On Sept. 28, 2020, in an article published in Nature Genetics, researchers confirmed that about 14% of all cases of cerebral palsy, a disabling brain disorder for which there are no cures, may be linked to a patient’s genes and suggest that many of those genes control how brain circuits become wired during early development. This conclusion is based on the largest genetic study of cerebral palsy ever conducted. The results led to recommended changes in the treatment of at least three patients, highlighting the importance of understanding the role genes play in the disorder. The work was largely funded by the National Institute of Neurological Disorders and Stroke.

Cerebral palsy affects approximately one in 323 children in the United States. Signs of the disorder appear early in childhood resulting in a wide range of permanently disabling problems with movement and posture, including spasticity, muscle weakness, and abnormal gait. Nearly 40% of patients need some assistance with walking. In addition, many patients may also suffer epileptic seizures, blindness, hearing and speech problems, scoliosis, and intellectual disabilities.

Since its first official description in 1862, scientists have hotly debated whether cerebral palsy is caused by problems at birth. For instance, it is known that babies born prematurely or who experience a lack of blood flow or oxygen during birth have a greater chance of suffering from the disorder. Later though, researchers concluded that a majority (85-90%) of all cases are congenital, or born with the disease, and some studies had suggested that cerebral palsy could be inherited. Despite this, the causes of many children’s cases had remained elusive.

Then in 2004, scientists discovered the first genetic mutation known to cause cerebral palsy. Since then several more mutations have been identified and depending on how an experiment was performed, scientists have estimated that anywhere from 2 to 30% of all cases may be linked to a misspelling in a patient’s DNA. In this study, the researchers provided support for a previous estimate and highlighted which genes may play a critical role in the disorder.

Initially the researchers found that the cerebral palsy patients had higher levels of potentially harmful de novo mutations than their parents. Many of these mutations appeared to be concentrated in genes that are highly sensitive to the slightest changes in the DNA letter code. In fact, they estimated that about 11.9% of the cases could be explained by damaging de novo mutations. This was especially true for the idiopathic cases which had no known cause and represented the majority (62.8%) of cases in the study. Approximately another 2% of the cases appeared to be linked to recessive, or weaker, versions of genes. This raised the estimate of cases that could be linked to genetic problems from 11.9% to 14%, as has been previously reported.

Further analysis of the results suggested that many of the genes they found in this study, including six of the eight genes that had two or more de novo mutations, control the wiring of neural circuits during early development. Specifically, these genes are known to be involved in either the construction of protein scaffolds that line the perimeters of neural circuits or in the growth and extension of neurons as they wire up.

Experiments on fruit flies, formally known as Drosophila melanogaster, supported this idea. To do this, the researchers mutated fly versions of the wiring genes they identified in the cerebral palsy patients. They found that mutations in 71% of these genes caused flies to have problems with movement, including walking, turning, and balancing. The results suggested that these genes play a critical role in movement. They estimated that there was only a 3% chance these problems would happen if they had blindly mutated any gene in the fly genome.