80 results on '"Malone, S"'
Search Results
2. Women and Organisational Culture in SMEs
- Author
-
Topic, M, Round, G, Carbery, C, Hunter, T, Young, M, Carr, R, Cockett, S, Eagles, S, Shaw, K, Fowler, M, Wajahat, A, Malone, S, Jekhine, D, Griggs, A, Topic, M, Round, G, Carbery, C, Hunter, T, Young, M, Carr, R, Cockett, S, Eagles, S, Shaw, K, Fowler, M, Wajahat, A, Malone, S, Jekhine, D, and Griggs, A
- Published
- 2022
3. Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain
- Author
-
Ye, Z, Chatterton, Z, Pflueger, J, Damiano, JA, McQuillan, L, Harvey, AS, Malone, S, Do, H, Maixner, W, Schneider, A, Nolan, B, Wood, M, Lee, WS, Gillies, G, Pope, K, Wilson, M, Lockhart, PJ, Dobrovic, A, Scheffer, IE, Bahlo, M, Leventer, RJ, Lister, R, Berkovic, SF, Hildebrand, MS, Ye, Z, Chatterton, Z, Pflueger, J, Damiano, JA, McQuillan, L, Harvey, AS, Malone, S, Do, H, Maixner, W, Schneider, A, Nolan, B, Wood, M, Lee, WS, Gillies, G, Pope, K, Wilson, M, Lockhart, PJ, Dobrovic, A, Scheffer, IE, Bahlo, M, Leventer, RJ, Lister, R, Berkovic, SF, and Hildebrand, MS
- Abstract
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 LIS1 p. Lys64* variant at 9.4% frequency; in a second patient with focal cortical dysplasia the TSC1 p. Phe581His*6 variant at 7.8% frequency; and in a third patient with ganglioglioma the BRAF 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 (P = 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.
- Published
- 2021
4. Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain (vol 3, fcaa235, 2021)
- Author
-
Ye, Z, Chatterton, Z, Pflueger, J, Damiano, JA, McQuillan, L, Harvey, AS, Malone, S, Do, H, Maixner, W, Schneider, A, Nolan, B, Wood, M, Lee, WS, Gillies, G, Pope, K, Wilson, M, Lockhart, PJ, Dobrovic, A, Scheffer, IE, Bahlo, M, Leventer, RJ, Lister, R, Berkovic, SF, Hildebrand, MS, Ye, Z, Chatterton, Z, Pflueger, J, Damiano, JA, McQuillan, L, Harvey, AS, Malone, S, Do, H, Maixner, W, Schneider, A, Nolan, B, Wood, M, Lee, WS, Gillies, G, Pope, K, Wilson, M, Lockhart, PJ, Dobrovic, A, Scheffer, IE, Bahlo, M, Leventer, RJ, Lister, R, Berkovic, SF, and Hildebrand, MS
- Abstract
[This corrects the article DOI: 10.1093/braincomms/fcaa235.][This corrects the article DOI: 10.1093/braincomms/fcaa235.].
- Published
- 2021
5. Self-care in People with Type 2 Diabetes Mellitus Research Protocol of a Multicenter Mixed Methods Study (SCUDO)
- Author
-
Luciani, M, Fabrizi, D, Rebora, P, Rossi, E, Di Mauro, S, Kohl Malone, S, Ausili, D, Luciani, Michela, Fabrizi, Diletta, Rebora, Paola, Rossi, Emanuela, Di Mauro, Stefania, Kohl Malone, Susan, Ausili, Davide, Luciani, M, Fabrizi, D, Rebora, P, Rossi, E, Di Mauro, S, Kohl Malone, S, Ausili, D, Luciani, Michela, Fabrizi, Diletta, Rebora, Paola, Rossi, Emanuela, Di Mauro, Stefania, Kohl Malone, Susan, and Ausili, Davide
- Abstract
About 11% of the adult global populations is estimated to be living with type 2 diabetes mellitus (T2DM) by 2040. T2DM requires people to make decisions regarding complex therapeutic regimes, to maintain their well-being and quality of life, to manage symptoms and to reduce disease complications. All these behaviours, requiring knowledge, motivation, experience, and skills, have been referred to the concept of self-care. The intricacy and multidimensionality of T2DM self-care requires a complex approach to its overall comprehension. This Embedded Mixed Method study aims to investigate the experience of self-care in Type 2 Diabetes Mellitus adult patients. It comprises a prospective observational design, and an interpretive description. Quantitative data will be collected with validated questionnaires from 300 patients at baseline and once a year for two years on: diabetes self-care, quality of life, diabetes related distress, and sleep quality. Socio-demographic and clinical data will be collected from medical records. Qualitative data will be collected using semi-structured interviews on circa 10-20 patients, at baseline and once a year for two years, analysed according to interpretive description. Quantitative and qualitative data will be analysed separately and then merged and interpreted. This study will expand our understanding of self-care in people with T2DM. The expected outcome will be a better understanding of the effect of self-care on glycaemic control and therefore clinical outcomes and costs.
