Medicine (Austin & Northern Health) - Research Publications

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    Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature.
    LaFlamme, CW ; Rastin, C ; Sengupta, S ; Pennington, HE ; Russ-Hall, SJ ; Schneider, AL ; Bonkowski, ES ; Almanza Fuerte, EP ; Galey, M ; Goffena, J ; Gibson, SB ; Allan, TJ ; Nyaga, DM ; Lieffering, N ; Hebbar, M ; Walker, EV ; Darnell, D ; Olsen, SR ; Kolekar, P ; Djekidel, N ; Rosikiewicz, W ; McConkey, H ; Kerkhof, J ; Levy, MA ; Relator, R ; Lev, D ; Lerman-Sagie, T ; Park, KL ; Alders, M ; Cappuccio, G ; Chatron, N ; Demain, L ; Genevieve, D ; Lesca, G ; Roscioli, T ; Sanlaville, D ; Tedder, ML ; Hubshman, MW ; Ketkar, S ; Dai, H ; Worley, KC ; Rosenfeld, JA ; Chao, H-T ; Undiagnosed Diseases Network, ; Neale, G ; Carvill, GL ; University of Washington Center for Rare Disease Research, ; Wang, Z ; Berkovic, SF ; Sadleir, LG ; Miller, DE ; Scheffer, IE ; Sadikovic, B ; Mefford, HC (Cold Spring Harbor Laboratory, 2023-10-12)
    Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations ("epivariants") can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct "episignature" biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature for CHD2 using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.
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    Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders
    Eratne, D ; Kang, M ; Malpas, C ; Simpson-Yap, S ; Lewis, C ; Dang, C ; Grewal, J ; Coe, A ; Dobson, H ; Keem, M ; Chiu, W-H ; Kalincik, T ; Ooi, S ; Darby, D ; Brodtmann, A ; Hansson, O ; Janelidze, S ; Blennow, K ; Zetterberg, H ; Walker, A ; Dean, O ; Berk, M ; Wannan, C ; Pantelis, C ; Loi, SM ; Walterfang, M ; Berkovic, SF ; Santillo, AF ; Velakoulis, D (SAGE PUBLICATIONS LTD, 2024-01)
    OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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    BRINGING THE BENCH TO THE BEDSIDE: UPDATES ON THE MIND STUDY AND WHAT A ROUTINELY AVAILABLE SIMPLE BLOOD TEST FOR NEUROFILAMENT LIGHT WOULD MEAN AT THE CLINICAL COAL FACE FOR PATIENTS AND FAMILIES, PSYCHIATRISTS, NEUROLOGISTS, GERIATRICIANS AND GENERAL PRACTITIONERS
    Eratne, D ; Lewis, C ; Cadwallader, C ; Kang, M ; Keem, M ; Santillo, A ; Li, QX ; Stehmann, C ; Loi, SM ; Walterfang, M ; Watson, R ; Yassi, N ; Blennow, K ; Zetterberg, H ; Janelidze, S ; Hansson, O ; Berry-Kravitz, E ; Brodtmann, A ; Darby, D ; Walker, A ; Dean, O ; Masters, CL ; Collins, S ; Berkovic, SF ; Velakoulis, D (SAGE PUBLICATIONS LTD, 2022-05)
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    Plasma neurofilament light chain and phosphorylated tau 181 in neurodegenerative and psychiatric disorders: moving closer towards a simple diagnostic test like a 'C‐reactive protein' for the brain?
    Eratne, D ; Santillo, A ; Li, Q ; Kang, M ; Keem, M ; Lewis, C ; Loi, SM ; Walterfang, M ; Hansson, O ; Janelidze, S ; Yassi, N ; Watson, R ; Berkovic, SF ; Masters, CL ; Collins, S ; Velakoulis, D (Wiley, 2021-12)
    Abstract Background Accurate, timely diagnosis of neurodegenerative disorders, in particular distinguishing primary psychiatric from neurological disorders and in younger people, can be challenging. There is a need for biomarkers to reduce the diagnostic odyssey and improve outcomes. Neurofilament light (NfL) has shown promise as a diagnostic biomarker in a wide range of disorders. Our Markers in Neuropsychiatric Disorders (MiND) Study builds on our pilot (Eratne et al, ANZJP, 2020), to explore the diagnostic and broader utility of plasma and cerebrospinal fluid (CSF) NfL and other novel markers such as phosphorylated tau 181 (p‐tau181), in a broad range of psychiatric and neurodegenerative/neurological disorders, with a view of translation into routine clinical practice. Methods We assessed plasma and/or CSF NfL and p‐tau181 concentrations in broad cohorts, including: patients assessed for neurocognitive/psychiatric symptoms at Neuropsychiatry and Melbourne Young‐Onset Dementia services and other services, in a wide range of disorders including Alzheimer disease, frontotemporal dementia, schizophrenia, bipolar disorder, depression, Niemann‐Pick Type C, epilepsy, functional neurological disorders. The most recent primary consensus diagnosis informed by established diagnostic criteria was categorised: primary psychiatric disorder (PPD), neurodegenerative/neurological disorder (ND), or healthy controls (HC). Results Findings from over 500 patients/participants will be presented, which indicate that CSF and plasma NfL levels are significantly elevated in a broad range of ND compared to a broad range of PPD, and HC, and bvFTD progressors from phenocopy syndromes, differentiating with areas under the curve of >0.90, sensitivity and specificity >90%. Plasma P‐tau181 levels distinguished Alzheimer disease (mainly younger sporadic), compared to other neurodegenerative disorders, with AUC 0.90, 90% sensitivity and specificity. As recruitment, sample analysis, data collection is ongoing, the most up to date results will be presented. Conclusions NfL shows great promise as a diagnostic test to assist with the common, challenging diagnostic dilemma of distinguishing neurodegenerative from non‐neurodegenerative and primary psychiatric disorders. Plasma p‐tau181 shows strong diagnostic utility in younger‐onset Alzheimer disease. A significantly elevated NfL in someone with a psychiatric diagnosis should prompt consideration of neurodegenerative differentials. Plasma NfL could dramatically alter clinical care of patients with neuropsychiatric and neurological symptoms, improving outcomes for patients, their families, the healthcare system, and clinical trials.
