published in the journal Systematic Reviews. It was funded by Novartis Gene Therapies.

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Rett syndrome is a rare neurodevelopmental disorder that occurs almost exclusively in girls. It is mainly caused by mutations in the MECP2 gene. This gene is responsible for the production of the MeCP2 protein, which regulates the activity of several genes, including ones involved in the brain’s development and function.

As with other rare diseases, the low prevalence of Rett syndrome — usually estimated to be about 1 in 10,000 female births — is a significant barrier to the planning and execution of clinical trials for new potential therapies.

To give a clearer picture of the prevalence of Rett syndrome in the general population, a team of researchers from the Netherlands and the U.S. conducted a systematic review and the first meta-analysis on the global prevalence of Rett syndrome. A meta-analysis uses statistical methods to pool together data from different studies to calculate one overall result.

The team assessed studies in English that reported prevalence and/or incidence of Rett syndrome (or enough data to calculate one) published between Jan. 1, 2000, and June 30, 2021. Prevalence refers to the proportion of a population who have a condition in a given time period, while incidence refers to new cases of disease in a population over a specified period of time.

Here, studies before 2000 were excluded to avoid discrepancies in diagnosis, since the link between Rett syndrome and MECP2 mutations was only found in 1999.

From an initial 3,234 studies assessed, 10 were determined to have relevant findings and to be of sufficient quality to include in the meta-analysis. Most studies (eight) were done in European countries, with one each from Australia and China. The pooled sample size was 9.57 million women and girls and 673 Rett syndrome female patients.

Five studies only included people younger than 18 years, while four included both children and adults (younger than 35 years); one had no indication of ages. The sample sizes varied greatly between studies, ranging from a little more than 5,000 female individuals to more than 4 million.

The pooled prevalence estimate was 7.1 cases of Rett syndrome for each 100,000 female individuals, which is in line with previous estimates. Although the included studies did not cover many world regions, the results “encompassed the prevalence estimates from several nations and covered many different patient populations,” the researchers wrote.

There was significant variability in the individual estimates of each study, which ranged from 0 cases per 100,000 females to 38.3. However, according to the scientists, most of the variability stemmed from some studies with imprecise estimates.

Despite the significant variability, an analysis of the confidence level of each pooled estimate showed that they were all compatible with a prevalence range of about 5 to 10 cases per 100,000 females.

“Interestingly, most estimates from the European region were of similar orders of magnitude as those from China and Australia,” the research team wrote.

This is the first systematic review and meta-analysis of [Rett syndrome] that reports pooled prevalence of RTT in the general female population.

Age was an important limitation of the study. All studies had populations younger than 35 years, and most included only individuals younger than 24 years. However, the researchers noted that studies have shown that people with Rett syndrome, once they reach age 25, have mortality rates similar to those of the general population.

“If that is indeed the case,” they wrote, “the pooled prevalence estimates presented could be extrapolated to the general population.”

The lack of greater geographic spread was another limitation of the study, and the researchers noted their surprise in the absence of studies from the U.S. done after 1999.

Overall, the findings “suggest that the prevalence [of Rett] remained stable for the last 20 years in the range of 5 to 10 cases per 100,000 females, without substantial regional variability,” the researchers concluded.