Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the ‘beyond epilepsy’ project

Amadori, Elisabetta; Scala, Marcello; Cereda, Giulia Sofia; Vari, Maria Stella; Marchese, Francesca; Pisa, Veronica Di; Mancardi, Maria Margherita; Giacomini, Thea; Siri, Laura; Vercellino, Fabiana; Serino, Domenico; Orsini, Alessandro; Bonuccelli, Alice; Bagnasco, Irene; Papa, Amanda; Minetti, Carlo; Cordelli, Duccio Maria; Striano, Pasquale

doi:10.1186/s13052-020-00860-1

Cited by 20 publications

(20 citation statements)

References 37 publications

(64 reference statements)

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“…Remarkably, patients with CLN2 disease in this study were diagnosed at a mean age of 38.7 months with a mean time from seizure onset to diagnosis of 10 months, a significantly shorter time compared to natural history diagnostic data [ 34 ], demonstrating that use of a comprehensive epilepsy gene panel can effectively and timely diagnose patients with CLN2 disease. Interestingly, consistent with our study, three other reports have recently shown TPP1 ( CLN2 ) pathogenic or likely pathogenic variants and CLN2 diagnosis being a relatively common finding when using NGS panels for diagnostics of pediatric seizure patients [ 10 , 26 ]. These findings stress the importance of the genes included in the selected panel when evaluating the diagnostic yield and appropriateness of the panel.…”

Section: Discussionsupporting

confidence: 92%

“…To our knowledge, this represents one of the first studies in patients with epilepsy onset between 24 to 60 months of life with comprehensive genetic testing [ 26 ]. The inclusion criteria were selected according to common early findings of CLN2 disease: unprovoked seizure after 2 years of age and at least one of motor disturbance, speech delay, MRI abnormalities and abnormal EEG.…”

Section: Discussionmentioning

confidence: 99%

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Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis

et al. 2021

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Epilepsy is one of the most common childhood-onset neurological conditions with a genetic etiology. Genetic diagnosis provides potential for etiologically-based management and treatment. Existing research has focused on early-onset (<24 months) epilepsies; data regarding later-onset epilepsies is limited. The goal of this study was to determine the diagnostic yield of a clinically available epilepsy panel in a selected pediatric epilepsy cohort with epilepsy onset between 24–60 months of life and evaluate whether this approach decreases the age of diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2). Next-generation sequencing (NGS)-based epilepsy panels, including genes associated with epileptic encephalopathies and inborn errors of metabolism (IEMs) that present with epilepsy, were used. Copy-number variant (CNV) detection from NGS data was included. Variant interpretation was performed per American College of Medical Genetics and Genomics (ACMG) guidelines. Results are reported from 211 consecutive patients with the following inclusion criteria: 24–60 months of age at the time of enrollment, first unprovoked seizure at/after 24 months, and at least one additional finding such as EEG/MRI abnormalities, speech delay, or motor symptoms. Median age was 42 months at testing and 30 months at first seizure onset; the mean delay from first seizure to comprehensive genetic testing was 10.3 months. A genetic diagnosis was established in 43 patients (20.4%). CNVs were reported in 25.6% diagnosed patients; 27.3% of CNVs identified were intragenic. Within the diagnosed cohort, 11 (25.6%) patients were diagnosed with an IEM. The predominant molecular diagnosis was CLN2 (14% of diagnosed patients). For these patients, diagnosis was achieved 12–24 months earlier than reported by natural history of the disease. This study supports comprehensive genetic testing for patients whose first seizure occurs ≥ 24 months of age. It also supports early application of testing in this age group, as the identified diagnoses can have significant impact on patient management and outcome.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis

et al. 2021

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“…Particularly, patients harbouring the p.(D146N) EPM2B mutation invariably show atypical milder LD, with delayed disease onset and prolonged disease course [9][10][11]. Nowadays, next-generation sequencing technologies have shortened the time needed for the diagnosis of several neurological disorders, including LD [12]. Nevertheless, predicting the prognosis and the evolution of LD remains challenging in most patients.…”

Section: Introductionmentioning

confidence: 99%

Ocular phenotype and electroretinogram abnormalities in Lafora disease and correlation with disease stage

et al. 2022

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Background Lafora disease (LD) is a neurodegenerative disorder featuring action and stimulus-sensitive myoclonus, epilepsy, and cognitive deterioration. Mutations in the EPM2A/EPM2B genes classically prove causative for the disease in most cases. Since full-field electroretinogram (ffERG) may reveal early-stage changes in a wide spectrum of diseases, we aimed to evaluate retinal cones and rods dysfunction in a cohort of Italian LD patients. Methods Patients with genetically confirmed LD were recruited and subjected to ffERG analysis following the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol. Results Six patients aged between 13 and 26 years (mean 19.5 years) were included. The mean age at disease onset was 12.5 years with a mean disease duration of 7 years. The ffERG analysis revealed a global mild to severe generalized cones dysfunction in all patients. Linear correlation was identified between disease stage and the degree of cones and rods dysfunction, as well as between the type of mutation and the cones and rods dysfunction. Conclusions This study brings further evidence of early retinal alterations in LD patients. The cones and rods dysfunction grade is related to disease duration. The ffERG is an important tool to determine the disease stage, allowing to evaluate either natural or treatment-related disease progression in a minimally invasive way.

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“…An example of how panels may be used to identify patients with genetic epilepsies is a prospective, multicenter study of targeted resequencing using a 283-gene next-generation sequencing panel to analyze samples from 21 children with neurodevelopmental abnormalities (aged 24-60 months) after the first unprovoked seizure [74]. Four children were diagnosed with a genetic disorder, resulting in a diagnostic yield of 19%.…”

Section: Expert Opinionmentioning

confidence: 99%

Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies

Mazurkiewicz-Bełdzińska

Toro

Haliloğlu

et al. 2021

Expert Review of Neurotherapeutics

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Introduction: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric neurodegenerative condition, which is usually fatal by mid-adolescence. Seizures are one of the most common early symptoms of CLN2 disease, but patients often experience language deficits, movement disorders, and behavioral problems. Diagnosis of CLN2 disease is challenging (particularly when differentiating between early-onset developmental, metabolic, or epileptic syndromes), and diagnostic delays often overlap with rapid disease progression. An enzyme replacement therapy (cerliponase alfa) is now available, adding CLN2 disease to the list of potentially treatable disorders requiring a prompt diagnosis. Areas covered: Although advances in enzymatic activity testing and genetic testing have facilitated diagnoses of CLN2 disease, our review highlights the presenting symptoms that are vital in directing clinicians to perform appropriate tests or seek expert opinion. We also describe common diagnostic challenges and some potential misdiagnoses that may occur during differential diagnosis. Expert opinion: An awareness of CLN2 disease as a potentially treatable disorder and increased understanding of the key presenting symptoms can support selection of appropriate tests and prompt diagnosis. The available enzyme replacement therapy heralds an even greater imperative for early diagnosis, and for clinicians to direct patients to appropriate diagnostic pathways.

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Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the ‘beyond epilepsy’ project

Cited by 20 publications

References 37 publications

Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis

Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis

Ocular phenotype and electroretinogram abnormalities in Lafora disease and correlation with disease stage

Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies

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