- Published
- 2019
6. SYNGAP1 encephalopathy A distinctive generalized developmental and epileptic encephalopathy
- Author
-
Vlaskamp, DRM, Shaw, BJ, Burgess, R, Mei, D, Montomoli, M, Xie, H, Myers, CT, Bennett, MF, XiangWei, W, Williams, D, Maas, SM, Brooks, AS, Mancini, GMS, van de Laar, IMBH, van Hagen, JM, Ware, TL, Webster, RI, Malone, S, Berkovic, SF, Kalnins, RM, Sicca, F, Korenke, GC, van Ravenswaaij-Arts, CMA, Hildebrand, MS, Mefford, HC, Jiang, Y, Guerrini, R, Scheffer, IE, Vlaskamp, DRM, Shaw, BJ, Burgess, R, Mei, D, Montomoli, M, Xie, H, Myers, CT, Bennett, MF, XiangWei, W, Williams, D, Maas, SM, Brooks, AS, Mancini, GMS, van de Laar, IMBH, van Hagen, JM, Ware, TL, Webster, RI, Malone, S, Berkovic, SF, Kalnins, RM, Sicca, F, Korenke, GC, van Ravenswaaij-Arts, CMA, Hildebrand, MS, Mefford, HC, Jiang, Y, Guerrini, R, and Scheffer, IE
- Abstract
OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
- Published
- 2019
7. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders
- Author
-
Guo, H, Bettella, E, Marcogliese, PC, Zhao, R, Andrews, JC, Nowakowski, TJ, Gillentine, MA, Hoekzema, K, Wang, T, Wu, H, Jangam, S, Liu, C, Ni, H, Willemsen, MH, van Bon, BW, Rinne, T, Stevens, SJC, Kleefstra, T, Brunner, HG, Yntema, HG, Long, M, Zhao, W, Hu, Z, Colson, C, Richard, N, Schwartz, CE, Romano, C, Castiglia, L, Bottitta, M, Dhar, SU, Erwin, DJ, Emrick, L, Keren, B, Afenjar, A, Zhu, B, Bai, B, Stankiewicz, P, Herman, K, Mercimek-Andrews, S, Juusola, J, Wilfert, AB, Abou Jamra, R, Buettner, B, Mefford, HC, Muir, AM, Scheffer, IE, Regan, BM, Malone, S, Gecz, J, Cobben, J, Weiss, MM, Waisfisz, Q, Bijlsma, EK, Hoffer, MJ, Ruivenkamp, CAL, Sartori, S, Xia, F, Rosenfeld, JA, Bernier, RA, Wangler, MF, Yamamoto, S, Xia, K, Stegmann, APA, Bellen, HJ, Murgia, A, Eichler, EE, Nickerson, DA, Bamshad, MJ, Guo, H, Bettella, E, Marcogliese, PC, Zhao, R, Andrews, JC, Nowakowski, TJ, Gillentine, MA, Hoekzema, K, Wang, T, Wu, H, Jangam, S, Liu, C, Ni, H, Willemsen, MH, van Bon, BW, Rinne, T, Stevens, SJC, Kleefstra, T, Brunner, HG, Yntema, HG, Long, M, Zhao, W, Hu, Z, Colson, C, Richard, N, Schwartz, CE, Romano, C, Castiglia, L, Bottitta, M, Dhar, SU, Erwin, DJ, Emrick, L, Keren, B, Afenjar, A, Zhu, B, Bai, B, Stankiewicz, P, Herman, K, Mercimek-Andrews, S, Juusola, J, Wilfert, AB, Abou Jamra, R, Buettner, B, Mefford, HC, Muir, AM, Scheffer, IE, Regan, BM, Malone, S, Gecz, J, Cobben, J, Weiss, MM, Waisfisz, Q, Bijlsma, EK, Hoffer, MJ, Ruivenkamp, CAL, Sartori, S, Xia, F, Rosenfeld, JA, Bernier, RA, Wangler, MF, Yamamoto, S, Xia, K, Stegmann, APA, Bellen, HJ, Murgia, A, Eichler, EE, Nickerson, DA, and Bamshad, MJ
- Abstract
Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
- Published
- 2019
8. Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination
- Author
-
Tea, F, Lopez, JA, Ramanathan, S, Merheb, V, Lee, FXZ, Zou, A, Pilli, D, Patrick, E, van der Walt, A, Monif, M, Tantsis, EM, Yiu, EM, Vucic, S, Henderson, APD, Fok, A, Fraser, CL, Lechner-Scott, J, Reddel, SW, Broadley, S, Barnett, MH, Brown, DA, Lunemann, JD, Dale, RC, Brilot, F, Sinclair, A, Kermode, AG, Kornberg, A, Bye, A, McGettigan, B, Trewin, B, Brew, B, Taylor, B, Bundell, C, Miteff, C, Troedson, C, Pridmore, C, Spooner, C, Yiannikas, C, O'Gorman, C, Clark, D, Suan, D, Jones, D, Kilfoyle, D, Gill, D, Wakefield, D, Hofmann, D, Mathey, E, O'Grady, G, Jones, HF, Beadnall, H, Butzkueven, H, Joshi, H, Andrews, I, Sutton, I, MacIntyre, J, Sandbach, JM, Freeman, J, King, J, O'Neill, JH, Parratt, J, Barton, J, Garber, J, Ahmad, K, Riney, K, Buzzard, K, Kothur, K, Cantrill, LC, Menezes, MP, Paine, MA, Marriot, M, Ghadiri, M, Boggild, M, Lawlor, M, Badve, M, Ryan, M, Aaqib, M, Shuey, N, Jordan, N, Urriola, N, Lawn, N, White, O, McCombe, P, Patel, R, Leventer, R, Webster, R, Smith, R, Gupta, S, Mohammad, SS, Pillai, S, Hawke, S, Simon, S, Calvert, S, Blum, S, Malone, S, Hodgkinson, S, Nguyen, TK, Hardy, TA, Kalincik, T, Ware, T, Fung, VSC, Huynh, W, Tea, F, Lopez, JA, Ramanathan, S, Merheb, V, Lee, FXZ, Zou, A, Pilli, D, Patrick, E, van der Walt, A, Monif, M, Tantsis, EM, Yiu, EM, Vucic, S, Henderson, APD, Fok, A, Fraser, CL, Lechner-Scott, J, Reddel, SW, Broadley, S, Barnett, MH, Brown, DA, Lunemann, JD, Dale, RC, Brilot, F, Sinclair, A, Kermode, AG, Kornberg, A, Bye, A, McGettigan, B, Trewin, B, Brew, B, Taylor, B, Bundell, C, Miteff, C, Troedson, C, Pridmore, C, Spooner, C, Yiannikas, C, O'Gorman, C, Clark, D, Suan, D, Jones, D, Kilfoyle, D, Gill, D, Wakefield, D, Hofmann, D, Mathey, E, O'Grady, G, Jones, HF, Beadnall, H, Butzkueven, H, Joshi, H, Andrews, I, Sutton, I, MacIntyre, J, Sandbach, JM, Freeman, J, King, J, O'Neill, JH, Parratt, J, Barton, J, Garber, J, Ahmad, K, Riney, K, Buzzard, K, Kothur, K, Cantrill, LC, Menezes, MP, Paine, MA, Marriot, M, Ghadiri, M, Boggild, M, Lawlor, M, Badve, M, Ryan, M, Aaqib, M, Shuey, N, Jordan, N, Urriola, N, Lawn, N, White, O, McCombe, P, Patel, R, Leventer, R, Webster, R, Smith, R, Gupta, S, Mohammad, SS, Pillai, S, Hawke, S, Simon, S, Calvert, S, Blum, S, Malone, S, Hodgkinson, S, Nguyen, TK, Hardy, TA, Kalincik, T, Ware, T, Fung, VSC, and Huynh, W
- Abstract
Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.
