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Genetic testing helped diagnose ceroid disease lipofuscinosis type 2 (CLN2) in six young children with symptoms including seizures, motor problems and language delays, while 37 other children with similar symptoms received diagnoses different, 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 epilepsies: diagnostic yield and impact on the diagnosis of ceroid lipofuscinosis type 2 (CLN2) neuronal disease,” was published in PLOS One.

Also called late childhood Batten disease, CLN2 disease is a genetic disorder resulting from mutations in a gene of the same name. Symptoms such as seizures and loss of vision, motor and intellectual abilities usually appear between 2 and 4 years of age.

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

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CLN5 mutations |  Batten Disease News |  cells illustration

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

It is unclear whether this approach is useful for diagnosing children with seizures that appear after age 2, as seen in CLN2 disease, however.

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

In the group, the average age was 3.5 years with an average age of onset of epilepsy at 2.5 years. A family history of seizures was reported for 16.6% of children.

At the time of the test, 70.1% of the children had language delays and 55.9% had motor disorders. Clinical records showed that 42.7% had abnormal results on an electroencephalogram and 30.8% had abnormal results on brain MRI.

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

The results of the NGS analysis established a genetic diagnosis in 43 people (20.4%). A “suspicious” variant of unknown significance was found in 17 other children, meaning the researchers suspected the variant was the cause of the disease, but this could not be confirmed.

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

CLN2 is recessively inherited, meaning a child must inherit two mutated copies of the gene – one from each parent – ​​to be symptomatic. This was the case for the six children diagnosed.

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 impairments.

“Remarkably, patients with CLN2 disease in this study were diagnosed at an average 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 the 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 childhood Batten disease, or CLN1 disease. Two patients had mutations in MFSD8which is associated with CLN7 disease, another form of late childhood Batten disease.

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

“Our results reinforce the importance of early use of genetic testing…in this age group to effectively identify serious disorders with available targeted management such as CLN2,” the researchers wrote.

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