Genetic Testing Allows Diagnosis of CLN2, Other Seizure Disorders

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Genetic testing enabled a diagnosis of ceroid lipofuscinosis type 2 disease (CLN2) in six young children with symptoms that included seizures, motor disturbances, and language delays, while 37 other children with similar symptoms were given different diagnoses, according to a recent study.

The findings support the use of genetic testing in this age group, which may mean earlier access to treatments, the researchers said.

The study, “Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis,” was published in PLOS One

Also called late infantile Batten disease, CLN2 disease is a genetic condition arising from mutations in a gene of the same name. Symptoms such as seizures, and loss of vision, motor, and intellectual skills typically emerge between the ages of 2 and 4.

Other genetic disorders are characterized by similar symptoms, particularly recurrent seizures, or epilepsy, which emerge in childhood, making an accurate disease diagnosis difficult.

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Next-generation sequencing (NGS) is a type of genetic testing wherein several genes are screened simultaneously to find a patient’s disease-causing mutations; the gene in which the mutation — or mutations —  resides helps clinicians make an accurate diagnosis.

It’s unclear if this approach is useful for diagnosing children with seizures that emerge after age 2, as is seen in CLN2 disease, however.

A team of researchers performed a NGS on a large panel of epilepsy-associated genes in 211 children, ages 2 to 5, from Europe and the Middle East who met the criteria for CLN2 disease: a first, unprovoked seizure between 2 and 5, and at least one of either a motor disturbance, a speech delay, MRI abnormalities, or an abnormal electroencephalogram, which can monitor seizure activity in the brain.

Among the group, the mean age was 3.5 with a mean age of epilepsy onset at 2.5. A family history of seizures was reported for 16.6% of the children.

At the time of testing, 70.1% of the children experienced language delays and 55.9% had motor disturbances. Clinical records showed that 42.7% had abnormal findings on an electroencephalogram and 30.8% had abnormal brain MRI findings.

Other observed symptoms included developmental delay (48.3%), behavioral abnormalities (41.7%), sleep disturbances (25.6%), and vision impairment (10.4%).

Results from the NGS analysis established a genetic diagnosis in 43 people (20.4%). A “suspicious” variant of unknown significance was found in an additional 17 children, meaning that the researchers suspected the variant to be the cause of disease, but it could not be confirmed.

Six were diagnosed with CLN2 disease based on mutations in the tripeptidyl peptidase 1 gene (TPP1/CLN2). Five had the same mutation (c.622C>T) while the sixth had a different mutation in that same gene (c.533del).

CLN2 is inherited in a recessive manner, meaning that a child must inherit two mutated copies of the gene — one from each parent — in order to be symptomatic. This was the case for all six diagnosed children.

The onset of the six children’s seizures ranged from 35 months (almost three years) to 44 months (about 3.5 years). All experienced language delays and motor disturbances.

“Remarkably, patients with CLN2 disease in this study were diagnosed at a mean age of 38.7 months [just over two years] with a mean time from seizure onset to diagnosis of 10 months, a significantly shorter time compared to natural history diagnostic data, demonstrating that use of a comprehensive epilepsy gene panel can effectively and timely diagnose patients with CLN2 disease,” the researchers wrote.

A few patients had mutations in genes associated with other forms of Batten disease. One had a mutation in the PPT1 gene, which is associated with infantile Batten disease, or CLN1 disease. Two patients had mutations in MFSD8, which is associated with CLN7 disease, another form of late-infantile Batten disease.

Dravet syndrome and Rett syndrome, among several others, were also able to be diagnosed. About 63% of the children were diagnosed with a disease for which there is a targeted treatment, and the diagnosis could provide them with quicker access to these therapies, the research team noted.

“Our findings further the importance of the early use of genetic testing … in this age group to efficiently identify severe disorders with targeted management available such as CLN2,” the researchers wrote.

“Considering the high prevalence of CLN2, this study supports the addition of TPP1 (CLN2) and other genes linked to [neuronal ceroid lipofuscinoses] in diagnostic NGS-based epilepsy panels,” they concluded.