Publications by authors named "Samuel F Berkovic"

374 Publications

Association Between Psychiatric Comorbidities and Mortality in Epilepsy.

Neurol Clin Pract 2021 Oct;11(5):429-437

Departments of Medicine and Neurology (GT, CA, RN, CBM, PP, ZC, AM, PK, TJO), The Royal Melbourne Hospital, The University of Melbourne; Department of Neuroscience (RN, SB, CBM, PP, ZC, AM, PK, TJO), The Alfred Hospital, Monash University Central Clinical School, Melbourne; Melbourne Neuropsychiatry Centre (LM, SA, DV), Department of Psychiatry, The Royal Melbourne Hospital, The University of Melbourne; Departments of Medicine and Neurology (SI, POB, MJC, WDS), St. Vincent's Hospital Melbourne, The University of Melbourne; and Department of Medicine (Neurology) (SFB), The University of Melbourne (Austin Health), Victoria, Australia.

Objective: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades.

Methods: A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System.

Results: Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02-1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without.

Conclusion: The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.
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http://dx.doi.org/10.1212/CPJ.0000000000001114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610550PMC
October 2021

Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases.

Neurol Genet 2021 Dec 12;7(6):e641. Epub 2021 Nov 12.

Neurophysiopathology (L.C., S.F.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; Department of Medical and Surgical Sciences (A.G., E.F.), Magna Graecia University, Catanzaro; IRCCS Istituto "G. Gaslini" (P.S., F.Z.), Genova; Department of Neurosciences (P.S., F.Z.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova; Department of Human Neurosciences (T.G., C.D.B., M.F.), Sapienza University of Rome, Viale dell'Università, Rome; IRCCS Istituto delle Scienze Neurologiche di Bologna (P.T., L.L.), Epilepsy Center, Bologna; Department of Biomedical and Neuromotor Sciences (P.T., L.L.), University of Bologna; IRCCS Istituto delle Scienze Neurologiche di Bologna (R.M., P.R.), Unit of Neurology, Bellaria Hospital, Bologna; Regional Epilepsy Centre (E.F.), BMM Great Metropolitan Hospital, Via Melacrino, Reggio Calabria; Department of Pediatric Neuroscience (T.G.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; Epilepsy Center (A.M.), Department of Clinical and Experimental Medicine, AOU Policlinico "G. Martino", Messina; Department of Neuroscience (A.F.), Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples; Department of Basic Medical Sciences (A.L.N.), Neuroscience and Sense Organs, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, Bari ; Perugia Hospital (T.A.C,), Neurophysiopathology Unit, Azienda Ospedaliera di Perugia, S. Andrea delle Fratte, Perugia; Unit of Genetics of Neurodegenerative and Metabolic Diseases (B.C., C.G.), IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Population Health and Immunity Division (M.B., K.L.O.), The Walter and Eliza Hall Institute of Medical Research, Parkville; Department of Medical Biology (M.B., K.L.O.), The University of Melbourne; Folkhälsan Research Center (C.C., A.E.L.); Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Finland; and Epilepsy Research Centre (K.L.O., S.F.B), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.

Background And Objectives: To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.

Methods: Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: "Unverricht-Lundborg disease-like PME," "late-onset PME," "PME plus developmental delay," and "PME plus dementia."

Results: Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in (2 families), (1 family), and in 13 nonfamilial patients in (3), (3), , , , , , , and . Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.

Discussion: The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.
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http://dx.doi.org/10.1212/NXG.0000000000000641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589262PMC
December 2021

State transitions through inhibitory interneurons in a cortical network model.

PLoS Comput Biol 2021 10 15;17(10):e1009521. Epub 2021 Oct 15.

Department of Biomedical Engineering, University of Melbourne, Melbourne, Australia.

Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.
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http://dx.doi.org/10.1371/journal.pcbi.1009521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550371PMC
October 2021

Identification of a recurrent mosaic variant in brain tissue from an individual with nevus sebaceous syndrome.

