title: Developmental delay in Rett syndrome: data from the natural history study.
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.
  
  
  BACKGROUND
  This NHS study, clinicaltrials.gov (NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination.
authors: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA ; Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
authors: Jeffrey L
authors: JL
authors: Neul
authors: Civitan International Research Center, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294-0021, USA.
authors: Jane B
authors: JB
authors: Lane
authors: Pediatrics Epidemiology Center, University of South Florida, Tampa, FL 33620, USA.
authors: Hye-Seung
authors: HS
authors: Lee
authors: Civitan International Research Center, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294-0021, USA.
authors: Suzanne
authors: S
authors: Geerts
authors: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Judy O
authors: JO
authors: Barrish
authors: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors: Fran
authors: F
authors: Annese
authors: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors: Lauren McNair
authors: LM
authors: Baggett
authors: Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Katherine
authors: K
authors: Barnes
authors: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors: Steven A
authors: SA
authors: Skinner
authors: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Kathleen J
authors: KJ
authors: Motil
authors: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Daniel G
authors: DG
authors: Glaze
authors: Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Walter E
authors: WE
authors: Kaufmann
authors: Civitan International Research Center, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294-0021, USA.
authors: Alan K
authors: AK
authors: Percy