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51. Loss of CLTRN function produces a neuropsychiatric disorder and a biochemical phenotype that mimics Hartnup disease

Author

Pillai NR, Yubero-Siles D, Shayota BJ, De Oyarzabal-Sanz AL, Ghosh R, Sun Q, Azamian MS, Arjona-Fernandez C, Brandi-Tarrau N, Palau F, Lalani SR, Artuch-Iriberri R, Garcia-Cazorla A, and Scott DA

Subjects
B(0)AT1, +AT, EAAC1, Hartnup disease, B0AT1, rBAT-b0,+AT, aminoaciduria, CLTRN, rBAT-b0
Abstract

Hartnup disease is an autosomal recessive condition characterized by neutral aminoaciduria and behavioral problems. It is caused by a loss of B(0) AT1, a neutral amino acid transporter in the kidney and intestine. CLTRN encodes the protein collectrin that functions in the transportation and activation of B(0) AT1 in the renal apical brush bordered epithelium. Collectrin deficient mice have severe aminoaciduria. However, the phenotype associated with collectrin deficiency in humans has not been reported. Here we report two patients, an 11-year-old male who is hemizygous for a small, interstitial deletion on Xp22.2 that encompasses CLTRN and a 22-year-old male with a deletion spanning exons 1 to 3 of CLTRN. Both of them present with neuropsychiatric phenotypes including autistic features, anxiety, depression, compulsions, and motor tics, as well as neutral aminoaciduria leading to a clinical diagnosis of Hartnup disease and treatment with niacin supplementation. Plasma amino acids were normal in both patients. One patient had low 5-hydroxyindoleacetic acid levels, a serotoninergic metabolite. We explored the expression of collectrin in the murine brain and found it to be particularly abundant in the hippocampus, brainstem, and cerebellum. We propose that collectrin deficiency in humans can be associated with aminoaciduria and a clinical picture similar to that seen in Hartnup disease. Further studies are needed to explore the role of collectrin deficiency in the neurological phenotypes.

Published
2019

52. Temporary analysis of the occorrence of equine infectious anemia in Brazil in the period 2005 to 2016

Author

Costa, Ana Maria Paes Scott da, Universidade Estadual Paulista (Unesp), and Mathias, Luis Antônio [UNESP]

Subjects
Análise temporal, Equideocultura, Equine Infectious Anemia, Anemia infecciosa equina, Epidemiology, National Equine Sanitation Program, Time series analysis, Epidemiologia, Equideoculture, Estatística, Programa Nacional de Sanidade Equina, Statistic
Abstract