Cold Spring Harb Mol Case Stud 2021 Oct 14. Epub 2021 Oct 14.

Epilepsy Research Centre, Department of Medicine (Austin Hospital), University of Melbourne, Heidelberg, Victoria, Australia; Murdoch Children Research Institute, Parkville, Victoria, Australia

Nevus sebaceous syndrome (NSS) is a rare multisystem neurocutaneous syndrome, characterised 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 post-zygotic variants in or in all patients studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signalling 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 utilized high depth gene panel sequencing and sensitive droplet digital 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 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 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 G12C mosaicism beyond nevus sebaceous to involve brain tissue and more specifically, hippocampal sclerosis.
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http://dx.doi.org/10.1101/mcs.a006133DOI Listing
October 2021

Association of Short-term Heart Rate Variability and Sudden Unexpected Death in Epilepsy.

Neurology 2021 Oct 14. Epub 2021 Oct 14.

Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States

Objective: We compared heart rate variability (HRV) in sudden unexpected death in epilepsy (SUDEP) cases and living epilepsy controls.

Methods: This international, multicenter, retrospective, nested case-control study examined patients admitted for video-EEG monitoring (VEM) between January 1, 2003 and December 31, 2014, and subsequently died of SUDEP. Time-domain and frequency-domain components were extracted from five-minute interictal electrocardiogram recordings during sleep and wakefulness from SUDEP cases and controls.

Results: We identified 31 SUDEP cases and 56 controls. Normalized low-frequency power (LFP) during wakefulness was lower in SUDEP cases (median 42.5, IQR 32.6-52.6) than epilepsy controls (55.5, IQR 40.7-68.9; =0.015, critical value=0.025). In the multivariable model, normalized LFP was lower in SUDEP cases compared to controls (contrast -11.01, 95% CI: -20.29--1.73; =0.020, critical value=0.025). There was a negative correlation between LFP and the latency to SUDEP, where each 1% incremental reduction in normalized LFP conferred a 2.7% decrease in the latency to SUDEP (95% CI: 0.95-0.995; =0.017, critical value=0.025). Increased survival duration from VEM to SUDEP was associated with higher normalized high-frequency power (HFP; =0.002, critical value=0.025). The survival model with normalized LFP was associated with SUDEP (C-statistic 0.66, 95% CI: 0.55-0.77), which non-significantly increased with the addition of normalized HFP (C-statistic 0.70, 95% CI 0.59-0.81; =0.209).

Conclusions: Reduced short-term LFP, which is a validated biomarker for sudden death, was associated with SUDEP. Increased HFP was associated with longer survival and may be cardioprotective in SUDEP. HRV quantification may help stratify individual SUDEP risk.

Classification Of Evidence: This study provides Class III evidence that in patients with epilepsy, some measures of heart rate variability are associated with SUDEP.
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http://dx.doi.org/10.1212/WNL.0000000000012946DOI Listing
October 2021

Hypothalamic Hamartomas: Evolving Understanding and Management.

Neurology 2021 Nov 4;97(18):864-873. Epub 2021 Oct 4.

From the Center for Neuroscience Research (N.T.C., W.D.G.), Children's National Hospital, The George Washington University School of Medicine, Washington, DC; UCL NIHR BRC Great Ormond Street Institute of Child Health (J.H.C.), Member of ERN-EpiCARE, London; Great Ormond Street Hospital for Children (J.H.C.), NHS Trust, London; Young Epilepsy (J.H.C.), Lingfield, Surrey, UK; Department of Pediatric Clinical Epileptology (A.A.), Sleep Disorders and Functional Neurology, Member of ERN-EpiCARE; HFME (A.A.), Hospices Civils de Lyon, France; Epilepsy Research Unit (A.A.), Barcelona's Children Hospital San Juan de Dios, Member of the ERN EpiCARE, Spain; Epilepsy Research Centre (S.F.B.), University of Melbourne, Australia; Division of Pediatric Neurology (J.F.K.), Barrow Neurological Institute at Phoenix Children's Hospital; Hope for Hypothalamic Hamartomas (I.P.M., E.W., L.S.), Phoenix, AZ; Epilepsy Surgery Program (A.C.), Clinica de Epilepsia de Sao Paulo, Brazil; Department of Epidemiology (D.K.H.), Columbia University Medical Center, New York, NY; RTI International (B.L.K.), Rockville, MD; Department of Neurology (C.B.S.), Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and Epilepsy Center (A.S.-B.), Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Germany.

Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in and other patterning genes are involved in HH pathogenesis. About 50%-80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.
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http://dx.doi.org/10.1212/WNL.0000000000012773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610628PMC
November 2021

Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies.

Expert Rev Neurother 2021 Nov 22;21(11):1309-1316. Epub 2021 Sep 22.

Department of Medicine (Austin Health), Epilepsy Research Centre, University of Melbourne, Heidelberg, Australia.

Introduction: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes.

Areas Covered: The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders.

Expert Opinion: These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
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http://dx.doi.org/10.1080/14737175.2021.1981288DOI Listing
November 2021

Improving Specificity of Cerebrospinal Fluid Liquid Biopsy for Genetic Testing.

Ann Neurol 2021 10 18;90(4):693-694. Epub 2021 Aug 18.

Department of Medicine (Austin Health), University of Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1002/ana.26191DOI Listing
October 2021

Postictal Psychosis in Epilepsy: A Clinicogenetic Study.

Ann Neurol 2021 09 3;90(3):464-476. Epub 2021 Aug 3.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Objective: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy-related psychoses, and has unknown causation.

Methods: We conducted a case-control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis; 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis; univariate associations with a p value < 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated.

Results: Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p < 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls (R  = 3%, p = 6 × 10 ), but not significantly different from 945 independent patients with schizophrenia (R  = 0.1%, p = 0.775).

Interpretation: Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021;90:464-476.
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http://dx.doi.org/10.1002/ana.26174DOI Listing
September 2021

Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants.

Hum Mutat 2021 Aug 15;42(8):1030-1041. Epub 2021 Jun 15.

Neurogenetics, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.

PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification.
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http://dx.doi.org/10.1002/humu.24237DOI Listing
August 2021

Association of Missense Variants With Genetic Epilepsy With Febrile Seizures Plus.

Neurology 2021 05 23;96(18):e2251-e2260. Epub 2021 Mar 23.

From the Adelaide Medical School, Faculty of Health and Medical Sciences (S.E.H., A.E.G., M.A.C., J.G.), and Robinson Research Institute (J.G.), The University of Adelaide; Epilepsy Research Centre, Department of Medicine (B.M.R., R.V.H., M.C., B.E.G., M.F.B., S.P., M.S.H., I.E.S., S.F.B.), Austin Health, University of Melbourne, Heidelberg; Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), University of Melbourne, Parkville, Australia; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia; Department of Neurology (M.R.S.), Thomas Jefferson University, Philadelphia, PA; Department of Neurology (S.H.), Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY; Institute of Neurology and Neurosurgery at Saint Barnabas (E.B.G.), Livingston, NJ; Department of Neurology (P.W.-W.), Beaumont Hospital, Dublin, Ireland; Royal Brisbane and Women's Hospital (J.T.P.), Brisbane, Australia; Centre for Genomics Research (S.P.), Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Institute for Genomic Medicine (E.L.H.), Columbia University Medical Center, New York, NY; Murdoch Children's Research Institute (M.S.H., I.E.S.), Parkville; Department of Paediatrics (I.E.S.), Royal Children's Hospital, University of Melbourne; Florey Institute of Neuroscience and Mental Health (I.E.S.), Melbourne; and Healthy Mothers, Babies and Children (J.G.), South Australian Health and Medical Research Institute, Adelaide, Australia.

