Targeted Epilepsy Genetic Testing Drives More, Sooner CLN2 Diagnoses

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A targeted epilepsy genetic testing program enabled more children to receive a diagnosis of ceroid lipofuscinosis type 2 disease (CLN2) — and in less than half the time it typically takes, a study reported.

In fact, children in the testing program with CLN2 disease were diagnosed, on average, less than 10 months after their seizures began. That is significantly earlier than the usual average time to diagnosis of nearly two years, according to researchers.

“These findings indicate that facilitated access to early epilepsy gene panel testing helps to increase diagnostic yield for CLN2 disease and shortens the time to diagnosis, enabling earlier intervention,” the team wrote.

The study, “Value of genetic testing for pediatric epilepsy: Driving earlier diagnosis of CLN2 Batten disease,” was published in Epilepsia.

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Genetic Testing Allows Diagnosis of CLN2, Other Seizure Disorders

CLN2 disease, also called late infantile Batten disease, is a rare neurological condition that arises from mutations in the TPP1 gene. Seizures, language delays, and motor function problems, among other Batten symptoms, usually begin to emerge between the ages of 2 and 4.

However, because the disease is rare and shares symptoms with a number of other childhood seizure disorders, children with CLN2 disease are often not correctly diagnosed until they are about 5 years old. At that point, marked neurodegeneration has already occurred.

Existing treatments, such as enzyme replacement therapy, can slow disease progression, but cannot reverse existing damage. Thus, an earlier diagnosis is critical, the research team noted.

Genetic testing for TPP1 mutations may be a helpful way to allow a sooner diagnosis — and access to potentially life-saving treatments.

Invitae’s Behind the Seizure program provides no-charge genetic testing for children younger than 5 with symptoms of unprovoked seizures. Results from the test, which looks for mutations in a large panel of genes known to be associated with seizures, usually arrive quickly — within 10-21 days.

According to researchers, however, such “definitive testing (e.g., TPP1 enzyme testing, TPP1 gene sequencing) is often sought late in the diagnostic odyssey.”

The team now investigated whether Behind the Seizure (BTS) could in fact help speed CLN2 diagnoses among children with symptoms of epilepsy compared with routine genetic screening outside of the sponsored program.

All children included in the study were younger than age 5, and had symptoms of unprovoked seizures that had emerged after the child turned 2 — a hallmark feature of CLN2 disease. Originally, the BTS program included only children older than 2, but in 2019, the criteria were expanded to include younger children.

In total, 4,246 kids were tested through BTS, 629 of whom received a genetic diagnosis. TPP1 mutations were found in 18 children, all of whom were between 3 and 4 years old.

Overall, the scientists found the rates of CLN2 diagnosis were higher among children tested under BTS than those tested outside of the program.

The first analysis involved children, only older than 2, from BTS, and an age-matched group tested outside BTS. The team found that while overall genetic diagnoses were not greater in the BTS group, CLN2 specifically was diagnosed at a 2.9 times higher rate in children in the testing program. Eighteen kids from BTS (1%) and eight from outside the program received that diagnosis.

When analyzing children of all ages (0–5) who participated in the program after 2019 (some of whom overlapped with the first analysis), the findings were similar, with a 1.5 times higher rate of CLN2 diagnoses in the BTS program compared with outside of it.

In children older than 2 who were tested with BTS, those patients who received any genetic diagnosis, and specifically a CLN2 diagnosis, more often had language delays, motor delays, MRI abnormalities, and abnormal findings on tests of the brain’s electrical activity than children who did not receive a diagnosis.

Among all patients who were diagnosed, there was a greater prevalence of developmental delays before seizures began compared with the undiagnosed group.

Further, the time between the emergence of seizures and genetic testing was longer in children who were unable to receive a genetic diagnosis — an average of 8.4 months — compared with children who were diagnosed, for whom the average time was 6.9 months.

The researchers noted that children with CLN2 disease were diagnosed an average of 9.8 months after their seizures began, which is significantly earlier than is typical for CLN2 disease. Natural history data shows that the average time to diagnosis is usually nearly two years, they said.

Altogether, the results demonstrate “the effectiveness of targeted testing programs in enriching testing cohorts for rare diseases,” the researchers wrote, adding that earlier genetic testing allows for sooner diagnoses and initiation of potentially life-saving treatments.

“The data presented here support the calls for clinical practice guidelines to consider the utilization of genetic testing as a first-tier test for individuals with epilepsy early in the diagnostic journey, or with neurodegenerative diseases presenting with epilepsy, such as CLN2 disease,” the researchers wrote.

BTS was established by BioMarin Pharmaceuticals and Invitae. The study was funded by BioMarin Pharmaceuticals. Notably, some of the study’s authors are affiliated with BioMarin or Invitae.