Submitted by Ana Maria Paes Scott da Costa (aninhascott@gmail.com) on 2019-01-18T03:33:39Z No. of bitstreams: 1 Dissertação definitiva.pdf: 3258363 bytes, checksum: cc7571bbb95978b90626d9e675875903 (MD5) Rejected by Neli Silvia Pereira null (nelisps@fcav.unesp.br), reason: Solicitamos que sejam realizadas as seguintes adequações: 1 - A CAPES exige que o agradecimento contenha a seguinte redação: "O presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Código de Financiamento 001" 2 - O título da tese na ficha catalográfica está em caixa alta. De acordo com a norma, somente a letra inicial do título e/ou nomes próprios são escritos com maiúscula. 3 - Entrar com as palavras chave do repositório com a primeira letra em maiúscula. Agradecemos a colaboração. on 2019-01-18T10:52:36Z (GMT) Submitted by Ana Maria Paes Scott da Costa (aninhascott@gmail.com) on 2019-01-18T12:37:40Z No. of bitstreams: 1 Dissertação Definitiva.pdf: 3251780 bytes, checksum: e32fbaea46f71cfcac0a8facffece0e1 (MD5) Approved for entry into archive by Tatiana Camila Gricio (tatiana.gricio@unesp.br) on 2019-01-18T12:42:33Z (GMT) No. of bitstreams: 1 costa_amps_me_jabo.pdf: 3223556 bytes, checksum: 55cce5e99086bc0b18ebd834b566b744 (MD5) Made available in DSpace on 2019-01-18T12:42:33Z (GMT). No. of bitstreams: 1 costa_amps_me_jabo.pdf: 3223556 bytes, checksum: 55cce5e99086bc0b18ebd834b566b744 (MD5) Previous issue date: 2018-12-05 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) A equideocultura possui grande importância econômica no Brasil, e a anemia infecciosa equina (AIE) representa ameaça para o crescimento do setor. Pouco se sabe sobre análise temporal da ocorrência da doença no Brasil, por isso este trabalho foi conduzido com o objetivo de investigar a frequência e distribuição da anemia infecciosa equina em todo o território brasileiro no período de 2005 a 2016, por meio das análises temporais do índice de morbidade, índice de eliminação de reagentes, razão entre o número de equídeos eliminados e o número de equídeos reagentes, índice de notificação de focos e índice de focos novos e antigos ao longo do período. Foi realizada uma análise de série temporal sobre AIE no período de 2005 a 2016, utilizando dois bancos de dados, o da OIE e o do MAPA. No Brasil, 2010 foi o ano que apresentou o menor índice de morbidade de AIE, com 100,9 casos por 100 mil cabeças, e 2009 apresentou o maior índice, com 159,1 por 100 mil cabeças, e a taxa de variação anual no período foi de -2,4% (-7,5% a 2,8%), revelando estabilidade desse indicador (P = 0,317). O índice de eliminação de reagentes por AIE no Brasil foi maior em 2010, com 62,7 por 100 mil cabeças, e menor em 2016, com 32,1. Durante todo o período estudado, a variação anual no país se mostrou estável, com valor de -6,1% (-18,2% a 7,8%) e valor de P não significativo (0,333). A razão entre o número de equídeos eliminados e o número de equídeos reagentes por 100 equídeos foi baixa em quase todas as UF’s e regiões. Os índices de notificação de focos no Brasil se apresentaram estáveis (P = 0,050) durante todo o período, com taxa de variação anual de -6,4% (-13,0 a 0,0). Os índices de focos novos e antigos nos anos de 2013, 2014, 2015 e 2016 sugerem crescimento em quase todos os estados. O programa é capaz de mapear a situação sanitária em determinadas circunstâncias delimitadas, mas para avançar seria necessário implementar mudanças na estratégia de ação de modo a alcançar melhores resultados no controle e na previsibilidade para uma possível erradicação da doença. Concluiu-se então que a frequência e distribuição da AIE entre 2005 e 2016 no Brasil permitiu caracterizar como estáveis em âmbito nacional os seguintes índices: índice de morbidade, índice de eliminação de reagentes, razão entre o número de equídeos eliminados e o número de equídeos reagentes e índice de notificação de focos; sugerindo uma estabilização do Programa Nacional de Sanidade Equina (PNSE) durante o período estudado. Equideoculture has a great economic importance in Brazil, and equine the infectious anemia (EIA) poses as a threat to the growth of the horse market. Little is known about the time series analysis of the disease in Brazil, so this work was conducted with the objective to investigate the frequency and distribution of equine infectious anemia in Brazil from 2005 to 2016, by the time series analysis of morbidity index, elimination rate of positive animals, ratio between the number of dead equines and the number of testing positive equines, outbreak notification rates and indexes of new and old outbreaks. A time series analysis was carried out on EIA in the period 2005 to 2016, using OIE and MAPA databases. In Brazil, 2010 was the year with the lowest EIA morbidity index, with 100.9 cases per 100,000 equines, and 2009 had the highest index, with 159.1 per 100,000 equines, and the annual variation rate was -2.4% (-7.5% to 2.8%), showing stability of this indicator (P = 0.317). The elimination rate of positive animals for EIA in Brazil was higher in 2010, with 62.7 per 100 thousand equines, and lower in 2016, with 32.1. Throughout the study period, the annual variation in the country was stable, with a value of -6.1% (-18.2% to 7.8%) and a non-significant statistical difference was found (P = 0.333). The ratio between the number of dead equines and the number of reared equines per 100 equines was low in almost all FU's and regions. Outbreak notification rates in Brazil were stable (P = 0.050) throughout the period, with an average annual rate of -6.4% (-13.0 to 0.0). The indexes of new and old outbreaks in the years 2013, 2014, 2015 and 2016 suggest a growth in almost all states. The program can map the health situation in certain limited circumstances, and to advance it would be necessary to implement changes in the strategic action in order to achieve better results in the control and possible predictability eradication of the disease. It was concluded that the frequency and distribution of the EIA in Brazil between 2005 and 2016 allowed us to characterize the following index as being stable at the national level: morbidity index, elimination rate of positive animals, ratio between the number of dead equines and the number of testing positive equines and outbreak notification rates; suggesting a stabilization of the National Program of Equine Health (PNSE) during the studied period.

