Advances in the development of biomarkers for epilepsy

Pitkänen, Asla; Löscher, Wolfgang; Vezzani, Annamaria; Becker, Albert; Simonato, Michele; Łukasiuk, Katarzyna; Gröhn, Olli; Bankstahl, Jens P.; Friedman, Alon; Aronica, Eleonora; Gorter, Jan A.; Ravizza, Teresa; Sisodiya, Sanjay M.; Kokaia, Mérab; Beck, Hanno

doi:10.1016/s1474-4422(16)00112-5

Cited by 310 publications

(223 citation statements)

References 129 publications

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“…Repeated and refractory seizures can cause long-term cognitive impairment, decreased social participation and significantly lower quality of life [1, 2]. Epilepsy is one of the most common neurological disorders with 50 to 100 million affected worldwide, and 2 to 4 million new cases diagnosed each year [3]. …”

Section: Introductionmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0–14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0392-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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“…Subsequently, the same authors [13], studying a clinically heterogeneous group of drug-resistant and drug-responsive patients with idiopathic and cryptogenic epilepsy found abnormal expression levels of hsa-miR-301a as a good candidate to discriminate these two groups. Because of the remarkable heterogeneity in terms of aetiology and underlying mechanisms in different forms of epilepsy, we designed the present study to include well defined epilepsy syndromes aiming to avoid the confounding factors which could hinder the identification of reliable biomarkers in epilepsy [30]. …”

Section: Discussionmentioning

confidence: 99%

MicroRNA hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy

et al. 2017

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Epilepsy is misdiagnosed in up to 25% of patients, leading to serious and long-lasting consequences. Recently, circulating microRNAs have emerged as potential biomarkers in a number of clinical scenarios. The purpose of this study was to identify and to validate circulating microRNAs that could be used as biomarkers in the diagnosis of epilepsy. Quantitative real-time PCR was used to measure plasma levels of three candidate microRNAs in two phases of study: an initial discovery phase with 14 patients with mesial temporal lobe epilepsy (MTLE), 13 with focal cortical dysplasia (FCD) and 16 controls; and a validation cohort constituted of an independent cohort of 65 patients with MTLE and 83 controls. We found hsa-miR-134 downregulated in patients with MTLE (p = 0.018) but not in patients with FCD, when compared to controls. Furthermore, hsa-miR-134 expression could be used to discriminate MTLE patients with an area under the curve (AUC) of 0.75. To further assess the robustness of hsa-miR-134 as a biomarker for MTLE, we studied an independent cohort of 65 patients with MTLE, 27 of whom MTLE patients were responsive to pharmacotherapy, and 38 patients were pharmacoresistant and 83 controls. We confirmed that hsa-miR-134 was significantly downregulated in the plasma of patients with MTLE when compared with controls (p < 0.001). In addition, hsa-miR-134 identified patients with MTLE regardless of their response to pharmacotherapy or the presence of MRI signs of hippocampal sclerosis. We revealed that decreased expression of hsa-miR-134 could be a potential non-invasive biomarker to support the diagnosis of patients with MTLE.

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“…Respective biomarkers are urgently needed for patient stratification following insults and for the follow-up of the efficacy of clinical intervention trials assessing antiepileptogenic strategies (Schmidt, 2012, Pitkanen et al, 2013, Trinka and Brigo, 2014, Pitkanen et al, 2016). In experimental studies respective biomarkers might serve as valuable tools decreasing the workload associated with the testing of preventive approaches otherwise requiring week-long seizure monitoring (Dedeurwaerdere et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Identification of brain regions predicting epileptogenesis by serial [18F]GE-180 positron emission tomography imaging of neuroinflammation in a rat model of temporal lobe epilepsy

Russmann

Brendel

Mille

et al. 2017

NeuroImage: Clinical

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Excessive activation of inflammatory signaling pathways seems to be a hallmark of epileptogenesis. Positron emission tomography (PET) allows in vivo detection of brain inflammation with spatial information and opportunities for longitudinal follow-up scanning protocols.Here, we assessed whether molecular imaging of the 18 kDa translocator protein (TSPO) can serve as a biomarker for the development of epilepsy. Therefore, brain uptake of [18F]GE-180, a highly selective radioligand of TSPO, was investigated in a longitudinal PET study in a chronic rat model of temporal lobe epilepsy. Analyses revealed that the influence of the epileptogenic insult on [18F]GE-180 brain uptake was most pronounced in the earlier phase of epileptogenesis. Differences were evident in various brain regions during earlier phases of epileptogenesis with [18F]GE-180 standardized uptake value enhanced by 2.1 to 2.7fold. In contrast, brain regions exhibiting differences seemed to be more restricted with less pronounced increases of tracer uptake by 1.8–2.5fold four weeks following status epilepticus and by 1.5–1.8fold in the chronic phase. Based on correlation analysis, we were able to identify regions with a predictive value showing a correlation with seizure development. These regions include the amygdala as well as a cluster of brain areas. This cluster comprises parts of different brain regions, e.g. the hippocampus, parietal cortex, thalamus, and somatosensory cortex.In conclusion, the data provide evidence that [18F]GE-180 PET brain imaging can serve as a biomarker of epileptogenesis. The identification of brain regions with predictive value might facilitate the development of preventive concepts as well as the early assessment of the interventional success. Future studies are necessary to further confirm the predictivity of the approach.

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Advances in the development of biomarkers for epilepsy

Cited by 310 publications

References 129 publications

Novel and de novo mutations in pediatric refractory epilepsy

Novel and de novo mutations in pediatric refractory epilepsy

MicroRNA hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy

Identification of brain regions predicting epileptogenesis by serial [18F]GE-180 positron emission tomography imaging of neuroinflammation in a rat model of temporal lobe epilepsy

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