Medicine (Austin & Northern Health) - Research Publications
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ItemSub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals(CELL PRESS, 2021-06-03)Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
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ItemCutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies(TAYLOR & FRANCIS LTD, 2021-11-02)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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ItemNo Preview AvailableClimate change and epilepsy: Insights from clinical and basic science studies(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-03)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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ItemIdentification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2021-12)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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ItemPostictal Psychosis in Epilepsy: A Clinicogenetic Study(WILEY, 2021-09)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 (R2 = 3%, p = 6 × 10-3 ), but not significantly different from 945 independent patients with schizophrenia (R2 = 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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ItemSCN1A Variants in vaccine-related febrile seizures: A prospective study(WILEY, 2020-02)OBJECTIVE: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. METHODS: We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. RESULTS: We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). INTERPRETATION: Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.
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ItemNo Preview AvailableGuidelines on the Diagnosis, Clinical Assessments, Treatment and Management for CLN2 Disease Patients( 2020)
Background:
CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2), or Late-Infantile Neuronal Ceroid Lipofuscinosis (LINCL), 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 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 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. This addresses the clinical need to complement other information available. -
ItemLoss-of-function variants in Kv11.1 cardiac channels as a biomarker for SUDEP(WILEY, 2021-07)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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ItemThe severe epilepsy syndromes of infancy: A population-based study(WILEY, 2021-02)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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ItemGuidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients(BMC, 2021-04-21)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.