Medicine (Austin & Northern Health) - Research Publications

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    Climate change and epilepsy: Insights from clinical and basic science studies
    Gulcebi, M ; Bartolini, E ; Lee, O ; Lisgaras, CP ; Onat, F ; Mifsud, J ; Striano, P ; Vezzani, A ; Hildebrand, MS ; Jimenez-Jimenez, D ; Junck, L ; Lewis-Smith, D ; Scheffer, IE ; Thijs, RD ; Zuberi, SM ; Blenkinsop, S ; Fowler, HJ ; Foley, A ; Sisodiya, SM ; Balestrini, S ; Berkovic, S ; Cavalleri, G ; Correa, DJ ; Custodio, HM ; Galovic, M ; Guerrini, R ; Henshall, D ; Howard, O ; Hughes, K ; Katsarou, A ; Koeleman, BPC ; Krause, R ; Lowenstein, D ; Mandelenaki, D ; Marini, C ; O'Brien, TJ ; Pace, A ; De Palma, L ; Perucca, P ; Pitkanen, A ; Quinn, F ; Selmer, KK ; Steward, CA ; Swanborough, N ; Thijs, R ; Tittensor, P ; Trivisano, M ; Weckhuysen, S ; Zara, F (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-02-10)
    Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.
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    Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome
    Green, TE ; MacGregor, D ; Carden, SM ; Harris, RV ; Hewitt, CA ; Berkovic, SF ; Penington, AJ ; Scheffer, IE ; Hildebrand, MS (COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2021-12-01)
    Nevus sebaceous syndrome (NSS) is a rare, multisystem neurocutaneous disorder, characterized by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular, and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with postzygotic variants in HRAS or KRAS in all individuals studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signaling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an individual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippocampal sclerosis without pathological evidence of a brain malformation. We used high-depth gene panel sequencing and droplet digital polymerase chain reaction (PCR) to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G > T; p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and, more specifically, hippocampal sclerosis.
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    Infantile-onset myoclonic developmental and epileptic encephalopathy: A new RARS2 phenotype
    de Valles-Ibanez, G ; Hildebrand, MS ; Bahlo, M ; King, C ; Coleman, M ; Green, TE ; Goldsmith, J ; Davis, S ; Gill, D ; Mandelstam, S ; Scheffer, IE ; Sadleir, LG (WILEY, 2021-11-18)
    Recessive variants in RARS2, a nuclear gene encoding a mitochondrial protein, were initially reported in pontocerebellar hypoplasia. Subsequently, a recessive RARS2 early-infantile (<12 weeks) developmental and epileptic encephalopathy was described with hypoglycaemia and lactic acidosis. Here, we describe two unrelated patients with a novel RARS2 phenotype and reanalyse the published RARS2 epilepsy phenotypes and variants. Our novel cases had infantile-onset myoclonic developmental and epileptic encephalopathy, presenting with a progressive movement disorder from 9 months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple drug-resistant generalized and focal seizures occurred with episodes of non-convulsive status epilepticus. Seizure types included absence, atonic, myoclonic, and focal seizures. Electroencephalograms showed diffuse slowing, multifocal, and generalised spike-wave activity, activated by sleep. Both patients had compound heterozygous RARS2 variants with likely impact on splicing and transcription. Remarkably, of the now 52 RARS2 variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to protein truncation or nonsense-mediated decay. We expand the RARS2 phenotypic spectrum to include infantile encephalopathy and suggest this gene is enriched for pathogenic variants that disrupt splicing.
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    Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy
    Bennett, MF ; Hildebrand, MS ; Kayumi, S ; Corbett, MA ; Gupta, S ; Ye, Z ; Krivanek, M ; Burgess, R ; Henry, OJ ; Damiano, JA ; Boys, A ; Gecz, J ; Bahlo, M ; Scheffer, IE ; Berkovic, SF (LIPPINCOTT WILLIAMS & WILKINS, 2022-02-01)
    BACKGROUND AND OBJECTIVES: The 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways. METHODS: We searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed. RESULTS: Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG; p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C>T; p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother. DISCUSSION: We identify a pathogenic germline mTOR pathway variant (NPRL3) and a somatic variant (WNT2) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.
