Genetics study to probe mystery of cerebral palsy

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Shriners Hospitals for Children has launched a 500-patient study to investigate how genetics might contribute to cerebral palsy, in collaboration with genetic researchers at the celebrated Jackson Laboratory.

This study has the potential to open up an entire new chapter on a disability once thought to be relatively well understood and straightforward, but that in recent years has become much more of an enigma.

The new chapter someday may produce diagnostic testing and treatments for this common neurological disorder, the researchers say. Currently there is no diagnostic test for cerebral palsy and there have been no new treatments for decades.

Not long ago, experts thought most cerebral palsy cases were caused by injury during the birthing process — specifically a temporary, but devastating, asphyxia at some point during labor or the birth. But, according to Jon Davids, M.D., the assistant chief of orthopedics at Shriners Hospitals for Children — Northern California, and the organizer of the new project, current evidence indicates that intrapartum hypoxia accounts for only about 9% of cerebral palsy incidence (1), at least in developed countries.

“For years I have had a nagging sense that we were missing something in cerebral palsy, and that if we could better understand the causes, we could develop better treatments,” said Dr. Davids.

A big-data study like this is an immense task, requiring not only expertise in different fields but also automation and sophisticated computing.

To conduct the study project, five Shriners hospitals are contributing patients. Dr. Davids and his colleague Anita Bagley, Ph.D., a clinical researcher at the Northern California Shriners Hospital, will provide the clinical and phenotypic characterization of the patients.

Whole genome sequencing of the DNA samples from each of the cerebral palsy patients and their parents will be performed by the Genomic Institute of Shriners Hospitals for Children, in Tampa, Fla.

Finally, Peter Robinson, M.D., Msc., a professor of computational biology at the Jackson Laboratory, and his team will develop algorithms and software that will analyze the huge and complicated exome and genome sequences.

“This initial but important study to look for specific genes that might predispose – or even cause – a child to develop cerebral palsy is being supported by an Shriners Hospitals for Children research grant.”

When initially it was noticed that not all children with cerebral palsy had a difficult birth, a theory was advanced that some portion of cases were caused by injury or some other problem inside the womb, during pregnancy.

But, if that was the case, MRI or CT imaging of the brain should show the result of that injury.

However, as imaging has become much more common, physicians have discovered that there are no obvious signs of injury in a significantabout the womb injury theory too.

“In many cases, with brain imaging we don’t get the answer, the parents don’t get the answer . . . the answer to why their child has cerebral palsy,” said Dr. Davids.

The situation with premature infants also suggests that brain injury during the vulnerable perinatal time is not a complete explanation, Dr. Davids added. Premature infants are at much greater risk of cerebral palsy than are full-term infants. But if prematurity causes injury that, in turn, causes cerebral palsy, then why do about only 10% of extremely premature infants get cerebral palsy? (2).

So, if injury and the womb environment cannot explain all of cerebral palsy, how much of a contribution is it likely that genetics makes? A study from Sweden, published back in 2004, suggested the possibility that genetic factors might have a role in 48% of idiopathic, congenital cases of cerebral palsy. (3)

Another study — a highly sophisticated study — was published last year (4). It was an international study led by Michael Kruer, M.D., from Phoenix Children’s Hospital. The researchers assembled a cohort of 250 patients and their parents. It examined their entire exomes, that is, their functional genes.

The examination indicated that 14% of those cases of cerebral palsy could be attributed to genetic mutations – not as large as the 48% figure, but notably larger than the percentage now thought to be associated with asphyxia during delivery. The study found many distinct, associated mutations. Many of them were de novo mutations. Some have previously been implicated in other neurological conditions, including autism and epilepsy, which should probably not be surprising.

The complicated picture for the Phoenix study makes the clarification that Dr. Davids’s project might provide all the more important.

This new study has the potential to identify more mutations and possibly really drill down some crucial ones, if only because it has twice the number of patients as the international study.

Moreover, since environment and injury surely play a role, it could help elucidate that interplay.

The Jackson Laboratory is one of the oldest and most renowned independent institutions for genetic research in the world. The “JAX” lab, as it is called colloquially, was founded in 1929, in the town of Bar Harbor, Maine, on Mount Desert Island, partly to settle the then-relevant question of whether cancer was caused mostly by genetics or mostly by infectious disease, a notion that had serious popularity at the time. Work at the lab has been associated with 26 Nobel Prizes and mice developed at the lab are some of the most important used in biomedical research.

Discoveries at the Jackson Laboratory include the discovery of the immune system’s major histocompatibility complex, which paved the way for organ transplants, and of the very first “embryonic pluripotent stem cells.”

“Despite discovering CP in the 19th century, little progress has been made in understanding its causes,” said Dr. Robinson about in an announcement about the project. “This is an excellent opportunity to gain a better understanding of the genetic variants and molecular pathways that underlie CP or contribute to increased susceptibility to it.”

Dr. Davids hopes that, somewhere down the road, this huge study may have a big impact on a medical condition that hasn’t had any innovations in care in decades.

“After a century of focusing our treatments on the musculoskeletal consequences of cerebral palsy, it is exciting to think that better understanding of the causes of cerebral palsy, as identified through genomic-based research, will lead to novel and more effective treatments in certain cases,” said Dr. Davids.

1.) NEJM 1986;315:81-86.
2.) Pediatr. 2018;141:e20171433.
3.) Ann Human Gen 2004;68:515-20.
4.) Nat Genet 2020;52:1046-56.

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