Objective: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients.

Methods: We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing.

Results: Eight previously unreported missense variants were identified in , coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE).

Conclusion: Missense variants in cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with variants.
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http://dx.doi.org/10.1212/WNL.0000000000011855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166436PMC
May 2021

Loss-of-function variants in K 11.1 cardiac channels as a biomarker for SUDEP.

Ann Clin Transl Neurol 2021 07 18;8(7):1422-1432. Epub 2021 May 18.

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.

Objective: To compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-function KCNH2 variants as predictive biomarkers of SUDEP risk.

Methods: We searched for KCNH2 variants with a minor allele frequency of <5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified.

Results: KCNH2 variants were found in 11.1% (10/90) of SUDEP individuals compared to 6.0% (20/332) of epilepsy controls (p = 0.11). Loss-of-function KCNH2 variants, defined as causing >20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (<1% allele frequency) associated with greater loss of function and an ~11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis.

Interpretation: These data show that loss-of-function KCNH2 variants are enriched in SUDEP patients when compared to an epilepsy population older than 50 years, suggesting that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an individual's SUDEP risk.
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http://dx.doi.org/10.1002/acn3.51381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283159PMC
July 2021

Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients.

Orphanet J Rare Dis 2021 04 21;16(1):185. Epub 2021 Apr 21.

Evelina, London Children's Hospital, London, UK.

Background: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition.

Methods: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria.

Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality).

Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available.
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http://dx.doi.org/10.1186/s13023-021-01813-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059011PMC
April 2021

Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy.

Brain 2021 08;144(7):2060-2073

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3052, Australia.

Pathogenic variants in HCN1 are associated with developmental and epileptic encephalopathies. The recurrent de novo HCN1 M305L pathogenic variant is associated with severe developmental impairment and drug-resistant epilepsy. We engineered the homologue Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse to explore the disease mechanism underlying an HCN1 developmental and epileptic encephalopathy. The Hcn1M294L mouse recapitulated the phenotypic features of patients with the HCN1 M305L variant, including spontaneous seizures and a learning deficit. Active epileptiform spiking on the electrocorticogram and morphological markers typical of rodent seizure models were observed in the Hcn1M294L mouse. Lamotrigine exacerbated seizures and increased spiking, whereas sodium valproate reduced spiking, mirroring drug responses reported in a patient with this variant. Functional analysis in Xenopus laevis oocytes and layer V somatosensory cortical pyramidal neurons in ex vivo tissue revealed a loss of voltage dependence for the disease variant resulting in a constitutively open channel that allowed for cation 'leak' at depolarized membrane potentials. Consequently, Hcn1M294L layer V somatosensory cortical pyramidal neurons were significantly depolarized at rest. These neurons adapted through a depolarizing shift in action potential threshold. Despite this compensation, layer V somatosensory cortical pyramidal neurons fired action potentials more readily from rest. A similar depolarized resting potential and left-shift in rheobase was observed for CA1 hippocampal pyramidal neurons. The Hcn1M294L mouse provides insight into the pathological mechanisms underlying hyperexcitability in HCN1 developmental and epileptic encephalopathy, as well as being a preclinical model with strong construct and face validity, on which potential treatments can be tested.
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http://dx.doi.org/10.1093/brain/awab145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370418PMC
August 2021

Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes.

Am J Hum Genet 2021 04;108(4):722-738

Neurology - Neurophysiology Unit, ASST dei Sette Laghi, Galmarini Tradate Hospital, Tradate 21049, Italy.

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059372PMC
April 2021

Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain.

Brain Commun 2021 21;3(1):fcaa235. Epub 2021 Jan 21.

Department of Medicine (Austin Health), University of Melbourne, Melbourne, Victoria 3084, Australia.

Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours. Here, we asked if cerebrospinal fluid liquid biopsy can be used to detect somatic mosaicism in non-malignant brain diseases. First, we reliably quantified cerebrospinal fluid cell-free DNA in 28 patients with focal epilepsy and 28 controls using droplet digital PCR. Then, in three patients we identified somatic mutations in cerebrospinal fluid: in one patient with subcortical band heterotopia the p. Lys64* variant at 9.4% frequency; in a second patient with focal cortical dysplasia the p. Phe581His*6 variant at 7.8% frequency; and in a third patient with ganglioglioma the p. Val600Glu variant at 3.2% frequency. To determine if cerebrospinal fluid cell-free DNA was brain-derived, whole-genome bisulphite sequencing was performed and brain-specific DNA methylation patterns were found to be significantly enriched ( = 0.03). Our proof of principle study shows that cerebrospinal fluid liquid biopsy is valuable in investigating mosaic neurological disorders where brain tissue is unavailable.
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http://dx.doi.org/10.1093/braincomms/fcaa235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954394PMC
January 2021

Newly diagnosed seizures assessed at two established first seizure clinics: Clinic characteristics, investigations, and findings over 11 years.

Epilepsia Open 2021 03 13;6(1):171-180. Epub 2021 Jan 13.

Epilepsy Research Centre Department of Medicine (Austin Health) University of Melbourne Melbourne Australia.

Objective: 'First seizure' clinics (FSCs) aim to achieve early expert assessment for individuals with possible new-onset epilepsy. These clinics also have substantial potential for research into epilepsy evolution, outcomes, and costs. However, a paucity of FSCs details has implications for interpretation and utilization of this research.

Methods: We reviewed investigation findings over 11 years (2000-2010) from two established independent FSCs at Austin Health (AH) and Royal Melbourne Hospital (RMH), Australia. These adult clinics are in major public hospitals and operate with similar levels of expertise. Organizational differences include screening and dedicated administration at AH. Included were N = 1555 patients diagnosed with new-onset unprovoked seizures/epilepsy (AH n = 901, RMH n = 654). Protocol-driven interviews and investigations had been recorded prospectively and were extracted from medical records for study.

Results: Median patient age was 37 (IQR 26-52, range 18-94) years (AH 34 vs RMH 42 years;  < .001). Eighty-six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days;  < .01). By their first appointment, 42% had experienced ≥2 seizures. An EEG was obtained within three weeks postindex seizure in 73% of patients, demonstrating epileptiform discharges in 25% (AH 33% vs RMH 15%). Seventy-six percent of patients had an MRI within 6 weeks. Of those with imaging (n = 1500), 19% had potentially epileptogenic abnormalities (RMH 28% vs AH 12%;  < .01). At both sites, changes due to previous stroke/hemorrhage were the commonest lesions, followed by traumatic brain injury. ≥WHO level 1 brain tumors diagnosed at presentation comprised a very small proportion (<1%) at each clinic. At both sites, epilepsy type could be determined in 60% of patients; RMH had more focal and AH more generalized epilepsy diagnoses.

Significance: Differences between the clinics' administrative and screening practices may contribute to differences in investigation findings. Insight into these differences will facilitate interpretation and utilization, and planning of future research.
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http://dx.doi.org/10.1002/epi4.12460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918310PMC
March 2021

The severe epilepsy syndromes of infancy: A population-based study.

Epilepsia 2021 02 21;62(2):358-370. Epub 2021 Jan 21.

Department of Neurology, Royal Children's Hospital, Melbourne, Vic, Australia.

Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.

Methods: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.

Results: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased.

Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
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http://dx.doi.org/10.1111/epi.16810DOI Listing
February 2021

Contribution of rare genetic variants to drug response in absence epilepsy.

Epilepsy Res 2021 02 4;170:106537. Epub 2021 Jan 4.

