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4. A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry

Author

Cortese, Andrea, Beecroft, Sarah J., Facchini, Stefano, Curro, Riccardo, Cabrera-Serrano, Macarena, Stevanovski, Igor, Chintalaphani, Sanjog R., Gamaarachchi, Hasindu, Weisburd, Ben, Folland, Chiara, Monahan, Gavin, Scriba, Carolin K., Dofash, Lein, Johari, Mridul, Grosz, Bianca R., Ellis, Melina, Fearnley, Liam G., Tankard, Rick, Read, Justin, Merve, Ashirwad, Dominik, Natalia, Vegezzi, Elisa, Schnekenberg, Ricardo P., Fernandez-Eulate, Gorka, Masingue, Marion, Giovannini, Diane, Delatycki, Martin B., Storey, Elsdon, Gardner, Mac, Amor, David J., Nicholson, Garth, Vucic, Steve, Henderson, Robert D., Robertson, Thomas, Dyke, Jason, Fabian, Vicki, Mastaglia, Frank, Davis, Mark R., Kennerson, Marina, Quinlivan, Ros, Hammans, Simon, Tucci, Arianna, Bahlo, Melanie, McLean, Catriona A., Laing, Nigel G., Stojkovic, Tanya, Houlden, Henry, Hanna, Michael G., Deveson, Ira W., Lockhart, Paul J., Lamont, Phillipa J., Fahey, Michael C., Bugiardini, Enrico, and Ravenscroft, Gianina

Published
2024
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5. Author Correction: A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry

Author

Cortese, Andrea, Beecroft, Sarah J., Facchini, Stefano, Curro, Riccardo, Cabrera-Serrano, Macarena, Stevanovski, Igor, Chintalaphani, Sanjog R., Gamaarachchi, Hasindu, Weisburd, Ben, Folland, Chiara, Monahan, Gavin, Scriba, Carolin K., Dofash, Lein, Johari, Mridul, Grosz, Bianca R., Ellis, Melina, Fearnley, Liam G., Tankard, Rick, Read, Justin, Merve, Ashirwad, Dominik, Natalia, Vegezzi, Elisa, Schnekenberg, Ricardo P., Fernandez-Eulate, Gorka, Masingue, Marion, Giovannini, Diane, Delatycki, Martin B., Storey, Elsdon, Gardner, Mac, Amor, David J., Nicholson, Garth, Vucic, Steve, Henderson, Robert D., Robertson, Thomas, Dyke, Jason, Fabian, Vicki, Mastaglia, Frank, Davis, Mark R., Kennerson, Marina, Quinlivan, Ros, Hammans, Simon, Tucci, Arianna, Bahlo, Melanie, McLean, Catriona A., Laing, Nigel G., Stojkovic, Tanya, Houlden, Henry, Hanna, Michael G., Deveson, Ira W., Lockhart, Paul J., Lamont, Phillipa J., Fahey, Michael C., Bugiardini, Enrico, and Ravenscroft, Gianina

Published
2024
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6. Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions

Author

Mohren, Lars, Erdlenbruch, Friedrich, Leitão, Elsa, Kilpert, Fabian, Hönes, G. Sebastian, Kaya, Sabine, Schröder, Christopher, Thieme, Andreas, Sturm, Marc, Park, Joohyun, Schlüter, Agatha, Ruiz, Montserrat, Morales de la Prida, Moisés, Casasnovas, Carlos, Becker, Kerstin, Roggenbuck, Ulla, Pechlivanis, Sonali, Kaiser, Frank J., Synofzik, Matthis, Wirth, Thomas, Anheim, Mathieu, Haack, Tobias B., Lockhart, Paul J., Jöckel, Karl-Heinz, Pujol, Aurora, Klebe, Stephan, Timmann, Dagmar, and Depienne, Christel

Published
2024
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8. Development and Evaluation of an Interdisciplinary Rotation for Anesthesia Residents in Laryngology

Author

Homer, Cole J., Carlson, Kristy, Haggar, Faye, Bingcang, Chris, Dutoit, Andrea, Lockhart, T. J., Ryan, Evan, and Dowdall, Jayme R.