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    Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes
    Skotte, L ; Fadista, J ; Bybjerg-Grauholm, J ; Appadurai, V ; Hildebrand, MS ; Hansen, TF ; Banasik, K ; Grove, J ; Albinana, C ; Geller, F ; Bjurstrom, CF ; Vilhjalmsson, BJ ; Coleman, M ; Damiano, JA ; Burgess, R ; Scheffer, IE ; Pedersen, OBV ; Erikstrup, C ; Westergaard, D ; Nielsen, KR ; Sorensen, E ; Bruun, MT ; Liu, X ; Hjalgrim, H ; Pers, TH ; Mortensen, PB ; Mors, O ; Nordentoft, M ; Dreier, JW ; Borglum, AD ; Christensen, J ; Hougaard, DM ; Buil, A ; Hviid, A ; Melbye, M ; Ullum, H ; Berkovic, SF ; Werge, T ; Feenstra, B (OXFORD UNIV PRESS, 2022-04-18)
    Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
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    Association of ultra-rare coding variants with genetic generalized epilepsy: A case-control whole exome sequencing study
    Koko, M ; Motelow, JE ; Stanley, KE ; Bobbili, DR ; Dhindsa, RS ; May, P (WILEY, 2022-01-15)
    OBJECTIVE: 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 [GABAA ] 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 GABAA 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.
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    PIGN encephalopathy: Characterizing the epileptology
    Bayat, A ; Valles-Ibanez, G ; Pendziwiat, M ; Knaus, A ; Alt, K ; Biamino, E ; Bley, A ; Calvert, S ; Carney, P ; Caro-Llopis, A ; Ceulemans, B ; Cousin, J ; Davis, S ; Portes, V ; Edery, P ; England, E ; Ferreira, C ; Freeman, J ; Gener, B ; Gorce, M ; Heron, D ; Hildebrand, MS ; Jezela-Stanek, A ; Jouk, P-S ; Keren, B ; Kloth, K ; Kluger, G ; Kuhn, M ; Lemke, JR ; Li, H ; Martinez, F ; Maxton, C ; Mefford, HC ; Merla, G ; Mierzewska, H ; Muir, A ; Monfort, S ; Nicolai, J ; Norman, J ; O'Grady, G ; Oleksy, B ; Orellana, C ; Orec, LE ; Peinhardt, C ; Pronicka, E ; Rosello, M ; Santos-Simarro, F ; Schwaibold, EMC ; Stegmann, APA ; Stumpel, CT ; Szczepanik, E ; Terczynska, I ; Thevenon, J ; Tzschach, A ; Van Bogaert, P ; Vittorini, R ; Walsh, S ; Weckhuysen, S ; Weissman, B ; Wolfe, L ; Reymond, A ; De Nittis, P ; Poduri, A ; Olson, H ; Striano, P ; Lesca, G ; Scheffer, IE ; Moller, RS ; Sadleir, LG (WILEY, 2022-02-18)
    OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.
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    Gain-of-function HCN2 variants in genetic epilepsy
    Li, M ; Maljevic, S ; Phillips, AM ; Petrovski, S ; Hildebrand, MS ; Burgess, R ; Mount, T ; Zara, F ; Striano, P ; Schubert, J ; Thiele, H ; Nuernberg, P ; Wong, M ; Weisenberg, JL ; Thio, LL ; Lerche, H ; Scheffer, IE ; Berkovic, SF ; Petrou, S ; Reid, CA (WILEY, 2018-02-01)
    Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism.
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    Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum
    Damiano, JA ; Burgess, R ; Kivity, S ; Lerman-Sagie, T ; Afawi, Z ; Scheffer, IE ; Berkovic, SF ; Hildebrand, MS (WILEY, 2017-03-01)
    Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.
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    De novo SCN1A pathogenic variants in the GEFS plus spectrum: Not always a familial syndrome
    Myers, KA ; Burgess, R ; Afawi, Z ; Damiano, JA ; Berkovic, SF ; Hildebrand, MS ; Scheffer, IE (WILEY, 2017-02-01)
    Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non-EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood-onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all individuals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling.