Clinical Features and Disease Progression in Older Individuals with Rett Syndrome

Abstract

Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in MECP2 associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of MECP2 variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old). Contrary to expectation, enrichment of a severe MECP2 variant (R106W) was observed in the older cohort. Overall severity was not different between the cohorts, but specific clinical features varied between the cohorts. Overall severity from first to last visit increased in the younger cohort but not in the older cohort. While some specific clinical features in the older cohort were stable from the first to the last visit, others showed improvement or worsening. These data do not support the hypothesis that mild MECP2 variants or less overall severity leads to increased longevity in RTT but demonstrate that clinical features change with increasing age in adults with RTT. Additional work is needed to understand disease progression in adults with RTT.

Keywords: MECP2; Rett syndrome; clinical severity; disease progression; old age.

Figure 1

Distributions of selected CSS and MBA item scores. Differences in clinical features between last visit in <30 yo cohort are compared to first visit in ≥30 yo cohort. (A–C) display the score distribution for representative items from the CSS or MBA that were increased in severity on the older (≥30 yo) compared to the younger (<30 yo) cohort. (D–F) display the score distribution for representative items from the CSS or MBA that were decreased in severity on the older (≥30 yo) compared to the younger (<30 yo) cohort. The specific items in each panel are labeled at the top of the graph, with the legend showing the item score responses and color labels. Graphs show the percentage of each item score response, with the least severe (score 0, light blue) on top to most severe score (score 4, dark green; or score 5, dark blue) on bottom.

Figure 2

Change in individual participant’s clinical features between first to last visit in younger (<30 yo) and older (≥30 yo) cohorts. (A–C) display clinical features that show progressive worsening from first to last visit in both cohorts. (D) displays a clinical feature (nonverbal communication) that shows progressive worsening from first to last visit in both cohorts. The specific items in each panel are labeled at the top of the graph, with the legend showing the item score responses and color labels. Graphs show the percentage of each item score response, with the least severe (score 0, light blue) on top to most severe score (score 4, dark green; or score 5, dark blue) on bottom.