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  • 1
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    Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Neurology Vol. 90, No. 4 ( 2018-01-23), p. e332-e341
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 90, No. 4 ( 2018-01-23), p. e332-e341
    Abstract: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 ( CFHR4 ) gene and phenytoin-induced MPE in Europeans ( p = 4.5 × 10 –11 ; odds ratio [95% confidence interval] 7 [3.2–16] ). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H ( CFH ) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000004853
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 2
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    Association of ultra‐rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study
    Wiley ; 2022
    In:  Epilepsia Vol. 63, No. 3 ( 2022-03), p. 723-735
    Details
    In: Epilepsia, Wiley, Vol. 63, No. 3 ( 2022-03), p. 723-735
    Abstract: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. Methods We performed a case–control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry‐matched controls. The association of ultra‐rare variants (URVs; in 18 834 protein‐coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ‐aminobutyric acid type A [GABA A ] receptors, 113 genes representing the GABAergic pathway). Results GABRG2 was associated with GGE ( p  = 1.8 × 10 −5 ), approaching study‐wide significance in familial GGE ( p  = 3.0 × 10 −6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABA A receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI]  = 1.9–7.8, false discovery rate [FDR]‐adjusted p  = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3–6.7, FDR‐adjusted p  = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3–2.5, FDR‐adjusted p  = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9–1.9, FDR‐adjusted p  = .19). Significance URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.
    Type of Medium: Online Resource
    ISSN: 0013-9580 , 1528-1167
    URL: Issue
    URL: Article
    DOI: 10.1111/epi.v63.3
    DOI: 10.1111/epi.17166
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2002194-X
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  • 3
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    Genomic and clinical predictors of lacosamide response in refractory epilepsies
    Wiley ; 2019
    In:  Epilepsia Open Vol. 4, No. 4 ( 2019-12), p. 563-571
    Details
    In: Epilepsia Open, Wiley, Vol. 4, No. 4 ( 2019-12), p. 563-571
    Abstract: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real‐world clinical setting. Methods We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome‐wide association studies and exome studies, comprising 281 candidate genes. Results Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders ( 〈 25% seizure reduction). No variants reached the genome‐wide significance threshold in our case‐control analysis. Significance No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.
    Type of Medium: Online Resource
    ISSN: 2470-9239 , 2470-9239
    URL: Issue
    URL: Article
    DOI: 10.1002/epi4.v4.4
    DOI: 10.1002/epi4.12360
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2863427-5
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  • 4
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    Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study
    Future Medicine Ltd ; 2020
    In:  Pharmacogenomics Vol. 21, No. 5 ( 2020-04), p. 325-335
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 21, No. 5 ( 2020-04), p. 325-335
    Abstract: Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials  & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p 〈 10 -5 ) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/pgs-2019-0179
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2020
    SSG: 15,3
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  • 5
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    Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy
    Wiley ; 2019
    In:  Epilepsia Open Vol. 4, No. 3 ( 2019-09), p. 420-430
    Details
    In: Epilepsia Open, Wiley, Vol. 4, No. 3 ( 2019-09), p. 420-430
    Abstract: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12‐month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08‐1.13], P   〈  0.001) and female sex (1.41 [1.07‐1.85], P  = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15‐5.02] , P   〈  0.001 and 1.93 [1.31‐2.86], P   〈  0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P  = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.
    Type of Medium: Online Resource
    ISSN: 2470-9239 , 2470-9239
    URL: Issue
    URL: Article
    DOI: 10.1002/epi4.v4.3
    DOI: 10.1002/epi4.12349
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2863427-5
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  • 6
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    A genome‐wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine
    Wiley ; 2019
    In:  Epilepsia Open Vol. 4, No. 1 ( 2019-03), p. 102-109
    Details
    In: Epilepsia Open, Wiley, Vol. 4, No. 1 ( 2019-03), p. 102-109
    Abstract: To ascertain the clinical and genetic factors contributing to carbamazepine‐ and oxcarbazepine‐induced hyponatremia ( COIH ), and to carbamazepine ( CBZ ) metabolism, in a retrospectively collected, cross‐sectional cohort of people with epilepsy. Methods We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC . We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ ‐diol to unchanged drug precursor substrate as measured in serum. Results Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome‐wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome‐wide significant associations with CBZ metabolic ratio were found. Significance Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.