Abstract

The medical fields of anesthesiology and otolaryngology (ENT -- ears, nose, throat) are defined by overlapping clinical expertise as it relates to the management of airway issues. As a result of this shared clinical domain, interdisciplinary educational experiences provide an opportunity for collaboration and a broadened experience for resident physician learning. Our institution developed a two-week rotation in otolaryngology for first-year anesthesiology interns with the goal of utilizing interdisciplinary coaching to develop both technical and non-technical skills in airway management. The purpose of this project is to perform a formal evaluation of this rotation and share our training methods and processes.

Published
2023

9. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Published
2024
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12. Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures

Author

Chang, Julia W, Reyes, Samuel D, Faure-Kumar, Emmanuelle, Lam, Sandi K, Lawlor, Michael W, Leventer, Richard J, Lew, Sean M, Lockhart, Paul J, Pope, Kathryn, Weiner, Howard L, Salamon, Noriko, Vinters, Harry V, Mathern, Gary W, Fallah, Aria, and Owens, Geoffrey C

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Neurosciences, Health Disparities, Rare Diseases, Minority Health, Epilepsy, Genetics, Tuberous Sclerosis, Brain Disorders, Clinical Research, Neurodegenerative, 2.1 Biological and endogenous factors, Neurological, Adoptive Transfer, Amino Acid Sequence, Biomarkers, Brain, Child, Clone Cells, Complementarity Determining Regions, Disease Management, Disease Susceptibility, Drug Resistant Epilepsy, Gene Expression, Gene Expression Profiling, Humans, Receptors, Antigen, T-Cell, Seizures, T-Cell Antigen Receptor Specificity, T-Lymphocyte Subsets, T-Lymphocytes, T cell receptor, epilepsy, Rasmussen encephalitis, focal cortical dysplasia, tuberous sclerosis complex, Biochemistry and cell biology
Abstract

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.

Published
2021

13. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Commerce, Management, Tourism and Services, SPARK Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

14. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Basic Helix-Loop-Helix Transcription Factors, CCCTC-Binding Factor, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein U, High-Throughput Nucleotide Sequencing, Humans, KCNQ3 Potassium Channel, Male, Mutation, Neurodevelopmental Disorders, RNA-Binding Proteins, Repressor Proteins, Transcription Factors, SPARK Consortium
Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF

Published
2020

17. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

Author

Marsh, Ashley PL, Edwards, Timothy J, Galea, Charles, Cooper, Helen M, Engle, Elizabeth C, Jamuar, Saumya S, Méneret, Aurélie, Moutard, Marie‐Laure, Nava, Caroline, Rastetter, Agnès, Robinson, Gail, Rouleau, Guy, Roze, Emmanuel, Spencer‐Smith, Megan, Trouillard, Oriane, de Villemeur, Thierry Billette, Walsh, Christopher A, Yu, Timothy W, Consortium, IRC5, Heron, Delphine, Sherr, Elliott H, Richards, Linda J, Depienne, Christel, Leventer, Richard J, and Lockhart, Paul J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Digestive Diseases, Brain Disorders, Neurosciences, Pediatric, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Abnormalities, Multiple, Agenesis of Corpus Callosum, Amino Acid Sequence, Binding Sites, Conserved Sequence, Databases, Genetic, Genes, DCC, Genetic Association Studies, Humans, Magnetic Resonance Imaging, Models, Molecular, Mutation, Netrin-1, Phenotype, Protein Binding, Protein Conformation, Protein Domains, Syndrome, ACC, agenesis of the corpus callosum, axon guidance, DCC, developmental split brain syndrome, horizontal gaze palsy with progressive scoliosis, mirror movements, mutation, NTN1, IRC5 Consortium, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Published
2018

18. Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α

Author

Kishnani, Priya, Tarnopolsky, Mark, Roberts, Mark, Sivakumar, Kumarswamy, Dasouki, Majed, Dimachkie, Mazen M, Finanger, Erika, Goker-Alpan, Ozlem, Guter, Karl A, Mozaffar, Tahseen, Pervaiz, Muhammad Ali, Laforet, Pascal, Levine, Todd, Adera, Matthews, Lazauskas, Richard, Sitaraman, Sheela, Khanna, Richie, Benjamin, Elfrida, Feng, Jessie, Flanagan, John J, Barth, Jay, Barlow, Carrolee, Lockhart, David J, Valenzano, Kenneth J, Boudes, Pol, Johnson, Franklin K, and Byrne, Barry

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Rare Diseases, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Disease, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 1-Deoxynojirimycin, Administration, Oral, Adult, Drug Administration Schedule, Drug Synergism, Drug Therapy, Combination, Enzyme Replacement Therapy, Female, Glycogen Storage Disease Type II, Humans, Infusions, Intravenous, Lysosomes, Male, Middle Aged, Muscle, Skeletal, Patient Safety, Treatment Outcome, alpha-Glucosidases, Pompe disease, enzyme replacement therapy, pharmacokinetics, pharmacological chaperone, Biological Sciences, Technology, Medical and Health Sciences, Biotechnology, Genetics, Clinical sciences, Medical biotechnology
Abstract

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.

Published
2017

19. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author

Marsh, Ashley PL, Heron, Delphine, Edwards, Timothy J, Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-Laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone A, McGillivray, George, McIlroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura R, Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail A, Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah EM, Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-Bitach, Tania, Delatycki, Martin B, Mandel, Jean-Louis, Amor, David J, Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Sherr, Elliott H, Leventer, Richard J, Richards, Linda J, Lockhart, Paul J, and Depienne, Christel

Subjects
Biological Sciences, Genetics, Abnormalities, Multiple, Agenesis of Corpus Callosum, Brain, Corpus Callosum, DCC Receptor, Developmental Disabilities, Family, Female, Humans, Male, Mutation, Nervous System Malformations, Neural Stem Cells, Penetrance, Phenotype, Receptors, Cell Surface, Tumor Suppressor Proteins, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017

20. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study

Author

Hughes, Derralynn A, Nicholls, Kathleen, Shankar, Suma P, Sunder-Plassmann, Gere, Koeller, David, Nedd, Khan, Vockley, Gerard, Hamazaki, Takashi, Lachmann, Robin, Ohashi, Toya, Olivotto, Iacopo, Sakai, Norio, Deegan, Patrick, Dimmock, David, Eyskens, François, Germain, Dominique P, Goker-Alpan, Ozlem, Hachulla, Eric, Jovanovic, Ana, Lourenco, Charles M, Narita, Ichiei, Thomas, Mark, Wilcox, William R, Bichet, Daniel G, Schiffmann, Raphael, Ludington, Elizabeth, Viereck, Christopher, Kirk, John, Yu, Julie, Johnson, Franklin, Boudes, Pol, Benjamin, Elfrida R, Lockhart, David J, Barlow, Carrolee, Skuban, Nina, Castelli, Jeffrey P, Barth, Jay, and Feldt-Rasmussen, Ulla

Subjects
Pediatric, Neurodegenerative, Clinical Trials and Supportive Activities, Rare Diseases, Clinical Research, Orphan Drug, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 1-Deoxynojirimycin, Administration, Oral, Adolescent, Adult, Aged, Enzyme Replacement Therapy, Fabry Disease, Female, Humans, Lysosomes, Male, Middle Aged, Molecular Chaperones, Treatment Outcome, alpha-Galactosidase, Fabry disease, Pharmacological chaperone, enzyme replacement therapy, lyso-Gb3, lysosomal storage disorder, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.MethodsThe main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.ResultsFifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.ConclusionsMigalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.Trial registration numberNCT00925301; Pre-results.

