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

Neul et al. Journal of Neurodevelopmental Disorders 2014, 6:20 http://www.jneurodevdisorders.com/content/6/1/20 RESEARCH Open Access Developmental delay in Rett syndrome: data from the natural history study Jeffrey L Neul1,2, Jane B Lane3, Hye-Seung Lee4, Suzanne Geerts3, Judy O Barrish1, Fran Annese5, Lauren McNair Baggett5, Katherine Barnes6, Steven A Skinner5, Kathleen J Motil1, Daniel G Glaze1, Walter E Kaufmann6 and Alan K Percy3* Abstract Background: Early 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. Methods: Developmental 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). Results: Early 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. Conclusions: Early 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 registration: This NHS study, clinicaltrials.gov (NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination. Background Rett syndrome (RTT), OMIM #312750, a neurodevelopmental disorder predominantly affecting females, has been characterized by ‘apparently’ normal initial development followed by frank regression of fine motor and communication skills typically between 6 and 18 months * Correspondence: 3 Civitan International Research Center, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294-0021, USA Full list of author information is available at the end of the article of age [1-3]. Despite absence of prospective evidence of delayed early development, retrospective review has suggested that abnormalities are evident within the first 6 months [4-7]. Infants have often been described as being hypotonic and occasionally being excessively irritable or having postural stiffness often belying the underlying hypotonia. Assessments of development have been hampered by relatively small numbers of participants, possibly allowing phenotypic variability to skew assessments, involved data derived from questionnaires without direct © 2014 Neul et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Neul et al. Journal of Neurodevelopmental Disorders 2014, 6:20 http://www.jneurodevdisorders.com/content/6/1/20 assessment of the participants by clinicians experienced in the diagnosis of RTT, or focused on specific skills or time periods rather than acquisition of developmental skills longitudinally [4-10]. Videotaped assessments have provided important retrospective observations with regard to specific early developmental skills. These prior studies indicate that the early period of development in RTT could be regarded as abnormal [6,7,10] and evidence of abnormal deceleration in head growth occurring as early as age 1.5 months based on recent data from the NICHD-sponsored Rare Disease Natural History Study (NHS) provides neuroanatomical support [11]. Information obtained over the past 7 years through the NHS has yielded extensive longitudinal data on a large cohort of individuals with classic and atypical RTT, providing definitive evidence for developmental patterns regarding the achievement of specific milestones that deviate from normal. Here, we capture and compare the acquisition of specific skills or abilities and whether these fall within the limits for achieving accepted milestones for the respective skills or abilities. Further, we extend the relationship between these developmental trajectories and specific MECP2 mutations and compare these trajectories in participants with classic and atypical RTT. Methods Data from initial enrollment in the NHS were assessed from 542 females who met criteria for classic RTT and 96 females who met criteria for atypical RTT and were enrolled into the study at an initial age under 10 years old. Although our overall cohort of individuals with RTT exceeded 900, we chose to restrict the analysis to subjects seen initially before 10 years of age in order to increase accuracy of parental recall for the acquisition of developmental skills or abilities (in the following sections, we will use the term ‘skills’ for both). Age at enrollment for this group ranged from 7 months to 10 years of age; median age was 4 for classic RTT, 4.5 for higher function atypical RTT, 3.5 for lower function atypical RTT. As individuals with atypical RTT have a bimodal distribution, those less severely affected and those more severely affected, this group was divided into 50 having better functional scores (clinical severity score ≤20) and 46 having poorer functional scores (clinical severity score >20). Criteria for enrollment were based on (...truncated)