Developmental delay in Rett syndrome: data from the natural history study

Abstract

BackgroundEarly development appears normal in Rett syndrome (OMIM #312750) and may be more apparent than real. A major purpose of the Rett Syndrome (RTT) Natural History Study (NHS) was to examine achievement of developmental skills or abilities in classic and atypical RTT and assess phenotype-genotype relations in classic RTT. MethodsDevelopmental skills in four realms, gross and fine motor, and receptive and expressive communication from initial enrollment and longitudinal assessments for up to 7 years, were assessed from 542 females meeting criteria for classic RTT and 96 females with atypical RTT divided into two groups: 50 with better and 46 with poorer functional scores. Data were analyzed for age at acquisition and loss of developmental features and for phenotype-genotype effects. Acquired, lost, and retained skills were compared between classic RTT and atypical RTT with better or poorer functional scores using Fisher's Exact test. To examine if the mean total score from the Motor Behavioral Assessment during follow-up differed for acquiring a skill, we used a generalized estimating equation assuming compound symmetry correlation structure within a subject. A general linear model was used to examine whether the mean age of acquisition or loss of a developmental skill differed by mutation type. P values <0.05 were considered significant and were two-sided without adjustment for multiple testing. Statistical analyses utilized SAS 9.3 (SAS Institute, Cary, NC, USA).ResultsEarly developmental skills or abilities were often acquired albeit later than normal. More complex motor and communication acquisitions were delayed or absent. Clinical severity was less in those achieving the respective skill. Individuals with R133C, R294X, and R306C point mutations and 3′ truncations tended to have better developmental outcomes.ConclusionsEarly developmental skills were acquired by many, but clear differences from normal emerged, particularly in skills expected after age 6 months. When comparing clinical severity, greater acquisition of specific skills was associated with specific mutations, confirming the impression that these mutations confer milder developmental abnormalities. These data may serve for planning and interpretation of early intervention studies in RTT.Trial registrationThis NHS study, clinicaltrials.gov (NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination.

Early development in Rett syndrome – the benefits and difficulties of a birth cohort approach

“…Overall the results, inconspicuous behavior at 6 months with more obvious deviations by 18 months, were in line with previous findings and the reports by Neul and colleagues 3 in their recent large-scale natural history study on developmental delays in RTT (in a retrospective design), in which they state “Early developmental skills in RTT are acquired by many, but clear differences emerge in skills expected after 6 months of age” (Conclusions, p. 8). They go onto suggest that the commonly denoted appearance of normal early development in individuals with RTT “may be more apparent than real” (Abstract, p. 1).…”

“…9–11,13,15–18,20,37,38 Such studies have also begun to delineate different profiles in early development according to both RTT variant and mutation type. 2,3,39–43 …”

“…1–4 The natural history of this disorder follows a four-stage trajectory including a period of regression with subsequent recovery or stabilization. 3,5 Hagberg 5 reported on 35 females characterized inter alia by loss of verbal communicative abilities and purposeful hand use with simultaneously occurring hand stereotypies (hand wringing, washing character). He published his findings under the eponym of the author who first described this symptom-complex some 50 years ago, the Austrian neuropediatrician Andreas Rett.…”

Rett Syndrome: Reaching for Clinical Trials

“…Detailed evaluation of the first 6 months of life established that developmental skills do not follow a typical timeline when viewed critically [23][24][25]. These findings of delayed or arrested developmental are sufficiently subtle that specific delays are not often suspected until the second year of life when frank regression, accompanied in some by autistic-like social avoidance, is noted.…”

Commentary: Are Developmental Skills Acquired Normally in Rett Syndrome?

“…In 2014, Neul et al 20 described the occurrence of developmental skills in more than 600 individuals with RTT, the largest reported to-date examined directly by teams consisting of a neurologist or geneticist and an experienced clinical coordinator. This allowed for a precise ascertainment of the timing of acquisition of specific developmental skills in this population.…”