Abstract

BackgroundChildhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies.MethodsThis is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age.ResultsThe average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects.ConclusionsOur findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.

Highlights

  • Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome

  • Genetic testing is very important since early genetic diagnosis of ceroid lipofuscinosis type 2 (CLN2) would allow to start intrathecal enzyme replacement therapy (ERT) with biosynthetic Tripeptidyl-peptidase I (TPP1) (Cerliponase alfa) before the patient develops the characteristic psychomotor regression

  • According to Human Splice Finder, this TPP1 variant alters the wild type acceptor splice site, leading to abnormal splicing. It has been previously reported in individuals with classic CLN2 and the phenotype of our patient was consistent with this form of the disease [13]

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Summary

Methods

This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. A 283-gene Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age

Results
Conclusions
Background
Discussion
B Parietal EA WMH
31 Pathogenic
Conclusion
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