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Although electroencephalogram (EEG) and MRI results can detect early signs of ceroid lipofuscinosis type 2 (CLN2) disease, they cannot independently diagnose the disease, according to a panel of specialists from disease.

For early diagnosis, the committee recommends that genetic testing be initiated soon after the onset of early clinical and EEG/MRI abnormalities.

The experts’ conclusions were published in the Journal of Childhood Neurologyin the study”Role of electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings in early recognition and diagnosis of ceroid neuronal disease lipofuscinosis type 2.”

CLN2, also known as classic late childhood Batten disease, is a rare disease caused by mutations in the CLN2 gene, which carries instructions to create an enzyme called tripeptidyl peptidase1 (TPP1). Such mutations lead to the toxic buildup of waste products inside cells, especially nerve cells. Signs and symptoms usually appear between ages 2 and 4, with early features such as recurrent seizures (epilepsy), language delays, and difficulty coordinating body movements (ataxia).

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CLN2 can be diagnosed by genetic testing and/or by measuring TPP1 activity. However, in the absence of systematic screening, the disease must first be suspected by the doctor making the diagnosis. Due to the rarity of CLN2, many healthcare providers may have limited knowledge of the disease. Even more difficult, early signs and symptoms are not unique to CLN2, increasing the risk of initial misdiagnosis and treatment delays.

Studies suggest that CLN2 patients may show atypical brain wave activity, measured by EEG, and changes in brain structure via MRI images.

Researchers based at Nationwide Children’s Hospital in Columbus, Ohio, brought together a panel of CLN2 specialists to discuss real-world EEG and MRI findings to raise awareness of early indicators of CLN2 in order to promote faster diagnosis and treatment.

The study was sponsored by BioMarin Pharmaceutical, the maker of Brineura (cerliponase alfa), an approved enzyme replacement therapy designed to slow walking decline in CLN2 children by providing an external source of the missing TTP1 enzyme.

Experts collected information on early clinical signs and EEG and MRI findings from 18 CLN2 patients, with the first clinical symptoms appearing between 1 and 3.5 years of age. Language difficulties were observed in all 18 patients and were the first symptom in 15 (83%) patients. The researchers noted that language delay alone was limited as an early indicator of CLN2 due to natural variation in the speed of language development.

Almost all patients (94.4%) had seizures, mainly after language delays. Eight (44%) patients had received other diagnoses prior to their CLN2 diagnosis, most commonly various forms of epilepsy. Diagnoses were revised with further decline or new symptoms. The CLN diagnosis was established from 2 years, 7 months to 4 years, 9 months, and the diagnosis delays extended up to 3 years, 5 months.

In most facilities, an EEG was required after the first seizure. On the initial EEG, 16 (88.9%) showed background slowing, representing developmental slowing in children. Epileptiform discharge, a rare abnormal pattern associated with epilepsy, was observed in 16 (88.9%) patients. An abnormal response to light stimulation occurred in seven of the 17 patients.

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genetic screening for epilepsy |  Batten Disease News |  DNA illustration

Experts agreed that an impaired response to light stimulation was usually not present until a six-month follow-up. Therefore, as an early indicator of CLN2, it might delay diagnosis. Overall, they recommended that each EEG facility develop a light stimulation testing protocol for young children with seizures and that any unusual EEG findings be followed up by a pediatric neurologist.

MRIs were usually performed with early seizures in children under 3 years old. During the first MRI scans, most patients (77.8%) had shrinkage (atrophy) of the cerebellum – the area of ​​the brain that controls coordination and balance. Atrophy of the main part of the brain, or cerebrum, was observed in nine patients (50%), while material abnormalities were found in 11 (61.1%).

However, the extent of atrophy on initial MRI was often subtle and sometimes recognized as abnormal only retrospectively; data on normally developing children were also missing, hampering interpretation. The panel recommended the implementation of age-appropriate tools to aid in the identification of early white matter abnormalities and atrophy in young children.

On follow-up MRIs, all 15 patients assessed had cerebellar and cerebral atrophy and white matter abnormalities. Although MRI results are consistent across patients and may be an early indicator, “atrophy is common to a number of diseases and therefore is not sufficient as a single diagnostic indicator,” the researchers wrote.

Based on the published literature and their own experience, the panel agreed that none of the EEG and MRI findings were unique to CLN2 or occurred at a high enough incidence to be an indicator. in itself. So, to get an early diagnosis, the team recommended that a combination of clinical abnormalities and EEG/MRI should raise a red flag for CLN2 and the need for rapid genetic testing.

Genetic testing is not uniform

Discussions also revealed that criteria for genetic testing differed between institutions and that seizure guidelines do not yet incorporate genetic testing as a first-line measure to assess new seizures.

Considering the impact of early diagnosis and treatment on the rate of progression of CLN2, panelists said that “a case can be made for routine screening of children who present with subtle clinical symptomatology encountered with CLN2, such as autism, global developmental delay or new onset developmental delay seizure.

“Greater awareness of early signs of CLN2, increased adoption of genetic testing early in the diagnostic journey, and better communication between specialties are needed to enable earlier diagnosis and initiation of targeted disease-modifying therapies” , the researchers concluded.