Published
2018

54. A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction

Author

Somers, K, Wen, VW, Middlemiss, SMC, Osborne, B, Forgham, H, Jung, MS, Karsa, M, Clifton, M, Bongers, A, Gao, J, Mayoh, C, Raoufi-Rad, N, Kusnadi, EP, Hannan, KM, Scott, DA, Kwek, A, Liu, B, Flemming, C, Chudakova, DA, Pandher, R, Failes, TW, Lim, J, Angeli, A, Osterman, AL, Imamura, T, Kees, UR, Supuran, CT, Pearson, RB, Hannan, RD, Davis, TP, McCarroll, J, Kavallaris, M, Turner, N, Gudkov, AV, Haber, M, Norris, MD, Henderson, MJ, Somers, K, Wen, VW, Middlemiss, SMC, Osborne, B, Forgham, H, Jung, MS, Karsa, M, Clifton, M, Bongers, A, Gao, J, Mayoh, C, Raoufi-Rad, N, Kusnadi, EP, Hannan, KM, Scott, DA, Kwek, A, Liu, B, Flemming, C, Chudakova, DA, Pandher, R, Failes, TW, Lim, J, Angeli, A, Osterman, AL, Imamura, T, Kees, UR, Supuran, CT, Pearson, RB, Hannan, RD, Davis, TP, McCarroll, J, Kavallaris, M, Turner, N, Gudkov, AV, Haber, M, Norris, MD, and Henderson, MJ

Abstract

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.

