The results confirmed that roughly almost 15% of cases are linked to genes and ultimately led to recommendations for more tailored treatments of 3 patients.
Michael Kruer, MD
Results from a study confirm that around 14% of cases in patients with cerebral palsy (CP) may be linked to a patient’s genes and suggest that many of those genes control how brain circuits are wired during early development.
Deemed the largest genetic study of CP ever conducted, the study’s findings influenced recommended changes in the treatment of at least 3 patients. Largely funded by the National Institute of Neurological Disorders and Stroke (NINDS), a National Institutes of Health (NIH) subsector, results also showed that 2% of cases are linked to recessive versions of genes.
“Our results provide the strongest evidence to date that a significant portion of cerebral palsy cases can be linked to rare genetic mutations, and in doing so identified several key genetic pathways involved,” Michael Kruer, MD, neurogeneticist, Phoenix Children’s Hospital and University of Arizona College of Medicine, said in a statement.
Led by Sheng Chih Jin, PhD, assistant professor of genetics, Washington University in St. Louis School of Medicine, the researchers searched for de novo mutations in the genes of 250 families from the United States, China, and Australia. Whole exome sequencing was used to read out and compare the exact codes of each gene inscribed in the chromosomes of the patients with that of their parents.
The initial data showed that patients with CP had higher levels of potentially harmful de novo mutations than their parents, many of which appeared to be concentrated in genes that are highly sensitive to the slightest changes in the DNA letter code. They then estimated that 11.9% of the cases could be explained by damaging de novo mutations. Notably, this was found to be especially true for those who were idiopathic, which represented 62.8% of the cases in the study.
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A closer look at the data showed that 8 genes had 2 or more damaging de novo mutations. Notably, 4 of those genes, labeled RHOB, FBX031, DHX32, and ALK, were newly implicated in CP while the other 4 had been identified previously.
They also noted that the results of RHOB and FBX031 were surprising. There were 2 cases in the study that had the same spontaneous mutation in RHOB. Likewise, 2 other cases had the same de novo mutation in FBX031.
A deeper look into the analysis showed that many of the genes, specifically 6 of the 8 that had 2 or more de novo mutations, control the wiring of neural circuits during early development. Investigators noted that these genes are known to be involved in the protein scaffolds that line the perimeters of neural circuits or in the growth and extension of neurons as they wire up.
“Cerebral palsy is one of neurology’s oldest unresolved mysteries. The results from this study show how advances in genomic research provide scientists with the hard evidence they need to unravel the causes behind this and other debilitating neurological disorders,” Jim Koenig, PhD, program director, NINDS, said in a statement.
The hypotheses about whether or not CP is caused by problems at birth have dated back to the first official description of the disorder in 1862. Previous studies have confirmed 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. According to the Centers for Disease Control and Prevention (CDC), a majority of CP cases (85% to 90%) are congenital or born with the disease. Some studies have suggested that CP could be inherited, but the real causes of many children’s cases have remained unsolved.
In 2004, scientists discovered the first genetic mutation known to cause CP. Since then, many more mutations have been found and researchers have estimated that anywhere from 2% to 30% of all cases may be linked to a misspelling in a patient’s DNA.
“Treatments for cerebral palsy patients have not changed for decades,” Kruer continued. “In the future we plan to explore how these results can be used to change that.”