- Published
- 2019
9. Self-care in People with Type 2 Diabetes Mellitus Research Protocol of a Multicenter Mixed Methods Study (SCUDO)
- Author
-
Luciani, M, Fabrizi, D, Rebora, P, Rossi, E, Di Mauro, S, Kohl Malone, S, Ausili, D, Luciani, Michela, Fabrizi, Diletta, Rebora, Paola, Rossi, Emanuela, Di Mauro, Stefania, Kohl Malone, Susan, Ausili, Davide, Luciani, M, Fabrizi, D, Rebora, P, Rossi, E, Di Mauro, S, Kohl Malone, S, Ausili, D, Luciani, Michela, Fabrizi, Diletta, Rebora, Paola, Rossi, Emanuela, Di Mauro, Stefania, Kohl Malone, Susan, and Ausili, Davide
- Abstract
About 11% of the adult global populations is estimated to be living with type 2 diabetes mellitus (T2DM) by 2040. T2DM requires people to make decisions regarding complex therapeutic regimes, to maintain their well-being and quality of life, to manage symptoms and to reduce disease complications. All these behaviours, requiring knowledge, motivation, experience, and skills, have been referred to the concept of self-care. The intricacy and multidimensionality of T2DM self-care requires a complex approach to its overall comprehension. This Embedded Mixed Method study aims to investigate the experience of self-care in Type 2 Diabetes Mellitus adult patients. It comprises a prospective observational design, and an interpretive description. Quantitative data will be collected with validated questionnaires from 300 patients at baseline and once a year for two years on: diabetes self-care, quality of life, diabetes related distress, and sleep quality. Socio-demographic and clinical data will be collected from medical records. Qualitative data will be collected using semi-structured interviews on circa 10-20 patients, at baseline and once a year for two years, analysed according to interpretive description. Quantitative and qualitative data will be analysed separately and then merged and interpreted. This study will expand our understanding of self-care in people with T2DM. The expected outcome will be a better understanding of the effect of self-care on glycaemic control and therefore clinical outcomes and costs.
- Published
- 2019
10. Seismic and acoustic signatures of surficial mass movements at volcanoes
- Author
-
Allstadt, K. E., Allstadt, K. E., Matoza, Robin Samuel, Lockhart, A. B., Moran, S. C., Caplan-Auerbach, J., Haney, M. M., Thelen, W. A., Malone, S. D., Allstadt, K. E., Allstadt, K. E., Matoza, Robin Samuel, Lockhart, A. B., Moran, S. C., Caplan-Auerbach, J., Haney, M. M., Thelen, W. A., and Malone, S. D.
- Published
- 2018
11. Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45
- Author
-
Carvill, GL, Liu, A, Mandelstam, S, Schneider, A, Lacroix, A, Zemel, M, McMahon, JM, Bello-Espinosa, L, Mackay, M, Wallace, G, Waak, M, Zhang, J, Yang, X, Malone, S, Zhang, Y-H, Mefford, HC, Scheffer, IE, Carvill, GL, Liu, A, Mandelstam, S, Schneider, A, Lacroix, A, Zemel, M, McMahon, JM, Bello-Espinosa, L, Mackay, M, Wallace, G, Waak, M, Zhang, J, Yang, X, Malone, S, Zhang, Y-H, Mefford, HC, and Scheffer, IE
- Abstract
Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.
- Published
- 2018
12. Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome
- Author
-
Hildebrand, MS, Harvey, AS, Malone, S, Damiano, JA, Do, H, Ye, Z, McQuillan, L, Maixner, W, Kalnins, R, Nolan, B, Wood, M, Ozturk, E, Jones, NC, Gillies, G, Pope, K, Lockhart, PJ, Dobrovic, A, Leventer, RJ, Scheffer, IE, Berkovic, SF, Hildebrand, MS, Harvey, AS, Malone, S, Damiano, JA, Do, H, Ye, Z, McQuillan, L, Maixner, W, Kalnins, R, Nolan, B, Wood, M, Ozturk, E, Jones, NC, Gillies, G, Pope, K, Lockhart, PJ, Dobrovic, A, Leventer, RJ, Scheffer, IE, and Berkovic, SF
- Abstract
OBJECTIVE: To determine whether the GNAQ R183Q mutation is present in the forme fruste cases of Sturge-Weber syndrome (SWS) to establish a definitive molecular diagnosis. METHODS: We used sensitive droplet digital PCR (ddPCR) to detect and quantify the GNAQ mutation in tissues from epilepsy surgery in 4 patients with leptomeningeal angiomatosis; none had ocular or cutaneous manifestations. RESULTS: Low levels of the GNAQ mutation were detected in the brain tissue of all 4 cases-ranging from 0.42% to 7.1% frequency-but not in blood-derived DNA. Molecular evaluation confirmed the diagnosis in 1 case in which the radiologic and pathologic data were equivocal. CONCLUSIONS: We detected the mutation at low levels, consistent with mosaicism in the brain or skin (1.0%-18.1%) of classic cases. Our data confirm that the forme fruste is part of the spectrum of SWS, with the same molecular mechanism as the classic disease and that ddPCR is helpful where conventional diagnosis is uncertain.
- Published
- 2018
13. Seismic and acoustic signatures of surficial mass movements at volcanoes
- Author
-
Allstadt, K. E., Allstadt, K. E., Matoza, Robin Samuel, Lockhart, A. B., Moran, S. C., Caplan-Auerbach, J., Haney, M. M., Thelen, W. A., Malone, S. D., Allstadt, K. E., Allstadt, K. E., Matoza, Robin Samuel, Lockhart, A. B., Moran, S. C., Caplan-Auerbach, J., Haney, M. M., Thelen, W. A., and Malone, S. D.
- Published
- 2018
14. Impacts of climate change on submerged and emergent wetland plants
- Author
-
Short, F.T., Kosten, S., Morgan, P.A., Malone, S., Moore, G.E., Short, F.T., Kosten, S., Morgan, P.A., Malone, S., and Moore, G.E.
- Abstract
Item does not contain fulltext
- Published
- 2016
15. Rasmussen encephalitis tissue transfer program
- Author
-
Kruse, CA, Pardo, CA, Hartman, AL, Jallo, G, Vining, EPG, Voros, J, Gaillard, WD, Liu, J, Oluigbo, C, Malone, S, Bleasel, AF, Dexter, M, Micati, A, Velasco, TR, Machado, HR, Martino, AM, Huang, A, Wheatley, BM, Grant, GA, Granata, T, Freri, E, Garbelli, R, Koh, S, Nordli, DR, Campos, AR, O'Neill, B, Handler, MH, Chapman, KE, Wilfong, AA, Curry, DJ, Yaun, A, Madsen, JR, Smyth, MD, Mercer, D, Bingaman, W, Harvey, AS, Leventer, RJ, Lockhart, PJ, Gillies, G, Pope, K, Giller, CA, Park, YD, Rojiani, AM, Sharma, SJ, Jenkins, P, Tung, S, Huynh, MN, Chirwa, TW, Cepeda, C, Levine, MS, Chang, JW, Owens, GC, Vinters, HV, Mathern, GW, Kruse, CA, Pardo, CA, Hartman, AL, Jallo, G, Vining, EPG, Voros, J, Gaillard, WD, Liu, J, Oluigbo, C, Malone, S, Bleasel, AF, Dexter, M, Micati, A, Velasco, TR, Machado, HR, Martino, AM, Huang, A, Wheatley, BM, Grant, GA, Granata, T, Freri, E, Garbelli, R, Koh, S, Nordli, DR, Campos, AR, O'Neill, B, Handler, MH, Chapman, KE, Wilfong, AA, Curry, DJ, Yaun, A, Madsen, JR, Smyth, MD, Mercer, D, Bingaman, W, Harvey, AS, Leventer, RJ, Lockhart, PJ, Gillies, G, Pope, K, Giller, CA, Park, YD, Rojiani, AM, Sharma, SJ, Jenkins, P, Tung, S, Huynh, MN, Chirwa, TW, Cepeda, C, Levine, MS, Chang, JW, Owens, GC, Vinters, HV, and Mathern, GW
- Published
- 2016
16. Impacts of climate change on submerged and emergent wetland plants
- Author
-
Short, F.T., Kosten, S., Morgan, P.A., Malone, S., Moore, G.E., Short, F.T., Kosten, S., Morgan, P.A., Malone, S., and Moore, G.E.
- Abstract
Item does not contain fulltext
- Published
- 2016
17. Impacts of climate change on submerged and emergent wetland plants
- Author
-
Short, F.T., Kosten, S., Morgan, P.A., Malone, S., Moore, G.E., Short, F.T., Kosten, S., Morgan, P.A., Malone, S., and Moore, G.E.
- Abstract
Item does not contain fulltext
- Published
- 2016
18. Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.
- Author
-
Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., Linder I., Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., and Linder I.
- Abstract
Objective We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. Methods Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. Results Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. Significance Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.Copyright © Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
- Published
- 2015
19. Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.
- Author
-
Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., Linder I., Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., and Linder I.
- Abstract
Objective We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. Methods Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. Results Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. Significance Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.Copyright © Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
- Published
- 2015
20. Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy
- Author
-
Leu, C, Balestrini, S, Maher, B, Hernandez-Hernandez, L, Gormley, P, Hamalainen, E, Heggeli, K, Schoeler, N, Novy, J, Willis, J, Plagnol, V, Ellis, R, Reavey, E, O'Regan, M, Pickrell, WO, Thomas, RH, Chung, S-K, Delanty, N, McMahon, JM, Malone, S, Sadleir, LG, Berkovic, SF, Nashef, L, Zuberi, SM, Rees, MI, Cavalleri, GL, Sander, JW, Hughes, E, Cross, JH, Scheffer, IE, Palotie, A, Sisodiya, SM, Leu, C, Balestrini, S, Maher, B, Hernandez-Hernandez, L, Gormley, P, Hamalainen, E, Heggeli, K, Schoeler, N, Novy, J, Willis, J, Plagnol, V, Ellis, R, Reavey, E, O'Regan, M, Pickrell, WO, Thomas, RH, Chung, S-K, Delanty, N, McMahon, JM, Malone, S, Sadleir, LG, Berkovic, SF, Nashef, L, Zuberi, SM, Rees, MI, Cavalleri, GL, Sander, JW, Hughes, E, Cross, JH, Scheffer, IE, Palotie, A, and Sisodiya, SM
- Abstract
Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10(- 3)) and non-epilepsy disease controls (P = 1.2 × 10(- 3)). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP.
- Published
- 2015
21. Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome
- Author
-
Grinton, BE, Heron, SE, Pelekanos, JT, Zuberi, SM, Kivity, S, Afawi, Z, Williams, TC, Casalaz, DM, Yendle, S, Linder, I, Lev, D, Lerman-Sagie, T, Malone, S, Bassan, H, Goldberg-Stern, H, Stanley, T, Hayman, M, Calvert, S, Korczyn, AD, Shevell, M, Scheffer, IE, Mulley, JC, Berkovic, SF, Grinton, BE, Heron, SE, Pelekanos, JT, Zuberi, SM, Kivity, S, Afawi, Z, Williams, TC, Casalaz, DM, Yendle, S, Linder, I, Lev, D, Lerman-Sagie, T, Malone, S, Bassan, H, Goldberg-Stern, H, Stanley, T, Hayman, M, Calvert, S, Korczyn, AD, Shevell, M, Scheffer, IE, Mulley, JC, and Berkovic, SF
- Abstract
OBJECTIVE: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. METHODS: Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. RESULTS: Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. SIGNIFICANCE: Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.
- Published
- 2015
22. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.
- Author
-
Mefford H.C., Andrade D.M., Freeman J.L., Sadleir L.G., Shendure J., Berkovic S.F., Scheffer I.E., Carvill G.L., Heavin S.B., Yendle S.C., McMahon J.M., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M.E., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Afawi Z., Zelnick N., Lerman-Sagie T., Lev D., Moller R.S., Gill D., Mefford H.C., Andrade D.M., Freeman J.L., Sadleir L.G., Shendure J., Berkovic S.F., Scheffer I.E., Carvill G.L., Heavin S.B., Yendle S.C., McMahon J.M., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M.E., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Afawi Z., Zelnick N., Lerman-Sagie T., Lev D., Moller R.S., and Gill D.
- Abstract
Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders. © 2013 Nature America, Inc. All rights reserved.
- Published
- 2013
23. Targeted resequencing in epileptic encephalopathies reveals marked genetic heterogeneity and novel genes.
- Author
-
Scheffer I.E., Shendure J., Berkovic S.F., Mefford H.C., Carvill G.L., Heavin S.B., Yendle S.C., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M.A., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Zelnick N., Lerman-Sagie T., Lev D., SteensbjerreMoller R., Andrade D.M., Freeman J.L., Sadleir L.G., Scheffer I.E., Shendure J., Berkovic S.F., Mefford H.C., Carvill G.L., Heavin S.B., Yendle S.C., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M.A., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Zelnick N., Lerman-Sagie T., Lev D., SteensbjerreMoller R., Andrade D.M., Freeman J.L., and Sadleir L.G.
- Abstract
Purpose: Epileptic encephalopathies (EEs) are a devastating group of epilepsies characterized by refractory seizures, cognitive arrest or regression, associated with ongoing epileptic activity, and a poor prognosis. De novo mutations in a number of genes, as well as rare, de novo copy number changes, are known to cause EE. However, the vast majority of cases have an unknown etiology. Method(s): We performed targeted massively parallel resequencing of 18 known and 47 candidate EE genes in 500 patients to identify novel genes, and investigate the phenotypic spectrum of known genes. Result(s): Overall, we identify pathogenic mutations in 10% of our cohort. Pathogenic variants were found in seven of our 47 candidate genes, collectively accounting for 3% of EE in our cohort. Most notably, we identify mutations in 1.2% of our cohort in a novel gene that acts in the chromatin remodeling pathway. Also, de novo mutations were detected in 1% of the cohort in SYNGAP1, a gene identified in individuals with intellectual disability. The remaining pathogenic variants were detected in known EE genes. For some, including SCN1A, SCN2A, and SCN8A, we expand the phenotypic spectrum, presenting novel clinical features associated with these genes. Conclusion(s): We have developed a rapid, cost-effective ($1/gene/proband) and efficient targeted resequencing approach to define the molecular etiology of EE. These results will transform molecular diagnostic approaches and facilitate the management of families affected by this devastating disorder. Furthermore, we have identified the chromatin remodeling pathway as a novel biological process involved in epileptogenesis. Future studies of this pathway will provide new avenues for development of therapeutic interventions.
- Published
- 2013
24. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.
- Author
-
Mefford H.C., Andrade D.M., Freeman J.L., Sadleir L.G., Shendure J., Berkovic S.F., Scheffer I.E., Carvill G.L., Heavin S.B., Yendle S.C., McMahon J.M., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M.E., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Afawi Z., Zelnick N., Lerman-Sagie T., Lev D., Moller R.S., Gill D., Mefford H.C., Andrade D.M., Freeman J.L., Sadleir L.G., Shendure J., Berkovic S.F., Scheffer I.E., Carvill G.L., Heavin S.B., Yendle S.C., McMahon J.M., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M.E., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Afawi Z., Zelnick N., Lerman-Sagie T., Lev D., Moller R.S., and Gill D.
- Abstract
Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders. © 2013 Nature America, Inc. All rights reserved.
- Published
- 2013
25. Targeted resequencing in epileptic encephalopathies reveals marked genetic heterogeneity and novel genes.
- Author
-
Scheffer I.E., Shendure J., Berkovic S.F., Mefford H.C., Carvill G.L., Heavin S.B., Yendle S.C., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M.A., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Zelnick N., Lerman-Sagie T., Lev D., SteensbjerreMoller R., Andrade D.M., Freeman J.L., Sadleir L.G., Scheffer I.E., Shendure J., Berkovic S.F., Mefford H.C., Carvill G.L., Heavin S.B., Yendle S.C., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M.A., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Zelnick N., Lerman-Sagie T., Lev D., SteensbjerreMoller R., Andrade D.M., Freeman J.L., and Sadleir L.G.
- Abstract
Purpose: Epileptic encephalopathies (EEs) are a devastating group of epilepsies characterized by refractory seizures, cognitive arrest or regression, associated with ongoing epileptic activity, and a poor prognosis. De novo mutations in a number of genes, as well as rare, de novo copy number changes, are known to cause EE. However, the vast majority of cases have an unknown etiology. Method(s): We performed targeted massively parallel resequencing of 18 known and 47 candidate EE genes in 500 patients to identify novel genes, and investigate the phenotypic spectrum of known genes. Result(s): Overall, we identify pathogenic mutations in 10% of our cohort. Pathogenic variants were found in seven of our 47 candidate genes, collectively accounting for 3% of EE in our cohort. Most notably, we identify mutations in 1.2% of our cohort in a novel gene that acts in the chromatin remodeling pathway. Also, de novo mutations were detected in 1% of the cohort in SYNGAP1, a gene identified in individuals with intellectual disability. The remaining pathogenic variants were detected in known EE genes. For some, including SCN1A, SCN2A, and SCN8A, we expand the phenotypic spectrum, presenting novel clinical features associated with these genes. Conclusion(s): We have developed a rapid, cost-effective ($1/gene/proband) and efficient targeted resequencing approach to define the molecular etiology of EE. These results will transform molecular diagnostic approaches and facilitate the management of families affected by this devastating disorder. Furthermore, we have identified the chromatin remodeling pathway as a novel biological process involved in epileptogenesis. Future studies of this pathway will provide new avenues for development of therapeutic interventions.
- Published
- 2013
26. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1
- Author
-
Carvill, GL, Heavin, SB, Yendle, SC, McMahon, JM, O'Roak, BJ, Cook, J, Khan, A, Dorschner, MO, Weaver, M, Calvert, S, Malone, S, Wallace, G, Stanley, T, Bye, AME, Bleasel, A, Howell, KB, Kivity, S, Mackay, MT, Rodriguez-Casero, V, Webster, R, Korczyn, A, Afawi, Z, Zelnick, N, Lerman-Sagie, T, Lev, D, Moller, RS, Gill, D, Andrade, DM, Freeman, JL, Sadleir, LG, Shendure, J, Berkovic, SF, Scheffer, IE, Mefford, HC, Carvill, GL, Heavin, SB, Yendle, SC, McMahon, JM, O'Roak, BJ, Cook, J, Khan, A, Dorschner, MO, Weaver, M, Calvert, S, Malone, S, Wallace, G, Stanley, T, Bye, AME, Bleasel, A, Howell, KB, Kivity, S, Mackay, MT, Rodriguez-Casero, V, Webster, R, Korczyn, A, Afawi, Z, Zelnick, N, Lerman-Sagie, T, Lev, D, Moller, RS, Gill, D, Andrade, DM, Freeman, JL, Sadleir, LG, Shendure, J, Berkovic, SF, Scheffer, IE, and Mefford, HC
- Abstract
Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.
- Published
- 2013
27. The spectrum of SCN1A-related infantile epileptic encephalopathies.
- Author
-
Crow Y., Seltzer W.K., Gardner A., Sutherland G., Berkovic S.F., Mulley J.C., Scheffer I.E., Abbott K., Andrews I., Appleton B., Bleasel A., Buchanan N., Burke C., Bye A., Camfield C., Camfield P., Chow G., Collins K., Cook M., Cross J.H., D'Agostino M.D., Delatycki M., Dunkley C., Fawke J., Ferrie C., Geraghty M., Graham G., Grattan-Smith P., Hallam E., Hamiwka L., Harding A., Harvey S., Hayman M., Hufton I., Humphries P., Jacob P., Jacquemard R., Jamison D., Jardine P., Jones S., Keene D., Kelley K., Ketteridge D., Kim A., Kivity S., Kneebone C., Kornberg A., Lamb C., Lander C., Lerman-Sagie T., Lev D., Leventer R., Mackay M., Malone S., Manson J., McLellan A., Moore P., Nagarajan L., Nash M., Nikanorova M., Nordli D., O'Regan M., Ouvrier R., Patel J., Pridmore C., Ramesh V., Reutens D., Rowe P., Shield L., Shillito P., Smith L., Spooner C., Wallace G., Watemberg N., Whitehouse W., Wirrell E., Harkin L.A., McMahon J.M., Iona X., Dibbens L., Pelekanos J.T., Zuberi S.M., Sadleir L.G., Andermann E., Gill D., Farrell K., Connolly M., Stanley T., Harbord M., Andermann F., Wang J., Batish S.D., Jones J.G., Crow Y., Seltzer W.K., Gardner A., Sutherland G., Berkovic S.F., Mulley J.C., Scheffer I.E., Abbott K., Andrews I., Appleton B., Bleasel A., Buchanan N., Burke C., Bye A., Camfield C., Camfield P., Chow G., Collins K., Cook M., Cross J.H., D'Agostino M.D., Delatycki M., Dunkley C., Fawke J., Ferrie C., Geraghty M., Graham G., Grattan-Smith P., Hallam E., Hamiwka L., Harding A., Harvey S., Hayman M., Hufton I., Humphries P., Jacob P., Jacquemard R., Jamison D., Jardine P., Jones S., Keene D., Kelley K., Ketteridge D., Kim A., Kivity S., Kneebone C., Kornberg A., Lamb C., Lander C., Lerman-Sagie T., Lev D., Leventer R., Mackay M., Malone S., Manson J., McLellan A., Moore P., Nagarajan L., Nash M., Nikanorova M., Nordli D., O'Regan M., Ouvrier R., Patel J., Pridmore C., Ramesh V., Reutens D., Rowe P., Shield L., Shillito P., Smith L., Spooner C., Wallace G., Watemberg N., Whitehouse W., Wirrell E., Harkin L.A., McMahon J.M., Iona X., Dibbens L., Pelekanos J.T., Zuberi S.M., Sadleir L.G., Andermann E., Gill D., Farrell K., Connolly M., Stanley T., Harbord M., Andermann F., Wang J., Batish S.D., and Jones J.G.
- Abstract
The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders. © The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
- Published
- 2012
28. The spectrum of SCN1A-related infantile epileptic encephalopathies.
- Author
-
Crow Y., Seltzer W.K., Gardner A., Sutherland G., Berkovic S.F., Mulley J.C., Scheffer I.E., Abbott K., Andrews I., Appleton B., Bleasel A., Buchanan N., Burke C., Bye A., Camfield C., Camfield P., Chow G., Collins K., Cook M., Cross J.H., D'Agostino M.D., Delatycki M., Dunkley C., Fawke J., Ferrie C., Geraghty M., Graham G., Grattan-Smith P., Hallam E., Hamiwka L., Harding A., Harvey S., Hayman M., Hufton I., Humphries P., Jacob P., Jacquemard R., Jamison D., Jardine P., Jones S., Keene D., Kelley K., Ketteridge D., Kim A., Kivity S., Kneebone C., Kornberg A., Lamb C., Lander C., Lerman-Sagie T., Lev D., Leventer R., Mackay M., Malone S., Manson J., McLellan A., Moore P., Nagarajan L., Nash M., Nikanorova M., Nordli D., O'Regan M., Ouvrier R., Patel J., Pridmore C., Ramesh V., Reutens D., Rowe P., Shield L., Shillito P., Smith L., Spooner C., Wallace G., Watemberg N., Whitehouse W., Wirrell E., Harkin L.A., McMahon J.M., Iona X., Dibbens L., Pelekanos J.T., Zuberi S.M., Sadleir L.G., Andermann E., Gill D., Farrell K., Connolly M., Stanley T., Harbord M., Andermann F., Wang J., Batish S.D., Jones J.G., Crow Y., Seltzer W.K., Gardner A., Sutherland G., Berkovic S.F., Mulley J.C., Scheffer I.E., Abbott K., Andrews I., Appleton B., Bleasel A., Buchanan N., Burke C., Bye A., Camfield C., Camfield P., Chow G., Collins K., Cook M., Cross J.H., D'Agostino M.D., Delatycki M., Dunkley C., Fawke J., Ferrie C., Geraghty M., Graham G., Grattan-Smith P., Hallam E., Hamiwka L., Harding A., Harvey S., Hayman M., Hufton I., Humphries P., Jacob P., Jacquemard R., Jamison D., Jardine P., Jones S., Keene D., Kelley K., Ketteridge D., Kim A., Kivity S., Kneebone C., Kornberg A., Lamb C., Lander C., Lerman-Sagie T., Lev D., Leventer R., Mackay M., Malone S., Manson J., McLellan A., Moore P., Nagarajan L., Nash M., Nikanorova M., Nordli D., O'Regan M., Ouvrier R., Patel J., Pridmore C., Ramesh V., Reutens D., Rowe P., Shield L., Shillito P., Smith L., Spooner C., Wallace G., Watemberg N., Whitehouse W., Wirrell E., Harkin L.A., McMahon J.M., Iona X., Dibbens L., Pelekanos J.T., Zuberi S.M., Sadleir L.G., Andermann E., Gill D., Farrell K., Connolly M., Stanley T., Harbord M., Andermann F., Wang J., Batish S.D., and Jones J.G.
- Abstract
The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders. © The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
- Published
- 2012
29. Status of U.S. testing of the High Performance Hall System SPT-140 Hall thruster
- Author
-
Michigan, Univ., Ann Arbor, USAF, Research Lab., Edwards AFB, CA, NASA, Glenn Research Center, Cleveland, OH, Space Systems Loral, Palo Alto, CA, Sverdrup Technology, Inc., Edwards AFB, CA, Hargus, W. Jr., Fife, J., Mcfall, K., Jankovsky, R., Mason, L., Snyder, J., Malone, S., Haas, J., Gallimore, A., Bauer, N., Michigan, Univ., Ann Arbor, USAF, Research Lab., Edwards AFB, CA, NASA, Glenn Research Center, Cleveland, OH, Space Systems Loral, Palo Alto, CA, Sverdrup Technology, Inc., Edwards AFB, CA, Hargus, W. Jr., Fife, J., Mcfall, K., Jankovsky, R., Mason, L., Snyder, J., Malone, S., Haas, J., Gallimore, A., and Bauer, N.
- Published
- 2010
30. Status of US Testing of the High Performance Hall System SPT-140 Hall Thruster
- Author
-
AIR FORCE RESEARCH LAB EDWARDS AFB CA SPACE AND MISSILE PROPULSION DIV, Hargus, W., Jr., Jankovsky, R., Mason, L., Snyder, J., Malone, S., AIR FORCE RESEARCH LAB EDWARDS AFB CA SPACE AND MISSILE PROPULSION DIV, Hargus, W., Jr., Jankovsky, R., Mason, L., Snyder, J., and Malone, S.