Published
2019

55. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Author

Koczkowska, M, Callens, T, Chen, Y, Gomes, A, Hicks, AD, Sharp, A, Johns, E, Uhas, KA, Armstrong, L, Bosanko, KA, Babovic-Vuksanovic, D, Baker, L, Basel, DG, Bengala, M, Bennett, JT, Chambers, C, Clarkson, LK, Clementi, M, Cortes, FM, Cunningham, M, D'Agostino, MD, Delatycki, MB, Digilio, MC, Dosa, L, Esposito, S, Fox, S, Freckmann, M-L, Fauth, C, Giugliano, T, Giustini, S, Goetsch, A, Goldberg, Y, Greenwood, RS, Griffis, C, Gripp, KW, Gupta, P, Haan, E, Hachen, RK, Haygarth, TL, Hernandez-Chico, C, Hodge, K, Hopkin, RJ, Hudgins, L, Janssens, S, Keller, K, Kelly-Mancuso, G, Kochhar, A, Korf, BR, Lewis, AM, Liebelt, J, Lichty, A, Listernick, RH, Lyons, MJ, Maystadt, I, Ojeda, MM, McDougall, C, McGregor, LK, Melis, D, Mendelsohn, N, Nowaczyk, MJM, Ortenberg, J, Panzer, K, Pappas, JG, Pierpont, ME, Piluso, G, Pinna, V, Pivnick, EK, Pond, DA, Powell, CM, Rogers, C, Shahar, NR, Rutledge, SL, Saletti, V, Sandaradura, SA, Santoro, C, Schatz, UA, Schreiber, A, Scott, DA, Sellars, EA, Sheffer, R, Siqveland, E, Slopis, JM, Smith, R, Spalice, A, Stockton, DW, Streff, H, Theos, A, Tomlinson, GE, Tran, G, Trapane, PL, Trevisson, E, Ullrich, NJ, Van den Ende, J, Vergano, SAS, Wallace, SE, Wangler, MF, Weaver, DD, Yohay, KH, Zackai, E, Zonana, J, Zurcher, V, Claes, KBM, Eoli, M, Martin, Y, Wimmer, K, De Luca, A, Legius, E, Messiaen, LM, Koczkowska, M, Callens, T, Chen, Y, Gomes, A, Hicks, AD, Sharp, A, Johns, E, Uhas, KA, Armstrong, L, Bosanko, KA, Babovic-Vuksanovic, D, Baker, L, Basel, DG, Bengala, M, Bennett, JT, Chambers, C, Clarkson, LK, Clementi, M, Cortes, FM, Cunningham, M, D'Agostino, MD, Delatycki, MB, Digilio, MC, Dosa, L, Esposito, S, Fox, S, Freckmann, M-L, Fauth, C, Giugliano, T, Giustini, S, Goetsch, A, Goldberg, Y, Greenwood, RS, Griffis, C, Gripp, KW, Gupta, P, Haan, E, Hachen, RK, Haygarth, TL, Hernandez-Chico, C, Hodge, K, Hopkin, RJ, Hudgins, L, Janssens, S, Keller, K, Kelly-Mancuso, G, Kochhar, A, Korf, BR, Lewis, AM, Liebelt, J, Lichty, A, Listernick, RH, Lyons, MJ, Maystadt, I, Ojeda, MM, McDougall, C, McGregor, LK, Melis, D, Mendelsohn, N, Nowaczyk, MJM, Ortenberg, J, Panzer, K, Pappas, JG, Pierpont, ME, Piluso, G, Pinna, V, Pivnick, EK, Pond, DA, Powell, CM, Rogers, C, Shahar, NR, Rutledge, SL, Saletti, V, Sandaradura, SA, Santoro, C, Schatz, UA, Schreiber, A, Scott, DA, Sellars, EA, Sheffer, R, Siqveland, E, Slopis, JM, Smith, R, Spalice, A, Stockton, DW, Streff, H, Theos, A, Tomlinson, GE, Tran, G, Trapane, PL, Trevisson, E, Ullrich, NJ, Van den Ende, J, Vergano, SAS, Wallace, SE, Wangler, MF, Weaver, DD, Yohay, KH, Zackai, E, Zonana, J, Zurcher, V, Claes, KBM, Eoli, M, Martin, Y, Wimmer, K, De Luca, A, Legius, E, and Messiaen, LM

Abstract

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.