Published
2017

21. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Author

Stessman, Holly AF, Xiong, Bo, Coe, Bradley P, Wang, Tianyun, Hoekzema, Kendra, Fenckova, Michaela, Kvarnung, Malin, Gerdts, Jennifer, Trinh, Sandy, Cosemans, Nele, Vives, Laura, Lin, Janice, Turner, Tychele N, Santen, Gijs, Ruivenkamp, Claudia, Kriek, Marjolein, van Haeringen, Arie, Aten, Emmelien, Friend, Kathryn, Liebelt, Jan, Barnett, Christopher, Haan, Eric, Shaw, Marie, Gecz, Jozef, Anderlid, Britt-Marie, Nordgren, Ann, Lindstrand, Anna, Schwartz, Charles, Kooy, R Frank, Vandeweyer, Geert, Helsmoortel, Celine, Romano, Corrado, Alberti, Antonino, Vinci, Mirella, Avola, Emanuela, Giusto, Stefania, Courchesne, Eric, Pramparo, Tiziano, Pierce, Karen, Nalabolu, Srinivasa, Amaral, David G, Scheffer, Ingrid E, Delatycki, Martin B, Lockhart, Paul J, Hormozdiari, Fereydoun, Harich, Benjamin, Castells-Nobau, Anna, Xia, Kun, Peeters, Hilde, Nordenskjöld, Magnus, Schenck, Annette, Bernier, Raphael A, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, Autism, Mental Health, Genetic Testing, Mental health, Autistic Disorder, Developmental Disabilities, Female, Humans, Intellectual Disability, Male, Mutation, Phenotype, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Published
2017

22. Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia.

Author

Wan, Jijun, Steffen, Janos, Yourshaw, Michael, Mamsa, Hafsa, Andersen, Erik, Rudnik-Schöneborn, Sabine, Pope, Kate, Howell, Katherine B, McLean, Catriona A, Kornberg, Andrew J, Joseph, Jörg, Lockhart, Paul J, Zerres, Klaus, Ryan, Monique M, Nelson, Stanley F, Koehler, Carla M, and Jen, Joanna C

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, Pediatric, Orphan Drug, Neurodegenerative, Rare Diseases, Brain Disorders, Congenital Structural Anomalies, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amino Acids, Animals, Animals, Genetically Modified, Brain, Cell Line, Transformed, Cells, Cultured, Cerebellar Diseases, Cohort Studies, Embryo, Nonmammalian, Female, Genetic Predisposition to Disease, Humans, Infant, Magnetic Resonance Imaging, Male, Mitochondria, Mitochondrial Dynamics, Mitochondrial Proteins, Models, Molecular, Mutation, Phosphate Transport Proteins, Polymorphism, Single Nucleotide, Zebrafish, pontocerebellar hypoplasia, SLC25A46, mitochondria, optic atrophy spectrum disorder, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.

Published
2016

27. Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase

Author

Warnock, David G, Bichet, Daniel G, Holida, Myrl, Goker-Alpan, Ozlem, Nicholls, Kathy, Thomas, Mark, Eyskens, Francois, Shankar, Suma, Adera, Mathews, Sitaraman, Sheela, Khanna, Richie, Flanagan, John J, Wustman, Brandon A, Barth, Jay, Barlow, Carrolee, Valenzano, Kenneth J, Lockhart, David J, Boudes, Pol, and Johnson, Franklin K

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Trials and Supportive Activities, Clinical Research, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 1-Deoxynojirimycin, Administration, Oral, Adult, Area Under Curve, Demography, Fabry Disease, Humans, Infusion Pumps, Isoenzymes, Male, Middle Aged, Recombinant Proteins, Skin, alpha-Galactosidase, General Science & Technology
Abstract

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871.

Published
2015

28. A GCase Chaperone Improves Motor Function in a Mouse Model of Synucleinopathy

Author

Richter, Franziska, Fleming, Sheila M, Watson, Melanie, Lemesre, Vincent, Pellegrino, Lee, Ranes, Brian, Zhu, Chunni, Mortazavi, Farzad, Mulligan, Caitlin K, Sioshansi, Pedrom C, Hean, Sindalana, De La Rosa, Krystal, Khanna, Richie, Flanagan, John, Lockhart, David J, Wustman, Brandon A, Clark, Sean W, and Chesselet, Marie-Françoise