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, 245 Burgundy St, Heidelberg, VIC, 3084, Australia; Department of Neurology, Royal Children's Hospital, The University of Melbourne, 50 Flemington Rd, Parkville, VIC, 3052, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville, VIC, 3052, Australia; Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia.

Objective: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive.

Methods: We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA.

Results: Sixty-two patients were included; 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43; 0.43-27.65; p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82; 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups; these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy.

Significance: We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger sample is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106537DOI Listing
February 2021

The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

J Neurol Sci 2021 01 3;420:117260. Epub 2020 Dec 3.

Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia; Australian Genomics Health Alliance, Melbourne, Australia.

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.
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http://dx.doi.org/10.1016/j.jns.2020.117260DOI Listing
January 2021

Epilepsy risk in offspring of affected parents; a cohort study of the "maternal effect" in epilepsy.

Ann Clin Transl Neurol 2021 01 29;8(1):153-162. Epub 2020 Nov 29.

National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus BSS, Aarhus University, Aarhus, Denmark.

Objective: To assess whether the risk of epilepsy is higher in offspring of mothers with epilepsy than in offspring of fathers with epilepsy.

Methods: In a prospective population-based register study, we considered all singletons born in Denmark between 1981 and 2016 (N = 1,754,742). From the Danish National Patient Register since 1977, we identified epilepsy diagnoses in all study participants and their family members. Cox regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CI), adjusted for relevant confounders.

Results: We included 1,754,742 individuals contributing > 30 million person-years of follow-up. The incidence rate of epilepsy in offspring of unaffected parents was 78.8 (95% CI: 77.8-79.8) per 100,000 person-years, while the corresponding rate in offspring with an affected father was 172 per 100,000 person-years (95% CI: 156-187) and in offspring with an affected mother was 260 per 100,000 person-years (95% CI: 243-277). Having an affected mother was associated with a 1.45-fold (95% CI: 1.30-1.63) higher risk of epilepsy in the offspring, compared to having an affected father. This maternal effect was found both in male (HR = 1.39, 95% CI: 1.19-1.62) and female offspring (HR = 1.53, 95% CI: 1.30-1.80), and across various ages at onset in the offspring. The maternal effect was also found in familial epilepsies (i.e. where the affected parent had an affected sibling; HR = 1.50, 95% CI: 1.04-2.16).

Interpretation: We found a clear maternal effect on offspring risk of epilepsy in this nationwide cohort study.
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http://dx.doi.org/10.1002/acn3.51258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818075PMC
January 2021

Transcriptome analysis of a ring chromosome 20 patient cohort.

Epilepsia 2021 01 18;62(1):e22-e28. Epub 2020 Nov 18.

Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.

Ring chromosomes occur when the ends of normally rod-shaped chromosomes fuse. In ring chromosome 20 (ring 20), intellectual disability and epilepsy are usually present, even if there is no deleted coding material; the mechanism by which individuals with complete ring chromosomes develop seizures and other phenotypic abnormalities is not understood. We investigated altered gene transcription as a contributing factor by performing RNA-sequencing (RNA-seq) analysis on blood from seven patients with ring 20, and 11 first-degree relatives (all parents). Geographic analysis did not identify altered expression in peritelomeric or other specific chromosome 20 regions. RNA-seq analysis revealed 97 genes potentially differentially expressed in ring 20 patients. These included one epilepsy gene, NPRL3, but this finding was not confirmed on reverse transcription Droplet Digital polymerase chain reaction analysis. Molecular studies of structural chromosomal anomalies such as ring chromosome are challenging and often difficult to interpret because many patients are mosaic, and there may be genome-wide chromosomal instability affecting gene expression. Our findings nevertheless suggest that peritelomeric altered transcription is not the likely pathogenic mechanism in ring 20. Underlying genetic mechanisms are likely complex and may involve differential expression of many genes, the majority of which may not be located on chromosome 20.
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http://dx.doi.org/10.1111/epi.16766DOI Listing
January 2021

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

Genet Med 2021 02 4;23(2):363-373. Epub 2020 Nov 4.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.

Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.

Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.

Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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http://dx.doi.org/10.1038/s41436-020-00988-9DOI Listing
February 2021

Generalized, focal, and combined epilepsies in families: New evidence for distinct genetic factors.

Epilepsia 2020 12 23;61(12):2667-2674. Epub 2020 Oct 23.

Epilepsy Research Centre, Department of Medicine, University of Melbourne (Austin Health), Heidelberg, VIC, Australia.

Objective: To determine the roles of shared and distinct genetic influences on generalized and focal epilepsy operating in individuals who manifest features of both types (combined epilepsies), and in families manifesting both generalized and focal epilepsies in separate individuals (mixed families).

Methods: We analyzed the deeply phenotyped Epi4K cohort of multiplex families (≥3 affected individuals per family) using methods that quantify the aggregation of phenotypes within families and the relatedness of individuals with different phenotypes within family pedigrees.

Results: The cohort included 281 families containing 1021 individuals with generalized (n = 484), focal (304), combined (51), or unclassified (182) epilepsies. The odds of combined epilepsy was higher in relatives of participants with combined epilepsy than in relatives of those with other epilepsy types (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.7-16.1, P = .004). Individuals with combined epilepsy co-occurred in families more often than expected by chance (P = .03). Within mixed families, individuals with each type of epilepsy were more closely related to relatives with the same type than to relatives with other types (P < .001).

Significance: These findings suggest that distinct genetic influences underlie the recently recognized entity of combined epilepsies, just as generalized epilepsies and focal epilepsies each have distinct genetic influences. Mixed families may in part reflect chance co-occurrence of these distinct genetic influences. These conclusions have important implications for molecular genetic studies aimed at identifying genetic determinants of the epilepsies.
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http://dx.doi.org/10.1111/epi.16732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725856PMC
December 2020

Anterior temporal encephaloceles: Elusive, important, and rewarding to treat.

Epilepsia 2020 12 23;61(12):2675-2684. Epub 2020 Oct 23.

Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Melbourne, Vic., Australia.

Objective: To investigate the etiology and longitudinal clinical, neuropsychological, psychosocial, and surgical outcome profile of patients with medication refractory epilepsy and temporal encephaloceles with a view to highlight diagnostic clues and management strategies.

Methods: The comprehensive epilepsy program databases at two surgical epilepsy centers from January 2000 to October 2018 were reviewed for this observational study, to identify patients with encephaloceles causing temporal lobe epilepsy (TLE) and treated with surgical resection. Their clinical, radiological, neuropsychological, psychiatric, and surgical data were obtained. Body mass index (BMI) data were also reviewed due to possible correlation between idiopathic intracranial hypertension and encephaloceles.

Results: Thirteen patients (eight female) were identified; only three were recognized on initial magnetic resonance imaging (MRI) report. Temporal encephaloceles were identified on the left in eight patients, on the right in three patients, and bilaterally in two patients. One patient had a strong family history of encephaloceles. The median BMI for patients with seizure onset ≤20 years of age was 22.4, whereas for patients with onset >20 years median BMI was 32.6 (P = .06). Five patients underwent a focal lesionectomy, three patients had limited temporal lobectomy, and five patients had standard anterior temporal lobectomy. Median postoperative follow-up was 5.5 years. All but one patient were free of disabling seizures. Nine of ten neuropsychologically tested patients had no discernable cognitive decline postoperatively. Postoperative psychosocial adjustment features were present in four patients.

Significance: Genetic factors and a possible association with idiopathic intracranial hypertension (given female predominance and elevated BMI) may contribute to the causation of temporal lobe encephaloceles. It is notable that a targeted surgical approach in the management of patients with TLE associated with encephaloceles has an excellent long-term clinical and neuropsychological outcome. Subtle encephaloceles should be actively searched for in patients with drug-resistant TLE because they significantly change surgical strategy and prognostication.
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http://dx.doi.org/10.1111/epi.16729DOI Listing
December 2020

Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS.