Published
2019

56. Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region

Author

Kelly, M, Park, M, Mihalek, I, Rochtus, A, Gramm, M, Perez-Palma, E, Axeen, ET, Hung, CY, Olson, H, Swanson, L, Anselm, I, Briere, LC, High, FA, Sweetser, DA, Kayani, S, Snyder, M, Calvert, S, Scheffer, IE, Yang, E, Waugh, JL, Lal, D, Bodamer, O, Poduri, A, Adams, DR, Aday, A, Alejandro, ME, Allard, P, Ashley, EA, Azamian, MS, Bacino, CA, Baker, E, Balasubramanyam, A, Barseghyan, H, Batzli, GF, Beggs, AH, Behnam, B, Bellen, HJ, Bernstein, JA, Bican, A, Bick, DP, Birch, CL, Bonner, D, Boone, BE, Bostwick, BL, Brokamp, E, Brown, DM, Brush, M, Burke, EA, Burrage, LC, Butte, MJ, Chen, S, Clark, GD, Coakley, TR, Cogan, JD, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, D'Souza, P, Davids, M, Davidson, JM, Dayal, JG, Dell'Angelica, EC, Dhar, SU, Dipple, KM, Donnell-Fink, LA, Dorrani, N, Dorset, DC, Douine, ED, Draper, DD, Dries, AM, Eckstein, DJ, Emrick, LT, Eng, CM, Enns, G-GM, Eskin, A, Esteves, C, Estwick, T, Fairbrother, L, Fernandez, L, Ferreira, C, Fieg, EL, Fisher, PG, Fogel, BL, Friedman, ND, Gahl, WA, Glanton, E, Godfrey, RA, Goldman, AM, Goldstein, DB, Gould, SE, Gourdine, J-PF, Groden, CA, Gropman, AL, Haendel, M, Hamid, R, Hanchard, NA, High, F, Holm, IA, Horn, J, Howerton, EM, Huang, Y, Jamal, F, Jiang, Y-H, Johnston, JM, Jones, AL, Karaviti, L, Koeller, DM, Kohane, IS, Kohler, JN, Konick, S, Koziura, M, Krasnewich, DM, Krier, JB, Kyle, JE, Lalani, SR, Lau, CC, Lazar, J, LeBlanc, K, Lee, BH, Lee, H, Levy, SE, Lewis, RA, Lincoln, SA, Loo, SK, Loscalzo, J, Maas, RL, Macnamara, EF, MacRae, CA, Maduro, VV, Majch-erska, MM, Malicdan, MC, Mamounas, LA, Manolio, TA, Markello, TC, Marom, R, Martin, MG, Martinez-Agosto, JA, Mar-waha, S, May, T, McConkie-Rosell, A, McCormack, CE, McCray, AF, Merker, JD, Metz, TO, Might, M, Moretti, PM, Morimoto, M, Mulvihill, JJ, Murdock, DR, Murphy, JL, Muzny, DM, Nehrebecky, ME, Nelson, SF, Newberry, JS, Newman, JH, Nicholas, SK, Novacic, D, Orange, JS, Orengo, JP, Pallais, JC, Palmer, CGS, Papp, JC, Parker, NH, Pena, LDM, Phillips, JA, Posey, JE, Postlethwait, JH, Potocki, L, Pusey, BN, Reuter, CM, Rives, L, Robertson, AK, Rodan, LH, Rosenfeld, JA, Sampson, JB, Samson, SL, Schoch, K, Scott, DA, Shakachite, L, Sharma, P, Shashi, V, Signer, R, Silverman, EK, Sinsheimer, JS, Smith, KS, Spillmann, RC, Stoler, JM, Stong, N, Sullivan, JA, Tan, QK-G, Tifft, CJ, Toro, C, Tran, AA, Urv, TK, Vilain, E, Vogel, TP, Waggott, DM, Wahl, CE, Walker, M, Walley, NM, Walsh, CA, Wan, J, Wangler, MF, Ward, PA, Waters, KM, Webb-Robertson, B-JM, Westerfield, M, Wheeler, MT, Wise, AL, Wolfe, LA, Worthey, EA, Yamamoto, S, Yang, Y, Yoon, AJ, Yu, G, Zastrow, DB, Zhao, C, Zheng, A, Kelly, M, Park, M, Mihalek, I, Rochtus, A, Gramm, M, Perez-Palma, E, Axeen, ET, Hung, CY, Olson, H, Swanson, L, Anselm, I, Briere, LC, High, FA, Sweetser, DA, Kayani, S, Snyder, M, Calvert, S, Scheffer, IE, Yang, E, Waugh, JL, Lal, D, Bodamer, O, Poduri, A, Adams, DR, Aday, A, Alejandro, ME, Allard, P, Ashley, EA, Azamian, MS, Bacino, CA, Baker, E, Balasubramanyam, A, Barseghyan, H, Batzli, GF, Beggs, AH, Behnam, B, Bellen, HJ, Bernstein, JA, Bican, A, Bick, DP, Birch, CL, Bonner, D, Boone, BE, Bostwick, BL, Brokamp, E, Brown, DM, Brush, M, Burke, EA, Burrage, LC, Butte, MJ, Chen, S, Clark, GD, Coakley, TR, Cogan, JD, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, D'Souza, P, Davids, M, Davidson, JM, Dayal, JG, Dell'Angelica, EC, Dhar, SU, Dipple, KM, Donnell-Fink, LA, Dorrani, N, Dorset, DC, Douine, ED, Draper, DD, Dries, AM, Eckstein, DJ, Emrick, LT, Eng, CM, Enns, G-GM, Eskin, A, Esteves, C, Estwick, T, Fairbrother, L, Fernandez, L, Ferreira, C, Fieg, EL, Fisher, PG, Fogel, BL, Friedman, ND, Gahl, WA, Glanton, E, Godfrey, RA, Goldman, AM, Goldstein, DB, Gould, SE, Gourdine, J-PF, Groden, CA, Gropman, AL, Haendel, M, Hamid, R, Hanchard, NA, High, F, Holm, IA, Horn, J, Howerton, EM, Huang, Y, Jamal, F, Jiang, Y-H, Johnston, JM, Jones, AL, Karaviti, L, Koeller, DM, Kohane, IS, Kohler, JN, Konick, S, Koziura, M, Krasnewich, DM, Krier, JB, Kyle, JE, Lalani, SR, Lau, CC, Lazar, J, LeBlanc, K, Lee, BH, Lee, H, Levy, SE, Lewis, RA, Lincoln, SA, Loo, SK, Loscalzo, J, Maas, RL, Macnamara, EF, MacRae, CA, Maduro, VV, Majch-erska, MM, Malicdan, MC, Mamounas, LA, Manolio, TA, Markello, TC, Marom, R, Martin, MG, Martinez-Agosto, JA, Mar-waha, S, May, T, McConkie-Rosell, A, McCormack, CE, McCray, AF, Merker, JD, Metz, TO, Might, M, Moretti, PM, Morimoto, M, Mulvihill, JJ, Murdock, DR, Murphy, JL, Muzny, DM, Nehrebecky, ME, Nelson, SF, Newberry, JS, Newman, JH, Nicholas, SK, Novacic, D, Orange, JS, Orengo, JP, Pallais, JC, Palmer, CGS, Papp, JC, Parker, NH, Pena, LDM, Phillips, JA, Posey, JE, Postlethwait, JH, Potocki, L, Pusey, BN, Reuter, CM, Rives, L, Robertson, AK, Rodan, LH, Rosenfeld, JA, Sampson, JB, Samson, SL, Schoch, K, Scott, DA, Shakachite, L, Sharma, P, Shashi, V, Signer, R, Silverman, EK, Sinsheimer, JS, Smith, KS, Spillmann, RC, Stoler, JM, Stong, N, Sullivan, JA, Tan, QK-G, Tifft, CJ, Toro, C, Tran, AA, Urv, TK, Vilain, E, Vogel, TP, Waggott, DM, Wahl, CE, Walker, M, Walley, NM, Walsh, CA, Wan, J, Wangler, MF, Ward, PA, Waters, KM, Webb-Robertson, B-JM, Westerfield, M, Wheeler, MT, Wise, AL, Wolfe, LA, Worthey, EA, Yamamoto, S, Yang, Y, Yoon, AJ, Yu, G, Zastrow, DB, Zhao, C, and Zheng, A