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Parkinson's Disease, Aging, Neurodegenerative, Genetics, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Neurological, Animals, Brain, Disease Models, Animal, Dopaminergic Neurons, Humans, Imino Pyranoses, Male, Mice, Motor Activity, Parkinson Disease, Protein Aggregates, Protein Transport, Substantia Nigra, Tartrates, alpha-Synuclein, beta-Glucosidase, Parkinson's disease, Alpha-synuclein, Acid-beta-glucosidase, Mouse model, Chaperone, Motor behavior, Acid-β-glucosidase, Public Health and Health Services, Neurology & Neurosurgery, Pharmacology and pharmaceutical sciences, Biological psychology
Abstract

Mutation of the lysosomal hydrolase acid-β-glucosidase (GCase), which leads to reduced GCase activity, is one of the most frequent genetic risk factors for Parkinson's disease (PD) and promotes α-synuclein accumulation in the brain, a hallmark of PD and other synucleinopathies. Whether targeting GCase pharmacologically is a valid therapeutic strategy for sporadic PD in the absence of GCase mutation is unknown. We have investigated whether increasing the stability, trafficking, and activity of wild-type GCase could be beneficial in synucleinopathies by administering the pharmacological chaperone AT2101 (afegostat-tartrate, isofagomine) to mice that overexpress human wild-type α-synuclein (Thy1-aSyn mice). AT2101 administered orally for 4 months to Thy1-aSyn mice improved motor and nonmotor function, abolished microglial inflammatory response in the substantia nigra, reduced α-synuclein immunoreactivity in nigral dopaminergic neurons, and reduced the number of small α-synuclein aggregates, while increasing the number of large α-synuclein aggregates. These data support the further investigation of pharmacological chaperones that target GCase as a therapeutic approach for sporadic PD and other synucleinopathies, even in the absence of glucocerebrosidase mutations.

Published
2014

29. Genetic abnormalities in a large cohort of Coffin–Siris syndrome patients

Author

Sekiguchi, Futoshi, Tsurusaki, Yoshinori, Okamoto, Nobuhiko, Teik, Keng Wee, Mizuno, Seiji, Suzumura, Hiroshi, Isidor, Bertrand, Ong, Winnie Peitee, Haniffa, Muzhirah, White, Susan M., Matsuo, Mari, Saito, Kayoko, Phadke, Shubha, Kosho, Tomoki, Yap, Patrick, Goyal, Manisha, Clarke, Lorne A., Sachdev, Rani, McGillivray, George, Leventer, Richard J., Patel, Chirag, Yamagata, Takanori, Osaka, Hitoshi, Hisaeda, Yoshiya, Ohashi, Hirofumi, Shimizu, Kenji, Nagasaki, Keisuke, Hamada, Junpei, Dateki, Sumito, Sato, Takashi, Chinen, Yasutsugu, Awaya, Tomonari, Kato, Takeo, Iwanaga, Kougoro, Kawai, Masahiko, Matsuoka, Takashi, Shimoji, Yoshikazu, Tan, Tiong Yang, Kapoor, Seema, Gregersen, Nerine, Rossi, Massimiliano, Marie-Laure, Mathieu, McGregor, Lesley, Oishi, Kimihiko, Mehta, Lakshmi, Gillies, Greta, Lockhart, Paul J., Pope, Kate, Shukla, Anju, Girisha, Katta Mohan, Abdel-Salam, Ghada M. H., Mowat, David, Coman, David, Kim, Ok Hwa, Cordier, Marie-Pierre, Gibson, Kate, Milunsky, Jeff, Liebelt, Jan, Cox, Helen, El Chehadeh, Salima, Toutain, Annick, Saida, Ken, Aoi, Hiromi, Minase, Gaku, Tsuchida, Naomi, Iwama, Kazuhiro, Uchiyama, Yuri, Suzuki, Toshifumi, Hamanaka, Kohei, Azuma, Yoshiteru, Fujita, Atsushi, Imagawa, Eri, Koshimizu, Eriko, Takata, Atsushi, Mitsuhashi, Satomi, Miyatake, Satoko, Mizuguchi, Takeshi, Miyake, Noriko, and Matsumoto, Naomichi

Published
2019
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30. Software and methods for oligonucleotide and cDNA array data analysis

