Clues to the underlying cause of intellectual disability in Down syndrome discovered

Changes in the normal pattern of many genes involved in brain function could be the cause of intellectual disability in individuals with Down syndrome (DS.)This discovery has been made by researchers in Professor Gudrun Moore’s team at the UCL, Institute of Child Health, a research partner of Great Ormond Street Hospital, along with  colleagues in the US, Professor Benjamin Tycko at Columbia University who led the overall study, Professor Jerzy Wegiel at the NYSIBR, and Professor Eugene Yu at Roswell Park Cancer Institute. The work could path the way for the development of treatments that protect the IQ of children with DS after they are born however additional research will be needed to determine whether all the changes are adverse, or whether some might be attempts by the brain cells to compensate for the extra chromosome 21.

Intellectual disability is commonly associated with DS and is often one of the biggest worries for parents as their child develops. Levels of intellectual disability can differ greatly from child to child and range from a low level delay in development, where very little support is needed in order for children and adults to lead an ordinary life, to higher level impairment where a significant level of support is needed in order to attain basic living skills.

It is widely known that an extra copy of chromosome 21 leads to DS but the mechanisms by which the extra chromosome leads to intellectual disability are not well understood. The study, published in the journal Genome Biology, now suggests that disruption in brain is related to changes in DNA methylation – a chemical process that determines whether genes are turned on or off.

The team looked at DNA methylation patterns in the cerebral and cerebellar cortex of adult brains and fetuses with DS at post mortem. They compared these to age matched controls who didn’t have the condition. They found that, in DS brains, there is altered methylation in groups of genes that are known to be important in brain development and function. Similar changes were observed in mouse models of Down syndrome.

They go on to highlight that 30% of the disturbances in methylation in DS happen prior to birth, but that some other changes in methylation may occur after birth. This implies that if we can target and change these methylation abnormalities in Down syndrome, we may be able to protect genes and help prevent the neurological disturbances that lead to impairments in IQ.

Gudrun Moore, at the UCL Institute of Child Health says ‘Further detailed work in DS cell based and mouse models will now been needed in order to test whether methylation patterns can be altered and important genes identified in the brain can be prevented from expressing abnormally.’