Abstract

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

Published
2019

59. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission

Author

Guo, H, Li, Y, Shen, Lucy, Wang, TY, Jia, XB, Liu, LJ, Xu, T, Ou, MZ, Hoekzema, K, Wu, HD, Gillentine, MA, Liu, CY, Ni, HL, Peng, PW, Zhao, RJ, Zhang, Y, Phornphutkul, C, Stegmann, APA, Prada, CE, Hopkin, RJ, Shieh, JT, McWalter, K, Monaghan, K G, van Hasselt, PM, van Gassen, K, Bai, T, Long, M, Han, L, Quan, YT, Chen, ML, Zhang, YW, Li, KKW, Zhang, QM, Tan, JQ, Zhu, TF, Liu, YN, Pang, N, Peng, J, Scott, DA, Lalani, SR, Azamian, M, Verheijen - Mancini, Grazia, Adams, DJ, Kvarnung, M, Lindstrand, A, Nordgren, A, Pevsner, J, Osei-Owusu, IA, Romano, C, Calabrese, G, Galesi, O, Gecz, J, Haan, E, Ranells, J, Racobaldo, M, Nordenskjold, M, Madan-Khetarpal, S, Sebastian, J, Ball, S, Zou, XB, Zhao, JP, Hu, ZM, Xia, F, Liu, PF, Rosenfeld, JA, de Vries, BBA, Bernier, RA, Xu, ZQD, Li, HH, Xie, W, Hufnagel, RB, Eichler, EE, Xia, K, Guo, H, Li, Y, Shen, Lucy, Wang, TY, Jia, XB, Liu, LJ, Xu, T, Ou, MZ, Hoekzema, K, Wu, HD, Gillentine, MA, Liu, CY, Ni, HL, Peng, PW, Zhao, RJ, Zhang, Y, Phornphutkul, C, Stegmann, APA, Prada, CE, Hopkin, RJ, Shieh, JT, McWalter, K, Monaghan, K G, van Hasselt, PM, van Gassen, K, Bai, T, Long, M, Han, L, Quan, YT, Chen, ML, Zhang, YW, Li, KKW, Zhang, QM, Tan, JQ, Zhu, TF, Liu, YN, Pang, N, Peng, J, Scott, DA, Lalani, SR, Azamian, M, Verheijen - Mancini, Grazia, Adams, DJ, Kvarnung, M, Lindstrand, A, Nordgren, A, Pevsner, J, Osei-Owusu, IA, Romano, C, Calabrese, G, Galesi, O, Gecz, J, Haan, E, Ranells, J, Racobaldo, M, Nordenskjold, M, Madan-Khetarpal, S, Sebastian, J, Ball, S, Zou, XB, Zhao, JP, Hu, ZM, Xia, F, Liu, PF, Rosenfeld, JA, de Vries, BBA, Bernier, RA, Xu, ZQD, Li, HH, Xie, W, Hufnagel, RB, Eichler, EE, and Xia, K

