A research collaboration, led by the University of Adelaide, has confirmed earlier findings that around 14% of cerebral palsy could be genetic in origin in one of the largest studies of its kind.
Around 10,000 babies with cerebral palsy, a non-progressive movement disorder that can also include intellectual disability, are born each year in the U.S. The condition was long thought to be caused by a lack of oxygen to the brain at birth, but while this is thought to be true in 8-10% cases, it does not explain the rest.
“Eliminating other known causes, including premature birth and trauma at birth, this leaves a large number of cases – as many as 40% in some studies – with an unknown origin,” said Alastair MacLennan, M.D., an emeritus professor at the University of Adelaide who co-led the research.
Some previous studies have suggested that variants in certain genes could increase a child’s risk of having cerebral palsy, perhaps accounting for up to 14% of cases, but earlier studies had minimal controls and functional validation of the highlighted mutations was not carried out. This is the first study to investigate the genetics of cerebral palsy more broadly, according to the researchers.
As reported in the journal Nature Genetics, the researchers carried out exome sequencing on 250 samples from cerebral palsy children and their parents and compared the sequence to that of 1800 control families without the condition.
The team identified 8 genes that contained multiple spontaneous mutations in children with the condition. Two in particular, TUBA1A and CTNNB1, had genome-wide significance.
They also discovered that single nucleotide polymorphism gene variants had occurred spontaneously in several individuals in the genes RHOB, involved in the formation of dendritic spines – the signalling part of a neuron, and FBXO31, known to be involved in neurological development in the brain.
Although most of the genetic variants seemed to occur spontaneously and not be inherited, the researchers did observe mutations in six genes known to be linked to a similar movement disorder known as hereditary spastic paraplegia.
Overall, the analysis confirmed previous suggestions that around 14% of cases of cerebral palsy could be genetic in origin. The team believes that around 12% of these cases are likely to occur spontaneously and around 2% could represent rare recessive mutations, similar to those seen in hereditary spastic paraplegia, which could also be causative for some cases of cerebral palsy.
In addition to the genetic screen of cerebral palsy families, the scientists assessed the function of the genes that were linked to disease risk by studying the orthologous genes in fruit flies. This screen confirmed that these genes regulate neuromotor function.
“As little as 30 years ago we were very limited in treatments for cerebral palsy, and the outlook for anyone diagnosed was grim,” said Jozef Gecz, Ph.D., a professor in neurogenetics at the University of Adelaide and co-author on the paper.
“As we come to recognize the role of genetics in cerebral palsy, we open the door for new treatments, earlier diagnosis and intervention, which could lead to greatly improved quality of life.”