- Abstract
The High Performance Hall System (HPHS) program supports the development and flight qualification of a 4.5 kW electric propulsion system that includes the SPT-140 Hall thruster. The Air Force Research Laboratory (AFRL) and International Space Technology, Inc (ISTI) are co-funding the HPHS program which is being conducted by a team led by Atlantic Research Corporation (ARC). The team includes ISTI, Experimental Design Bureau Fakel (Fakel), and Space Systems Loral (S/SL). The Research Institute of Applied Mechanics and Electrodynamics (RIAME) also provided support for this project. The SPT-140 is being designed, developed, manufactured, and tested by Fakel in Kaliningrad, Russia, where extensive performance testing and advanced development have been performed. In addition to the testing in Russia, a suite of experiments on the development model and the qualification model thrusters, sponsored by the U.S. Government, has occurred during 1999 and is scheduled to occur in 2000. These experiments include thruster performance, plume characterization, electromagnetic compatibility, and life characterization., Presented at the AIAA Aerospace Sciences Meeting held in Reno, NV on 10 Jan 2000. AIAA-2000-1053.
- Published
- 2000
31. Spacecraft Interaction Test Results of the High Performance Hall System SPT-140 (Postprint)
- Author
-
AIR FORCE RESEARCH LAB EDWARDS AFB CA PROPULSION DIRECTORATE, Fife, J. M., Hargus Jr, W. A., Jaworske, D. A., Sarmiento, C., Mason, L., Jankovsky, R., Snyder, J. S., Malone, S., Haas, J., Gallimore, A., AIR FORCE RESEARCH LAB EDWARDS AFB CA PROPULSION DIRECTORATE, Fife, J. M., Hargus Jr, W. A., Jaworske, D. A., Sarmiento, C., Mason, L., Jankovsky, R., Snyder, J. S., Malone, S., Haas, J., and Gallimore, A.
- Abstract
Ground tests were performed to help characterize modes of interaction between the SPT-140 Hall thruster and spacecraft components. The experiments were performed at NASA Glenn Research Center and at the University of Michigan. Measurements were made of thruster plume current density, electromagnetic interference (EMl), and surface sputtering and contamination. Diagnostics included Faraday probes, collimated sputter/deposition targets, and radio-frequency detectors. Ion current density measurements showed exponential decay with off-axis angle up to approximately 30 degrees. At off-axis angles greater than 30 degrees, results varied with chamber background pressure, presumably due to ambient charge exchange plasma. Sputter rates of solar cell coverglass. Kapton, and RTV were accurately measured I in from the thruster exit for off-axis angles less than 60 degrees. At off-axis angles greater than 60 degrees, the sputter rate was on the order of the measurement uncertainty. EMI tests found very little emission in the traditional RF communication bands. At the lowest frequencies, one band of E-field emission (10kHz to 20MHz) was detected which exceeded the MIL-STD-461C specification by up to 53dB., Presented at the AIAA/ASME/SAE/ASEE Joint Propulsion Conference (AIAA 36th) held in Huntsville, AL on 16-19 Jul 2000.
- Published
- 2000
32. Accomplishment, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the word 'Accomplishment,' lettered by penman S. C. Malone in Old Gothic Script.
- Published
- 1907
33. Modern Egyptian alphabet, 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study of the alphabet in Modern Egyptian Spurred, dated 1907
- Published
- 1907
34. Alphabets, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) on the word 'Alphabets,' lettered in Artistic Roman script by penman S. C. Malone.
- Published
- 1907
35. The Master's Touch, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the Horatius Bonar poem The Master's Touch, executed by penman S. C. Malone. The design features a scroll tablet, laurel spray, and a torch. The lettering is in hair-line Plain Gothic style.
- Published
- 1907
36. Beautiful Penmanship, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) on the words 'Beautiful Penmanship,' lettered in Modern Gothic script by penman S. C. Malone.
- Published
- 1907
37. Fantastic Roman alphabet, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the alphabet in Fantastic Roman lettering, by penman S. C. Malone.
- Published
- 1907
38. Classic Gothic alphabet, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the alphabet in Classic Gothic script, by penman S. C. Malone of Baltimore, M.D.
- Published
- 1907
39. Artistic Modern Roman alphabet, 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study of the alphabet in Artistic Modern Roman, dated 1907
- Published
- 1907
40. Modern Shield, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Modern Shield design (dated ca. 1907) with Greek Laurel wreath and lettering by penman S. C. Malone.
- Published
- 1907
41. Jamestown, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) on the text Jamestown, lettered in Modern Gothic by penman S. C. Malone.
- Published
- 1907
42. Modern Roman alphabet, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the alphabet in Modern Roman script, by penman S. C. Malone.
- Published
- 1907
43. Modern Old English alphabet, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the alphabet in condensed Modern Old English script, by penman S. C. Malone.
- Published
- 1907
44. Beautiful Penmanship, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) on the words 'Beautiful Penmanship,' lettered in Modern Gothic script by penman S. C. Malone.
- Published
- 1907
45. Classic Gothic alphabet, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the alphabet in Classic Gothic script, by penman S. C. Malone of Baltimore, M.D.
- Published
- 1907
46. Fantastic Roman alphabet, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the alphabet in Fantastic Roman lettering, by penman S. C. Malone.
- Published
- 1907
47. Modern Old English alphabet, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the alphabet in condensed Modern Old English script, by penman S. C. Malone.
- Published
- 1907
48. Alphabets, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) on the word 'Alphabets,' lettered in Artistic Roman script by penman S. C. Malone.
- Published
- 1907
49. The Master's Touch, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the Horatius Bonar poem The Master's Touch, executed by penman S. C. Malone. The design features a scroll tablet, laurel spray, and a torch. The lettering is in hair-line Plain Gothic style.
- Published
- 1907
50. Accomplishment, ca. 1907
- Author
-
Malone, S. C. and Malone, S. C.
- Abstract
Penmanship study (dated ca. 1907) of the word 'Accomplishment,' lettered by penman S. C. Malone in Old Gothic Script.
- Published
- 1907
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.