Published
2019

62. 1p36 deletion syndrome: an update

Author

Jordan VK, Zaveri HP, and Scott DA

Subjects
lcsh:R5-920, lcsh:Genetics, lcsh:QH426-470, lcsh:Medicine (General)
Abstract

Valerie K Jordan,1 Hitisha P Zaveri,2 Daryl A Scott1,2 1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Abstract: Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes. Keywords: chromosome 1p36, chromosome deletion, 1p36 deletion syndrome, monosomy 1p36

Published
2015

67. Cognitive Function Before and After Left Heart Catheterization

Author

Scott, DA, Evered, L, Maruff, P, MacIsaac, A, Maher, S, Silbert, BS, Scott, DA, Evered, L, Maruff, P, MacIsaac, A, Maher, S, and Silbert, BS

Abstract

BACKGROUND: Hospital procedures have been associated with cognitive change in older patients. This study aimed to document the prevalence of mild cognitive impairment in individuals undergoing left heart catheterization (LHC) before the procedure and the incidence of cognitive decline to 3 months afterwards. METHODS AND RESULTS: We conducted a prospective, observational, clinical investigation of elderly participants undergoing elective LHC. Cognition was assessed using a battery of written tests and a computerized cognitive battery before the LHC and then at 3 months afterwards. The computerized tests were also administered at 24 hours (or discharge) and 7 days after LHC. A control group of 51 community participants was recruited to calculate cognitive decline using the Reliable Change Index. Of 437 participants, mild cognitive impairment was identified in 226 (51.7%) before the procedure. Computerized tests detected an incidence of cognitive decline of 10.0% at 24 hours and 7.5% at 7 days. At 3 months, written tests detected an incidence of cognitive decline of 13.1% and computerized tests detected an incidence of 8.5%. Cognitive decline at 3 months using written tests was associated with increasing age, whereas computerized tests showed cognitive decline was associated with baseline amnestic mild cognitive impairment, diabetes mellitus, and prior coronary stenting. CONCLUSIONS: More than half the patients aged >60 years presenting for LHC have mild cognitive impairment. LHC is followed by cognitive decline in 8% to 13% of individuals at 3 months after the procedure. Subtle cognitive decline both before and after LHC is common and may have important clinical implications. CLINICAL TRIAL REGISTRATION INFORMATION: URL: www.anzctr.org.au. Unique identifier: ACTRN12607000051448.