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    Aicardi Syndrome Is a Genetically Heterogeneous Disorder
    Ha, TT ; Burgess, R ; Newman, M ; Moey, C ; Mandelstam, SA ; Gardner, AE ; Ivancevic, AM ; Pham, D ; Kumar, R ; Smith, N ; Patel, C ; Malone, S ; Ryan, MM ; Calvert, S ; van Eyk, CL ; Lardelli, M ; Berkovic, SF ; Leventer, RJ ; Richards, LJ ; Scheffer, IE ; Gecz, J ; Corbett, MA (MDPI, 2023-08)
    Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.
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    Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders
    Kang, MJY ; Eratne, D ; Dobson, H ; Malpas, CBB ; Keem, M ; Lewis, C ; Grewal, J ; Tsoukra, V ; Dang, C ; Mocellin, R ; Kalincik, T ; Santillo, AFF ; Zetterberg, H ; Blennow, K ; Stehmann, C ; Varghese, S ; Li, Q-X ; Masters, CLL ; Collins, S ; Berkovic, SF ; Evans, A ; Kelso, W ; Farrand, S ; Loi, SMM ; Walterfang, M ; Velakoulis, D (CAMBRIDGE UNIV PRESS, 2024-02)
    OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
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    Brain mosaicism of hedgehog signalling and other cilia genes in hypothalamic hamartoma
    Green, TE ; Fujita, A ; Ghaderi, N ; Heinzen, EL ; Matsumoto, N ; Klein, KM ; Berkovic, SF ; Hildebrand, MS (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-09)
    Hypothalamic hamartoma (HH) is a rare benign developmental brain lesion commonly associated with a well characterized epilepsy phenotype. Most individuals with HH are non-syndromic without additional developmental anomalies nor a family history of disease. Nonetheless, HH is a feature of Pallister-Hall (PHS) and Oro-Facial-Digital Type VI (OFD VI) syndromes, both characterized by additional developmental anomalies. Initial genetic of analysis HH began with syndromic HH, where germline inherited or de novo variants in GLI3, encoding a central transcription factor in the sonic hedgehog (Shh) signalling pathway, were identified in most individuals with PHS. Following these discoveries in syndromic HH, the hypothesis that post-zygotic mosaicism in related genes may underly non-syndromic HH was tested. We discuss the identified mosaic variants within individuals with non-syndromic HH, review the analytical methodologies and diagnostic yields, and explore understanding of the functional role of the implicated genes with respect to Shh signalling, and cilia development and function. We also outline future challenges in studying non-syndromic HH and suggest potential novel strategies to interrogate brain mosaicism in HH.
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    ILAE Genetics Literacy series: Progressive myoclonus epilepsies
    Cameron, JM ; Ellis, CA ; Berkovic, SF ; ILAE, GC ; ILAE, GLTF (WILEY, 2023-10)
    Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterized by the development of progressively worsening myoclonus, ataxia, and seizures. A molecular diagnosis can now be established in approximately 80% of individuals with PME. Almost fifty genetic causes of PME have now been established, although some remain extremely rare. Herein, we provide a review of clinical phenotypes and genotypes of the more commonly encountered PMEs. Using an illustrative case example, we describe appropriate clinical investigation and therapeutic strategies to guide the management of this often relentlessly progressive and devastating epilepsy syndrome. This manuscript in the Genetic Literacy series maps to Learning Objective 1.2 of the ILAE Curriculum for Epileptology (Epileptic Disord. 2019;21:129).
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    Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy
    Perucca, P ; Stanley, K ; Harris, N ; McIntosh, AM ; Asadi-Pooya, AA ; Mikati, MA ; Andrade, DM ; Dugan, P ; Depondt, C ; Choi, H ; Heinzen, EL ; Cavalleri, GL ; Buono, RJ ; Devinsky, O ; Sperling, MR ; Berkovic, SF ; Delanty, N ; Goldstein, DB ; O'Brien, TJ (WILEY, 2023-04)
    OBJECTIVE: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS: We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS: Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION: Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.
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    Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress
    Knowles, JK ; Helbig, I ; Metcalf, CS ; Lubbers, LS ; Isom, LL ; Demarest, S ; Goldberg, EM ; George, AL ; Lerche, H ; Weckhuysen, S ; Whittemore, V ; Berkovic, SF ; Lowenstein, DH (WILEY, 2022-10)
    The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.