Author

Zapala, Matthew A, Lockhart, Daniel J, Pankratz, Daniel G, Garcia, Anthony J, Barlow, Carrolee, and Lockhart, David J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Computational Biology, DNA, Complementary, Database Management Systems, Databases, Genetic, Gene Expression Profiling, Oligonucleotide Array Sequence Analysis, Oligonucleotides, Software, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

Two HTML-based programs were developed to analyze and filter gene-expression data: 'Bullfrog' for Affymetrix oligonucleotide arrays and 'Spot' for custom cDNA arrays. The programs provide intuitive data-filtering tools through an easy-to-use interface. A background subtraction and normalization program for cDNA arrays was also built that provides an informative summary report with data-quality assessments. These programs are freeware to aid in the analysis of gene-expression results and facilitate the search for genes responsible for interesting biological processes and phenotypes.

Published
2002

34. DNA variation and brain region-specific expression profiles exhibit different relationships between inbred mouse strains: implications for eQTL mapping studies

Author

Hovatta, Iiris, Zapala, Matthew A, Broide, Ron S, Schadt, Eric E, Libiger, Ondrej, Schork, Nicholas J, Lockhart, David J, and Barlow, Carrolee

Subjects
Biological Sciences, Genetics, Biotechnology, Neurosciences, Human Genome, Analysis of Variance, Animals, Brain, Chromosome Mapping, Cluster Analysis, Gene Expression Profiling, Gene Regulatory Networks, Genetic Variation, Mice, Mice, Inbred Strains, Oligonucleotide Array Sequence Analysis, Phylogeny, Quantitative Trait Loci, Regression Analysis, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundExpression quantitative trait locus (eQTL) mapping is used to find loci that are responsible for the transcriptional activity of a particular gene. In recent eQTL studies, expression profiles were derived from either homogenized whole brain or collections of large brain regions. However, the brain is a very heterogeneous organ, and expression profiles of different brain regions vary significantly. Because of the importance and potential power of eQTL studies in identifying regulatory networks, we analyzed gene expression patterns in different brain regions from multiple inbred mouse strains and investigated the implications for the design and analysis of eQTL studies.ResultsGene expression profiles of five brain regions in six inbred mouse strains were studied. Few genes exhibited a significant strain-specific expression pattern, whereas a large number of genes exhibited brain region-specific patterns. We constructed phylogenetic trees based on the expression relationships between the strains and compared them with a DNA-level relationship tree. The trees based on the expression of strain-specific genes were constant across brain regions and mirrored DNA-level variation. However, the trees based on region-specific genes exhibited a different set of strain relationships, depending on the brain region. An eQTL analysis showed enrichment of cis-acting regulators among strain-specific genes, whereas brain region-specific genes appear to be mainly regulated by trans-acting elements.ConclusionOur results suggest that many regulatory networks are highly brain region specific and indicate the importance of conducting eQTL mapping studies using data from brain regions or tissues that are physiologically and phenotypically relevant to the trait of interest.

Published
2007

40. De novo variants in the RNU4-2snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2as a syndromic NDD gene. RNU4-2encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2is highly expressed in the developing human brain, in contrast to RNU4-1and other U4 homologues. Using RNA sequencing, we show how 5′ splice-site use is systematically disrupted in individuals with RNU4-2variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024
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41. Challenges facing repeat expansion identification, characterisation, and the pathway to discovery

Author

Read, Justin L., Davies, Kayli C., Thompson, Genevieve C., Delatycki, Martin B., and Lockhart, Paul J.

Abstract

Tandem repeat DNA sequences constitute a significant proportion of the human genome. While previously considered to be functionally inert, these sequences are now broadly accepted as important contributors to genetic diversity. However, the polymorphic nature of these sequences can lead to expansion beyond a gene-specific threshold, causing disease. More than 50 pathogenic repeat expansions have been identified to date, many of which have been discovered in the last decade as a result of advances in sequencing technologies and associated bioinformatic tools. Commonly utilised diagnostic platforms including Sanger sequencing, capillary array electrophoresis, and Southern blot are generally low throughput and are often unable to accurately determine repeat size, composition, and epigenetic signature, which are important when characterising repeat expansions. The rapid advances in bioinformatic tools designed specifically to interrogate short-read sequencing and the development of long-read single molecule sequencing is enabling a new generation of high throughput testing for repeat expansion disorders. In this review, we discuss some of the challenges surrounding the identification and characterisation of disease-causing repeat expansions and the technological advances that are poised to translate the promise of genomic medicine to individuals and families affected by these disorders.