Published
2018

68. Acute Pain Management: Scientific Evidence (4th edition)

Author

Halliwell, R, Palmer, GM, Schug, SA, Scott, DA, Trinca, J, Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J, APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine, Halliwell, R, Palmer, GM, Schug, SA, Scott, DA, Trinca, J, Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J, and APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine

Abstract

This is the fourth edition of Acute Pain Management: Scientific Evidence. The first three were published in 1999, 2005 and 2010, respectively. This fourth edition sums up the evidence currently available to assist health professionals in the management of acute pain. Additional literature has been reviewed from August 2009 to August 2014. Levels of evidence have been documented according to the National Health and Medical Research Council (NHMRC) designation (NHMRC 1999). The Jadad scoring instrument was used to score the quality of all randomised controlled trials (RCTs) (Jadad 1996). Acute Pain Management: Scientific Evidence messages for each topic are specified with the highest level of evidence available to support them, or with a symbol showing that they are based on clinical experience or expert opinion.

Published
2015

69. Backcover

Author

Scott, David, Posner, C.M., Martin, Chris, and Guzman, Elsa

Published
2018

70. Ch10

Author

Scott, David, Posner, C.M., Martin, Chris, and Guzman, Elsa

Published
2018

72. The past, present and future of the postanesthesia care unit (PACU) in Japan.

Author

Scott, DA, Sento, Yoshiki, Suzuki, Toshiyasu, Suzuki, Yasuyuki, Scott, David A, Sobue, Kazuya, Scott, DA, Sento, Yoshiki, Suzuki, Toshiyasu, Suzuki, Yasuyuki, Scott, David A, and Sobue, Kazuya

Abstract

The postanesthesia care unit (PACU), which is run and coordinated by anesthesiologists, delivers general medical supervision as well as close and constant care to patients who have just undergone a surgical procedure under anesthesia. Although PACU management has been considered a standard procedure in many developed countries since the 1940s, Japanese hospitals have tended to cease their management, and only 16.1% of hospitals in Japan currently have PACUs. In today's efficiency-required atmosphere in Japan, we need to consider a better postoperative management method, including facilities similar to the PACU, to prevent serious adverse events and improve the postoperative outcomes and quality of life. Nevertheless, the way postoperative patients are treated and cared for, and the location in which they receive such attention, will likely need to be modified to fit the Japanese style due to Japan's unique medical systems and traditions. Here, we describe the past, present and future of the PACU and postanesthesia care in Japan compared with other countries.

Published
2017

84. Acute Pain Management: Scientific Evidence (3rd edition)

Author

Macintyre, PE, Schug, SA, Scott, DA, Visser, EJ, Walker, SM, Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM, APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine, Macintyre, PE, Schug, SA, Scott, DA, Visser, EJ, Walker, SM, Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM, and APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine

Abstract

This is the third edition of Acute Pain Management: Scientific Evidence. The first two were published in 1999 and 2005, respectively. This third edition sums up the evidence currently available to assist health professionals in the management of acute pain. Levels of evidence have been documented according to the National Health and Medical Research Council (NHMRC) designation (NHMRC 1999). The Jadad scoring instrument was used to score the quality of all randomised controlled trials (RCTs) (Jadad 1996). Acute Pain Management: Scientific Evidence messages for each topic are specified with the highest level of evidence available to support them, or with a symbol showing that they are based on clinical experience or expert opinion.

Published
2010

85. Reduction in healthcare and societal resource utilization associated with Cladribine tablets in patients with relapsing-remitting multiple sclerosis: analysis of economic data from the CLARITY study

Author

Ali S, Paracha N, Cook S, Giovannoni G, Rammohan K, Rieckmann P, Sorensen PS, Vermersch P, Greenberg S, Scott DA, Joyeux A, CLARITY Study Group, COMI , GIANCARLO, Ali, S, Paracha, N, Cook, S, Giovannoni, G, Comi, Giancarlo, Rammohan, K, Rieckmann, P, Sorensen, P, Vermersch, P, Greenberg, S, Scott, Da, Joyeux, A, and CLARITY Study, Group

Published
2012

86. Index

Author

Scott, Darieck

Published
2022

89. Notes

Author

Scott, Darieck

Published
2022

93. Contents

Author

Scott, Darieck

Published
2022

96. Dedication

Author

Scott, Darieck

Published
2022

97. Title

Author

Scott, Darieck

Published
2022

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