Medicine (Austin & Northern Health) - Research Publications

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    Unexpected diagnosis of myotonic dystrophy type 2 repeat expansion by genome sequencing
    Rafehi, H ; Green, C ; Bozaoglu, K ; Gillies, G ; Delatycki, MB ; Lockhart, PJ ; Scheffer, IE ; Bahlo, M (SPRINGERNATURE, 2022-08-09)
    Several neurological disorders, such as myotonic dystrophy are caused by expansions of short tandem repeats (STRs) which can be difficult to detect by molecular tools. Methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. We recruited a multi-generational family (family A) ascertained for genetic studies of autism spectrum disorder. WGS was performed on seven children from four nuclear families from family A and analyzed for REs of STRs known to cause neurological disorders. We detected an expansion of a heterozygous intronic CCTG STR in CNBP in two siblings. This STR causes myotonic dystrophy type 2 (DM2). The expansion did not segregate with the ASD phenotype. Repeat-primed PCR showed that the DM2 CCTG motif was expanded above the pathogenic threshold in both children and their mother. On subsequent examination, the mother had mild features of DM2. We show that screening of STRs in WGS datasets has diagnostic utility, both in the clinical and research domain, with potential management and genetic counseling implications.
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    Randomized Controlled Trial of Melatonin for Sleep Disturbance in Dravet Syndrome: The DREAMS Study
    Myers, KA ; Davey, MJ ; Ching, M ; Ellis, C ; Grinton, BE ; Roten, A ; Lightfoot, PA ; Scheffer, IE (AMER ACAD SLEEP MEDICINE, 2018-01-01)
    Dravet syndrome is a severe developmental and epileptic encephalopathy, in which 75% of patients have sleep disturbance. Melatonin is often used for sleep problems in childhood; however, there is no quality evidence supporting its use in Dravet syndrome. We hypothesized that melatonin would increase total sleep and quality of life for patients with Dravet syndrome.Methods: A double-blind crossover randomized placebo-controlled trial was conducted, comparing 6 mg regular-release melatonin to placebo for patients with Dravet syndrome and sleep disturbance. The primary outcome measure was total sleep measured by actigraphy, with secondary outcomes including wakefulness after sleep onset (WASO), Sleep Disturbance Scale in Children and Quality of Life in Children with Epilepsy 55 questionnaires, caregiver reports of clinical change, seizure diary and serum antiepileptic drug levels. We also compared actigraphy data of patients with Dravet syndrome to an age-matched healthy control group.Results: A total of 13 patients completed the study. There was no difference in total sleep or WASO between melatonin and placebo. However, of the 11 patients for whom caregivers reported a clear clinical difference between treatments (blinded), 8 reported improvement on melatonin (P < .05). Interestingly, when compared to patients in the control group, patients with Dravet syndrome had significantly increased total sleep (P = .002).Conclusions: Melatonin did not increase total sleep; however, blinded caregiver reports indicate treatment with melatonin provided considerable clinical benefit for some patients with Dravet syndrome and sleep disturbance.
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    Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
    Motelow, JE ; Povysil, G ; Dhindsa, RS ; Stanley, KE ; Allen, AS ; Feng, Y-CA ; Howrigan, DP ; Abbott, LE ; Tashman, K ; Cerrato, F ; Cusick, C ; Singh, T ; Heyne, H ; Byrnes, AE ; Churchhouse, C ; Watts, N ; Solomonson, M ; Lal, D ; Gupta, N ; Neale, BM ; Cavalleri, GL ; Cossette, P ; Cotsapas, C ; De Jonghe, P ; Dixon-Salazar, T ; Guerrini, R ; Hakonarson, H ; Heinzen, EL ; Helbig, I ; Kwan, P ; Marson, AG ; Petrovski, S ; Kamalakaran, S ; Sisodiya, SM ; Stewart, R ; Weckhuysen, S ; Depondt, C ; Dlugos, DJ ; Scheffer, IE ; Striano, P ; Freyer, C ; Krause, R ; May, P ; McKenna, K ; Regan, BM ; Bennett, CA ; Leu, C ; Leech, SL ; O'Brien, TJ ; Todaro, M ; Stamberger, H ; Andrade, DM ; Ali, QZ ; Sadoway, TR ; Krestel, H ; Schaller, A ; Papacostas, SS ; Kousiappa, I ; Tanteles, GA ; Christou, Y ; Sterbova, K ; Vlckova, M ; Sedlackova, L ; Lassuthova, P ; Klein, KM ; Rosenow, F ; Reif, PS ; Knake, S ; Neubauer, BA ; Zimprich, F ; Feucht, M ; Reinthaler, EM ; Kunz, WS ; Zsurka, G ; Surges, R ; Baumgartner, T ; von Wrede, R ; Pendziwiat, M ; Muhle, H ; Rademacher, A ; van Baalen, A ; von Spiczak, S ; Stephani, U ; Afawi, Z ; Korczyn, AD ; Kanaan, M ; Canavati, C ; Kurlemann, G ; Muller-Schluter, K ; Kluger, G ; Haeusler, M ; Blatt, I ; Lemke, JR ; Krey, I ; Weber, YG ; Wolking, S ; Becker, F ; Lauxmann, S ; Bosselmann, C ; Kegele, J ; Hengsbach, C ; Rau, S ; Steinhoff, BJ ; Schulze-Bonhage, A ; Borggraefe, I ; Schankin, CJ ; Schubert-Bast, S ; Schreiber, H ; Mayer, T ; Korinthenberg, R ; Brockmann, K ; Wolff, M ; Dennig, D ; Madeleyn, R ; Kalviainen, R ; Saarela, A ; Timonen, O ; Linnankivi, T ; Lehesjoki, A-E ; Rheims, S ; Lesca, G ; Ryvlin, P ; Maillard, L ; Valton, L ; Derambure, P ; Bartolomei, F ; Hirsch, E ; Michel, V ; Chassoux, F ; Rees, M ; Chung, S-K ; Pickrell, WO ; Powell, R ; Baker, MD ; Fonferko-Shadrach, B ; Lawthom, C ; Anderson, J ; Schneider, N ; Balestrini, S ; Zagaglia, S ; Braatz, V ; Johnson, MR ; Auce, P ; Sills, GJ ; Baum, LW ; Sham, PC ; Cherny, SS ; Lui, CHT ; Delanty, N ; Doherty, CP ; Shukralla, A ; El-Naggar, H ; Widdess-Walsh, P ; Barisi, N ; Canafoglia, L ; Franceschetti, S ; Castellotti, B ; Granata, T ; Ragona, F ; Zara, F ; Iacomino, M ; Riva, A ; Madia, F ; Vari, MS ; Salpietro, V ; Scala, M ; Mancardi, MM ; Nobili, L ; Amadori, E ; Giacomini, T ; Bisulli, F ; Pippucci, T ; Licchetta, L ; Minardi, R ; Tinuper, P ; Muccioli, L ; Mostacci, B ; Gambardella, A ; Labate, A ; Annesi, G ; Manna, L ; Gagliardi, M ; Parrini, E ; Mei, D ; Vetro, A ; Bianchini, C ; Montomoli, M ; Doccini, V ; Barba, C ; Hirose, S ; Ishii, A ; Suzuki, T ; Inoue, Y ; Yamakawa, K ; Beydoun, A ; Nasreddine, W ; Zgheib, NK ; Tumiene, B ; Utkus, A ; Sadleir, LG ; King, C ; Caglayan, SH ; Arslan, M ; Yapici, Z ; Topaloglu, P ; Kara, B ; Yis, U ; Turkdogan, D ; Gundogdu-Eken, A ; Bebek, N ; Tsai, M-H ; Ho, C-J ; Lin, C-H ; Lin, K-L ; Chou, I-J ; Poduri, A ; Shiedley, BR ; Shain, C ; Noebels, JL ; Goldman, A ; Busch, RM ; Jehi, L ; Najm, IM ; Ferguson, L ; Khoury, J ; Glauser, TA ; Clark, PO ; Buono, RJ ; Ferraro, TN ; Sperling, MR ; Lo, W ; Privitera, M ; French, JA ; Schachter, S ; Kuzniecky, R ; Devinsky, O ; Hegde, M ; Greenberg, DA ; Ellis, CA ; Goldberg, E ; Helbig, KL ; Cosico, M ; Vaidiswaran, P ; Fitch, E ; Berkovic, SF ; Lerche, H ; Lowenstein, DH ; Goldstein, DB (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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    Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial
    Scheffer, IE ; Halford, JJ ; Miller, I ; Nabbout, R ; Sanchez-Carpintero, R ; Shiloh-Malawsky, Y ; Wong, M ; Zolnowska, M ; Checketts, D ; Dunayevich, E ; Devinsky, O (WILEY, 2021-08-18)
    OBJECTIVE: Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. METHODS: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. RESULTS: Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. SIGNIFICANCE: We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.
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    Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies
    Ye, Z ; Bennett, MF ; Bahlo, M ; Scheffer, IE ; Berkovic, SF ; Perucca, P ; Hildebrand, MS (TAYLOR & FRANCIS LTD, 2021-09-24)
    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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    Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development
    Kaspi, A ; Hildebrand, MS ; Jackson, VE ; Braden, R ; van Reyk, O ; Howell, T ; Debono, S ; Lauretta, M ; Morison, L ; Coleman, MJ ; Webster, R ; Coman, D ; Goel, H ; Wallis, M ; Dabscheck, G ; Downie, L ; Baker, EK ; Parry-Fielder, B ; Ballard, K ; Harrold, E ; Ziegenfusz, S ; Bennett, MF ; Robertson, E ; Wang, L ; Boys, A ; Fisher, SE ; Amor, DJ ; Scheffer, IE ; Bahlo, M ; Morgan, AT (SPRINGERNATURE, 2022-09-18)
    Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials.
