This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype-phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.

BackgroundResearch findings investigating the sociodemographics of autism spectrum disorder (ASD) have been inconsistent and rarely considered the presence of intellectual disability (ID).MethodsWe used population data on Western Australian singletons born from 1984 to 1999 (n = 398,353) to examine the sociodemographic characteristics of children diagnosed with ASD with or without ID, or ID without ASD compared with non-affected children.ResultsThe profiles for the four categories examined, mild-moderate ID, severe ID, ASD without ID and ASD with ID varied considerably and we often identified a gradient effect where the risk factors for mild-moderate ID and ASD without ID were at opposite extremes while those for ASD with ID were intermediary. This was demonstrated clearly with increased odds of ASD without ID amongst older mothers aged 35 years and over (odds ratio (OR) = 1.69 [CI: 1.18, 2.43]), first born infants (OR = 2.78; [CI: 1.67, 4.54]), male infants (OR = 6.57 [CI: 4.87, 8.87]) and increasing socioeconomic advantage. In contrast, mild-moderate ID was associated with younger mothers aged less than 20 years (OR = 1.88 [CI: 1.57, 2.25]), paternal age greater than 40 years (OR = 1.59 [CI: 1.36, 1.86]), Australian-born and Aboriginal mothers (OR = 1.60 [CI: 1.41, 1.82]), increasing birth order and increasing social disadvantage (OR = 2.56 [CI: 2.27, 2.97]). Mothers of infants residing in regional or remote areas had consistently lower risk of ASD or ID and may be linked to reduced access to services or under-ascertainment rather than a protective effect of location.ConclusionsThe different risk profiles observed between groups may be related to aetiological differences or ascertainment factors or both. Untangling these pathways is challenging but an urgent public health priority in view of the supposed autism epidemic.

Modifications to diagnostic criteria and introduction of genetic testing have likely affected the pattern and timing of Rett syndrome diagnosis. The trends in incidence and prevalence of Rett syndrome in Australia were examined; the cumulative risk of a female being diagnosed determined; and the impact of changes to diagnostic criteria and availability of genetic testing on these frequencies investigated. The population-based Australian Rett Syndrome Database was used to identify a total of 349 verified Rett syndrome females born 1976-2006 and diagnosed 1982-2008. The proportion of female cases born and diagnosed per year and the cumulative risk of a diagnosis were determined. The median age of Rett syndrome diagnosis decreased from 4.5 years if diagnosed before 2000 to 3.5 years if diagnosed after 1999. The cumulative risk of diagnosis had almost doubled by 32 y of age [1/8,905 or 11.23 per 100,000 person-years (95% CI, 10.03–12.45)] in comparison with 5 y of age [1/15,361 or 6.51 per 100,000 person-years (95% CI, 5.65–7.39)]. Earlier age of diagnosis may result in families experiencing less stress and emotional strain compared to those with delayed diagnosis.

The most important predictors of maternal health were children's behavioral difficulties, everyday functioning and current health status. Mothers of children with Down syndrome appear to experience poorer mental health and may require greater support and services to improve behavior management skills for their child and their own psychological well-being.