Rett syndrome: exploring the autism link

Abstract

The presence of autism in individuals with neurodevelopmental disorders, whether transient as in Rett syndrome (RTT) or enduring as in fragile X syndrome or Down syndrome, suggests the possibility of common neurobiologic mechanisms whose elucidation could fundamentally advance our understanding. This review explores the commonalities and differences between autism and RTT at clinical and molecular levels with respect to current status and challenges for each, highlights recent findings from the Rare Disease Network Natural History study on RTT, and summarizes the broad range of phenotypes resulting from mutations in the methyl-CpG-binding protein 2 gene (MECP2), which is responsible for RTT in 95% of individuals with the disorder. For RTT, animal models have been critical resources for advancing pathobiologic discovery and promise to be important test beds for evaluating new therapies. Fundamental understanding of autism based on unique genetic mechanism(s) must await similar advances.

Conflict of interest statement

The author reports no conflicts.

Figures

Figure. Pyramidal Neuron Dendritic Spines from Rat Hippocampal Slice Cultures and Human Hippocampus

Upper panels: Rat CA1 neurons (96 hours post-transfection with enhanced yellow fluorescent protein, eYFP) from slice cultures showing similar spine density to controls with wildtype MECP2 over-expression (~2-fold) and decrease in spine density with mutant R106W (p< 0.05) and T158M (p< 0.01) MECP2 expression when compared with control slice cultures. Data in each bar graph represent the mean and standard deviation. The number of observations represented are control = 30 cells from 14 slices; T158M = 31 cells from 23 slices; R106W 16 cells from 11 slices; and wild-type MECP2 = 18 cells from 16 slices. Lower panels: CA1 pyramidal neurons from human hippocampus stained with DiI showing marked reduction and aberrant morphology of dendritic spines (p< 0.01) from child (age 5) and adult (age 21) with RTT, compared to non-MR controls, child (age 3) and adult (age 35), respectively. Data in each bar graph represent the mean and standard deviation of ten RTT and nine control individuals, respectively. [Unpublished data graciously provided courtesy of Christopher Chapleau and Lucas Pozzo-Miller.]