Ann Neurol 2021 02 5;89(2):402-407. Epub 2020 Nov 5.

Genetics Department, Lyon Civil Hospices, Lyon, France.

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss-of-function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402-407.
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http://dx.doi.org/10.1002/ana.25941DOI Listing
February 2021

Are Variants Causing Cardiac Arrhythmia Risk Factors in Sudden Unexpected Death in Epilepsy?

Front Neurol 2020 8;11:925. Epub 2020 Sep 8.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of premature mortality in individuals with epilepsy. Acute and adaptive changes in heart rhythm in epilepsy implicate cardiac dysfunction as a potential pathogenic mechanism in SUDEP. Furthermore, variants in genes associated with Long QT syndrome (LQTS) have been identified in patients with SUDEP. LQTS is a cardiac arrhythmia condition that causes sudden cardiac death with strong similarities to SUDEP. Here, we discuss the possibility of an additive risk of death due to the functional consequences of a pathogenic variant in an LQTS gene interacting with seizure-mediated changes in cardiac function. Extending this general concept, we propose a hypothesis that common variants in LQTS genes, which cause a subtle impact on channel function and would not normally be considered risk factors for cardiac disease, may increase the risk of sudden death when combined with epilepsy. A greater understanding of the interaction between epilepsy, cardiac arrhythmia, and SUDEP will inform our understanding of SUDEP risk and subsequent potential prophylactic treatment.
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http://dx.doi.org/10.3389/fneur.2020.00925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505992PMC
September 2020

Novel Missense Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy.

Int J Mol Sci 2020 Aug 31;21(17). Epub 2020 Aug 31.

Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia.

The gene encodes the low-voltage-activated Ca3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Ca3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Ca3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with mutations, corroborating further the causal association with distinct complex phenotypes.
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http://dx.doi.org/10.3390/ijms21176333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503748PMC
August 2020

Enlarged hippocampal fissure in psychosis of epilepsy.

Epilepsy Behav 2020 10 24;111:107290. Epub 2020 Jul 24.

Melbourne School of Psychological Sciences, The University of Melbourne, Australia; Comprehensive Epilepsy Program, Austin Health, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, Australia.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2020.107290DOI Listing
October 2020

Mortality in patients with psychogenic nonepileptic seizures.

Neurology 2020 08 20;95(6):e643-e652. Epub 2020 Jul 20.

From the Department of Neuroscience, Central Clinical School (R.N., S.B., C.B.M., P.P., Z.C., S.S., P.K., T.J.O.), and Clinical Epidemiology, School of Public Health and Preventive Medicine (Z.C.), Monash University, Melbourne; Departments of Medicine (R.N., C.A., G.T., C.B.M., P.P., A.M., Z.C., S.S., P.K., T.J.O.) and Neurology (R.N., C.A., G.T., C.B.M., P.P., S.S., P.K., T.J.O.) and Neuropsychiatry Unit (L.M., S.J., S.A., D.V.), The Royal Melbourne Hospital, and The Melbourne School of Psychological Sciences (C.B.M.), The University of Melbourne, Parkville; Department of Medicine (R.N.) and Epilepsy Research Centre, Department of Medicine (A.M., S.F.B.), Austin Health, The University of Melbourne, Heidelberg; Department of Neurology (C.B.M., P.P., A.M., S.S., P.K., T.J.O.), The Alfred Hospital, Melbourne; and Department of Medicine (S.I., M.J.C., W.D.), St. Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.

Objective: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population.

Methods: This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports.

Results: A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0-3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4-19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and "epilepsy" was recorded as the cause of death in 24%.

Conclusions: Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.
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http://dx.doi.org/10.1212/WNL.0000000000009855DOI Listing
August 2020
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