Published
2023
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42. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

Author

Rivera, Barbara, Gayden, Tenzin, Carrot-Zhang, Jian, Nadaf, Javad, Boshari, Talia, Faury, Damien, Zeinieh, Michele, Blanc, Romeo, Burk, David L., Fahiminiya, Somayyeh, Bareke, Eric, Schüller, Ulrich, Monoranu, Camelia M., Sträter, Ronald, Kerl, Kornelius, Niederstadt, Thomas, Kurlemann, Gerhard, Ellezam, Benjamin, Michalak, Zuzanna, Thom, Maria, Lockhart, Paul J., Leventer, Richard J., Ohm, Milou, MacGregor, Duncan, Jones, David, Karamchandani, Jason, Greenwood, Celia M. T., Berghuis, Albert M., Bens, Susanne, Siebert, Reiner, Zakrzewska, Magdalena, Liberski, Pawel P., Zakrzewski, Krzysztof, Sisodiya, Sanjay M., Paulus, Werner, Albrecht, Steffen, Hasselblatt, Martin, Jabado, Nada, Foulkes, William D., and Majewski, Jacek

Published
2016
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45. An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels

Author

Yiu, Eppie M., Tai, Geneieve, Peverill, Roger E., Lee, Katherine J., Croft, Kevin D., Mori, Trevor A., Scheiber-Mojdehkar, Barbara, Sturm, Brigitte, Praschberger, Monika, Vogel, Adam P., Rance, Gary, Stephenson, Sarah E. M., Sarsero, Joseph P., Stockley, Creina, Lee, Chung-Yung J., Churchyard, Andrew, Evans-Galea, Marguerite V., Ryan, Monique M., Lockhart, Paul J., Corben, Louise A., and Delatycki, Martin B.

Published
2015
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46. Using PANDA (Preventing the Abuse of Tobacco, Narcotics, Drugs, and Alcohol) in a Baltimore City Head Start Setting: A Preliminary Study.

Author

Belcher, Harolyn M. E., Lockhart, Paula J., Perkins-Parks, Susan, and McNally, Margaret

Abstract

Describes an evaluation of a substance abuse prevention curriculum, Preventing the Abuse of Tobacco, Narcotics, Drugs, and Alcohol (PANDA), taught to African American Head Start preschool students, examining changes in children's self-concept following participation. Overall, students demonstrated significantly improved self-concept, and PANDA proved to be easy to administer, developmentally and culturally appropriate, and economically accessible. (SM)

Published
2000

48. The School Counselor's Role in Facilitating Multisystemic Change.

Author

Keys, Susan G. and Lockhart, Estes J.

Abstract

Examines how school counselors can apply systems theory and social ecology to problem conceptualization and intervention planning. Also explores the implications of this broadened paradigm for the school counselor's role. Asserts that in order to achieve broad-based change, schools, families, and communities must engage in collaborative problem solving that engages the multiple expertise of members of each system. (Contains 30 references.) (GCP)

Published
1999

49. The Mental Health Counseling Role of School Counselors.

Author

Lockhart, Estes J. and Keys, Susan G.

Abstract

Expanding social stress, changing school demographics, and decreasing community mental health services have expanded the range of services required of the school counselor. The list of necessary mental health skills and implications for counselor education are discussed. It is recommended that "guidance" counselors redefine themselves as "school mental health counselors." (EMK)

Published
1998

50. Transforming School Counseling to Serve the Mental Health Needs of At-Risk Youth.

Author

Keys, Susan G., Bemak, Fr, and Lockhart, Estes J.

Abstract

School counselors have an important role in responding to students whose mental-health needs place them at risk for school failure. Shortcomings of the current developmental guidance-and-counseling service delivery model are defined and a transformed model proposed with suggestions for specific changes. Barriers to change are identified. (Author/EMK)

Published
1998

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