Genetic Diagnosis in Cerebral Palsy Patients Could Change Treatment Approach

Cerebral palsy, a nonprogressive motor impairment that begins in early childhood, is widely thought to result from lack of oxygen during labor or other birth-related factors such as prematurity. While this is true for many children, new research from Boston Children’s Hospital has revealed that up to 1 in 4 have an underlying genetic condition that has the potential to change the overall approach to their care. The study appears in Annals of Clinical and Translational Neurology.

“When people think of cerebral palsy, the first thing many doctors think of is birth injuries or asphyxia,” says lead investigator Siddharth Srivastava, MD, a neurologist with the Boston Children’s Cerebral Palsy and Spastity Program who specializes in neurogenetic disorders. “This idea has become pervasive, both in neurology and orthopedic education and in the general public.”

The idea that birth injuries are to blame for cerebral palsy (CP) has prompted some families to file lawsuits. Other families have blamed themselves, believing that something that happened during pregnancy caused their child’s condition.

A mother of an adult child with CP told us his genetic diagnosis cleared her of more than three decades of guilt. Many families felt they finally had a sense of completion.”

Siddharth Srivastava, MD, Study Senior Investigator and Neurologist for Pediatric Cerebral Palsy, Boston Children’s Hospital

Genetic Findings

The research team sequenced the DNA of 50 patients with CP through the genomics initiative of the hospital’s Children’s Rare Disease Cohorts (CRDC).

Clinical examinations and MRIs of the brain were performed on the patients, whose average age was 10 years. They fell into three groups: 20 had a known risk factor for CP, such as prematurity, cerebral hemorrhage, or hypoxia; 24 had no known risk factors; and 5 were “CP Masqueraders” -; who meet most of the criteria for CP but experience worsening of their condition over time (by definition, CP is a non-progressive disease).

“We wanted to include these three groups to reflect the range of patients we see,” explains Srivastava.

Overall, sequencing identified a causative or probable causative genetic variant in 13 patients (26 percent). These variants involved 13 different genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, and ATL1).

CP masquerade veins were most likely to have a genetic diagnosis: a cause was identified in 3 out of 5 patients with progressive CP-like disease (60 percent). Next came patients with CP and no known risk factors: a genetic cause was found in 7 out of 24 (29 percent).

Surprisingly, even in some patients with a known risk factor for CP, such as B. asphyxia at birth, identified a genetic mutation (3 in 20 patients or 15 percent).

“These three patients are particularly intriguing,” says Maya Chopra, MBBS, FRACP, a clinical geneticist and director of Translational Genomic Medicine at Boston Children’s Rosamund Stone Zander Translational Neuroscience Center. Chopra was co-first author of the article along with pediatric resident Dustin L. Gable MD, PhD.

“In one child we identified a rare genetic disorder that predisposes to an early stroke. The other two had genetic conditions not known to be associated with cerebral palsy. Could these have made her more susceptible to early brain injury? We still have much to learn about the interplay between rare gene variants and perinatal events in the development of CP.”

Implications of a genetic diagnosis in CP

In some cases, the genetic findings led to changes in the patient’s treatment plan. For example, one child was found to have a gene associated with a metabolic disorder and was referred to the metabolic clinic; one adult was referred for eye and kidney evaluation for his mutation; and an adolescent diagnosed with CP throughout his life was found to have a genetic mutation linked to a progressive neurological disorder, alerting his care team to watch for his condition worsening.

Based on their findings, the researchers urge parents and clinicians to consider and appropriately investigate or refer a genetic cause for any child with CP without known risk factors or with CP-like features but whose condition is deteriorating.

They also suggest considering genetic testing in children with established risk factors for CP if they have characteristics suggestive of a genetic condition, such as B. Congenital abnormalities or other affected family members. Finally, they suggest that children with CP be reassessed periodically to ensure other aspects of their condition have not been overlooked or to see if new features have emerged over time.

“This work is groundbreaking and very exciting,” says Benjamin Shore, MD, MPH, co-director of the Cerebral Palsy and Spasticity Center. “In the past, a diagnosis of CP was attributed to many children who exhibit muscle tightness and developmental delays without really understanding the cause. We can now examine these causes in much more detail. I hope that in the future we can provide genetic diagnostics for many more children, especially CP Masquerade.”

Annapurna Poduri, MD, MPH, co-senior author of the paper, sees a parallel with epilepsy. She directs the Epilepsy Genetics Program and the CRDC Epilepsy Cohort Study at Boston Children’s.

“We now have the scientific knowledge to make an accurate diagnosis for children with CP that is not just descriptive but provides answers and potentially opens a door to treating some of the underlying conditions we are uncovering,” she says. “Precision diagnostics will enable precision treatments for more and more children with CP, epilepsy and other neurodevelopmental disorders.”

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