Intellectual disability (ID) occurs in 2-3% of newborns, resulting in a lifetime of dependency on family and health care systems. ID has traditionally been viewed as untreatable. Recently, however, this view has been challenged with increasing evidence that the early postnatal period, during which the brain continues to develop, provides a potential therapeutic window. We focus on disorders with ID caused by mutations in chromatin modifying enzymes. These chromatin modifiers regulate gene expression in the developing and maturing brain. The biochemical activity of chromatin modifiers is inherently reversible – for example, DNA can be methylated by DNA methyltransferases and subsequently demethylated through the action of TET enzymes – and we are investigating potential interventions to reverse the biochemical dysfunction that occurs in chromatin-based ID disorders.
Tatton-Brown-Rahman syndrome is a disorder of overgrowth and ID, caused by mutations in the DNA methyltransferase gene, DNMT3A. We are characterizing a Dnmt3a mouse mutant to understand the behavioural and molecular consequences of Tatton-Brown-Rahman syndrome-associated mutations and to identify and test potential treatments. Further, we are developing numerous experimental approaches to test potential interventions in vitro, including through the introduction of various patient-specific mutations into a human neuronal precursor cell line as well as the establishment of viable post-natal mouse neuronal cultures.
The improvement of a patient’s ID from moderate to mild is expected to increase their chance of inclusion in mainstream schooling and workplaces. Therefore, finding interventions that improve the developmental outcomes of children with ID will substantially improve quality of life for patients and their families.