    Type of Medium: Online Resource
    ISSN: 2470-9239 , 2470-9239
    URL: Issue
    URL: Article
    DOI: 10.1002/epi4.2019.4.issue-1
    DOI: 10.1002/epi4.12297
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2863427-5
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  • 7
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    Carbamazepine‐ and oxcarbazepine‐induced hyponatremia in people with epilepsy
    Wiley ; 2017
    In:  Epilepsia Vol. 58, No. 7 ( 2017-07), p. 1227-1233
    Details
    In: Epilepsia, Wiley, Vol. 58, No. 7 ( 2017-07), p. 1227-1233
    Abstract: To ascertain possible determinants of carbamazepine ( CBZ )– and oxcarbazepine ( OXC )–induced hyponatremia in a large cohort of people with epilepsy. Methods We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC . We defined hyponatremia as Na+ ≤134 mE q/L and severe hyponatremia as Na+ ≤128 mE q/L. Results We identified 1,782 people who had used CBZ (n = 1,424) or OXC (n = 358), of whom 50 were treated with both drugs. Data on sodium level measurements were available in 1,132 on CBZ and in 289 on OXC . Hyponatremia occurred in 26% of those taking CBZ and 46% of those taking OXC . This was severe in 7% in the CBZ group and 22% in the OXC group. Hyponatremia was symptomatic in 48% and led to admissions in 3%. Age over 40 years, high serum levels of CBZ and OXC , and concomitant use of other antiepileptic drugs were the main risk factors for hyponatremia in both treatment groups. Female patients on OXC were at a higher risk than male patients of hyponatremia. The risk of hyponatremia on CBZ was significantly associated with the risk of hyponatremia on OXC within a subgroup that used both drugs consecutively. Significance Hyponatremia is a common problem in people taking CBZ or OXC . Regular ascertainment of sodium levels in those taking either drug is recommended and results should be acted on.
    Type of Medium: Online Resource
    ISSN: 0013-9580 , 1528-1167
    URL: Issue
    URL: Article
    DOI: 10.1111/epi.2017.58.issue-7
    DOI: 10.1111/epi.13777
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2002194-X
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  • 8
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    Assessing the role of rare genetic variants in drug‐resistant, non‐lesional focal epilepsy
    Wiley ; 2021
    In:  Annals of Clinical and Translational Neurology Vol. 8, No. 7 ( 2021-07), p. 1376-1387
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 8, No. 7 ( 2021-07), p. 1376-1387
    Abstract: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v8.7
    DOI: 10.1002/acn3.51374
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2740696-9
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  • 9
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    A systems‐level analysis highlights microglial activation as a modifying factor in common epilepsies
    Wiley ; 2022
    In:  Neuropathology and Applied Neurobiology Vol. 48, No. 1 ( 2022-02)
    Details
    In: Neuropathology and Applied Neurobiology, Wiley, Vol. 48, No. 1 ( 2022-02)
    Abstract: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis. Methods Imaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy. Results We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post‐mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non‐spatial memory test seen in epileptic mice not depleted of microglia. Conclusions These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
    Type of Medium: Online Resource
    ISSN: 0305-1846 , 1365-2990
    URL: Issue
    URL: Article
    DOI: 10.1111/nan.v48.1
    DOI: 10.1111/nan.12758
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2008293-9
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  • 10
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    Data_Sheet_1.docx
    Frontiers Media SA ; 2023
    In:  Frontiers in Neuroscience Vol. 17 ( 2023-9-8)
    Details
    In: Frontiers in Neuroscience, Frontiers Media SA, Vol. 17 ( 2023-9-8)
    Abstract: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug. Methods Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals ( n  = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants. Results The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing. Conclusion We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.
    Type of Medium: Online Resource
    ISSN: 1662-453X
    URL: Article
    URL: Article
    DOI: 10.3389/fnins.2023.1156362
    DOI: 10.3389/fnins.2023.1156362.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
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