A study conducted by researchers at the University of Arizona College of Medicine-Phoenix and an international team of researchers shows about 14% of cerebral palsy cases may be tied to de novo genetic mutations or mutations that appear in a child but not in the parents.
According to the CDC, CP is a group of movement disorders that impacts a person’s ability to maintain posture and balance. Abnormal brain development or damage to the brain are attributed as the cause of this disorder.
Dr. Michael Kruer, a neurologist at the Phoenix Children’s Hospital with specializations in Pediatric Movement Disorders and Neurogenetics, spoke about how neurodevelopmental disorders like Autism and Intellectual Disability had a strong genetic component, and after working with a family where all four kids had CP, he wondered whether it was also possible for cerebral palsy to have a genetic component?
“We met a lot of resistance because as I started to talk with colleagues about the idea, people would blow it off and say there’s no proof of that … you’re barking up the wrong tree,” said Kruer.
After indeed finding out that there was a common mutation in the gene among the four patients, he decided to pursue this idea. As he and his team continued research on this topic, other researchers in other American universities, as well as teams from Australia, China and Sweden, simultaneously were interested in this idea. Over the span of several years, the various teams ended up meeting, collaborating and forming the International Cerebral Palsy Genomics Consortium, which Kruer is the governing chair of.
Through years of slow and steady research, gradual increases in funding, an NIH grant and an international team of scientists, they were able to collect saliva samples from over 250 cerebral palsy patients and their parents from around the world.
After getting samples, the entire genomes, or the collection of all genes in a person’s DNA, were sequenced to be analyzed in later steps.
Two of the leading authors and researchers in this study were Somayeh Bakhtiari and Sarah Lewis, two postdoctoral fellows at Phoenix Children’s hospitals. They were part of the team that implemented various computational tools to analyze the massive amounts of data generated.
They first applied filters relating to characteristics, like the frequency of a gene mutation, to narrow down the gene pool they were working with. After this step, they ended up with a list of genes with unknown functions. They then performed different analyses to figure out which types of biological processes these genes were involved with.
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Kruer said that one of the processes that they found in many gene mutations was related to how neurons grow, branch out and form connections with other neurons. They also found that gene mutations were found in pathways related to the cytoskeleton, or the external set of fibers and proteins that help give a cell its structure.
Another way they observed the potential effects of these genes in relation to cerebral palsy was through the use of Drosophila melanogaster, or fruit flies. If they disrupted the function of a fly gene equivalent to the human gene, they could see how that gene could impact the movement of the fly.
“We saw some differences in how fast they traveled, if they stopped moving, … whether they could right themselves if they were flipped over, and how they responded to external triggers,” Lewis said.
They also found that many of the genes that they determined were involved with CP were also linked to other conditions like epilepsy and autism.
These findings provide solid evidence of the idea that there is a genetic component to CP. Kruer said that these results should start a new discussion about how patients with CP are diagnosed.
“Even amongst CP specialists, although 70% would diagnose CP in a child with a genetic condition, this means roughly 30% of physicians wouldn’t … We need to revisit this idea of what it means to have CP so we give clear messages to parents,” Kruer said.
An understanding of the genetics of CP in a patient can also impact the types of treatments doctors give to patients. Because of genetics, a treatment that doctors don’t usually give to patients may end up being the best option. The clinical applications are vast and exciting.
The international team is exploring other interesting questions. For example, they are exploring how consanguineous families, or families where the parents are related or somewhat related, can potentially contribute.
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“With consanguineous families, the parents are somewhat related, so they are more likely to have recessive phenotypes and gene mutations,” Bakhtiari said. “We are studying samples from places like Iran, Saudi Arabia and Egypt, to see this impact.”
Lewis said that even though 250 patients and their parents is a fairly large sample size, we still need a larger sample size to come to more definitive conclusions about the prevalence of the genetic causes of CP and to be able to associate flaws with certain biological components to more specific subsets of movement challenges.
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