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    Natural History Studies and Clinical Trial Readiness for Genetic Developmental and Epileptic Encephalopathies
    Palmer, EE ; Howell, K ; Scheffer, IE (SPRINGER, 2021-10-27)
    The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies. They usually begin in infancy or childhood with drug-resistant seizures, epileptiform EEG patterns, developmental slowing or regression, and cognitive impairment. DEEs have a high mortality and profound morbidity; comorbidities are common including autism spectrum disorders. With advances in genetic sequencing, over 400 genes have been implicated in DEEs, with a genetic cause now identified in over 50% patients. Each genetic DEE typically has a broad genotypic-phenotypic spectrum, based on the underlying pathophysiology. There is a pressing need to improve health outcomes by developing novel targeted therapies for specific genetic DEE phenotypes that not only improve seizure control, but also developmental outcomes and comorbidities. Clinical trial readiness relies firstly on a deep understanding of phenotype-genotype correlation and evolution of a condition over time, in order to select appropriate patients for clinical trials. Understanding the natural history of the disorder informs assessment of treatment efficacy in terms of both clinical outcome and biomarker utility. Natural history studies (NHS) provide a high quality, integrated, comprehensive approach to understanding a complex disease and underpin clinical trial design for novel therapies. NHS are pre-planned observational studies designed to track the course of a disease and identify demographic, genetic, environmental, and other variables, including biomarkers, that correlate with the disease's evolution and outcomes. Due to the rarity of individual genetic DEEs, appropriately funded high-quality DEE NHS will be required, with sustainable frameworks and equitable access to affected individuals globally.
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    Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions
    Green, TE ; Motelow, JE ; Bennett, MF ; Ye, Z ; Bennett, CA ; Griffin, NG ; Damiano, JA ; Leventer, RJ ; Freeman, JL ; Harvey, AS ; Lockhart, PJ ; Sadleir, LG ; Boys, A ; Scheffer, IE ; Major, H ; Darbro, BW ; Bahlo, M ; Goldstein, DB ; Kerrigan, JF ; Heinzen, EL ; Berkovic, SF ; Hildebrand, MS (OXFORD UNIV PRESS, 2022-02-08)
    Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.
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    Epidemiology of Treated Epilepsy in New Zealand Children A Focus on Ethnicity
    Ali, S ; Stanley, J ; Davis, S ; Keenan, N ; Scheffer, IE ; Sadleir, LG (LIPPINCOTT WILLIAMS & WILKINS, 2021-11-09)
    BACKGROUND AND OBJECTIVES: To determine the period prevalence and incidence of treated epilepsy in a New Zealand pediatric cohort with a focus on ethnicity and socioeconomic status. METHODS: This was a retrospective cohort study. The New Zealand Pharmaceutical Collection database was searched for individuals ≤18 years of age dispensed an antiseizure medication (ASM) in 2015 from areas capturing 48% of the New Zealand pediatric population. Medical records of identified cases were reviewed to ascertain the indication for the ASM prescription. Population data were derived from the New Zealand 2013 Census. RESULTS: A total of 3,557 ASMs were prescribed during 2015 in 2,594 children, of whom 1,717 (66%) children had epilepsy. An indication for prescription was ascertained for 3,332/3,557 (94%) ASMs. The period prevalence of treated epilepsy was 3.4 per 1,000 children. Children in the most deprived areas had 1.9 times the rate of treated epilepsy (95% confidence interval [CI] 1.6-2.2) as those from the least deprived areas. Prevalence was similar for most ethnic groups (European/other: 3.7, 95% CI 3.4-3.9; Pacific Peoples: 3.6, 95% CI 3.2-4.1; Māori: 3.4, 95% CI 3.1-3.8) apart from Asians, who had a lower prevalence of 2.3 per 1,000 (95% CI 2.0-2.6). However, when adjusted for socioeconomic deprivation, the prevalence of epilepsy was highest in European and similar in Māori, Pacific, and Asian children. DISCUSSION: This is the largest pediatric epidemiology epilepsy study where diagnosis of epilepsy was confirmed by case review. This is the first study to provide epidemiologic information for pediatric epilepsy in Māori and Pacific children.
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    Precision Medicine Approaches for Infantile-Onset Developmental and Epileptic Encephalopathies
    Myers, KA ; Scheffer, IE (ANNUAL REVIEWS, 2022-01-01)
    Epilepsy is an etiologically heterogeneous condition; however, genetic factors are thought to play a role in most patients. For those with infantile-onset developmental and epileptic encephalopathy (DEE), a genetic diagnosis is now obtained in more than 50% of patients. There is considerable motivation to utilize these molecular diagnostic data to help guide treatment, as children with DEEs often have drug-resistant seizures as well as developmental impairment related to cerebral epileptiform activity. Precision medicine approaches have the potential to dramatically improve the quality of life for these children and their families. At present, treatment can be targeted for patients with diagnoses in many genetic causes of infantile-onset DEE, including genes encoding sodium or potassium channel subunits, tuberous sclerosis, and congenital metabolic diseases. Precision medicine may refer to more intelligent choices of conventional antiseizure medications, repurposed agents previously used for other indications, novel compounds, enzyme replacement, or gene therapy approaches.