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1. APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain

Author

Ferguson, Cole J, Urso, Olivia, Bodrug, Tatyana, Gassaway, Brandon M, Watson, Edmond R, Prabu, Jesuraj R, Lara-Gonzalez, Pablo, Martinez-Chacin, Raquel C, Wu, Dennis Y, Brigatti, Karlla W, Puffenberger, Erik G, Taylor, Cora M, Haas-Givler, Barbara, Jinks, Robert N, Strauss, Kevin A, Desai, Arshad, Gabel, Harrison W, Gygi, Steven P, Schulman, Brenda A, Brown, Nicholas G, and Bonni, Azad

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Brain Disorders, Neurosciences, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Adolescent, Animals, Antigens, CD, Apc7 Subunit, Anaphase-Promoting Complex-Cyclosome, Behavior, Animal, Brain, Cadherins, Cell Line, Child, Child, Preschool, Disease Models, Animal, Female, Heterochromatin, Humans, Infant, Intellectual Disability, Intelligence, Ki-67 Antigen, Male, Mice, Inbred C57BL, Mice, Knockout, Mitosis, Mutation, Neural Stem Cells, Neurogenesis, Proteolysis, Signal Transduction, Syndrome, Ubiquitination, Young Adult, APC7, Cdh1, Ki-67, anaphase-promoting complex, brain, chromatin, heterochromatin, neurodevelopment, ubiquitin, ubiquitin ligase, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.

Published
2022

3. Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Author

Grange, Laura J., Reynolds, John J., Ullah, Farid, Isidor, Bertrand, Shearer, Robert F., Latypova, Xenia, Baxley, Ryan M., Oliver, Antony W., Ganesh, Anil, Cooke, Sophie L., Jhujh, Satpal S., McNee, Gavin S., Hollingworth, Robert, Higgs, Martin R., Natsume, Toyoaki, Khan, Tahir, Martos-Moreno, Gabriel Á., Chupp, Sharon, Mathew, Christopher G., Parry, David, Simpson, Michael A., Nahavandi, Nahid, Yüksel, Zafer, Drasdo, Mojgan, Kron, Anja, Vogt, Petra, Jonasson, Annemarie, Seth, Saad Ahmed, Gonzaga-Jauregui, Claudia, Brigatti, Karlla W., Stegmann, Alexander P. A., Kanemaki, Masato, Josifova, Dragana, Uchiyama, Yuri, Oh, Yukiko, Morimoto, Akira, Osaka, Hitoshi, Ammous, Zineb, Argente, Jesús, Matsumoto, Naomichi, Stumpel, Constance T.R.M., Taylor, Alexander M. R., Jackson, Andrew P., Bielinsky, Anja-Katrin, Mailand, Niels, Le Caignec, Cedric, Davis, Erica E., and Stewart, Grant S.

Published
2022
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4. Preemptive dual therapy for children at risk for infantile‐onset spinal muscular atrophy.

Author

Matesanz, Susan E., Brigatti, Karlla W., Young, Millie, Yum, Sabrina W., and Strauss, Kevin A.

Subjects
*SPINAL muscular atrophy, *ACTION potentials, *GENE therapy, *ALPHA 1-antitrypsin deficiency
Abstract

Objective: Compare efficacy of gene therapy alone (monotherapy) or in combination with an SMN2 augmentation agent (dual therapy) for treatment of children at risk for spinal muscular atrophy type 1. Methods: Eighteen newborns with biallelic SMN1 deletions and two SMN2 copies were treated preemptively with monotherapy (n = 11) or dual therapy (n = 7) and followed for a median of 3 years. Primary outcomes were independent sitting and walking. Biomarkers were serial muscle ultrasonography (efficacy) and sensory action potentials (safety). Results: Gene therapy was administered by 7–43 postnatal days; dual therapy with risdiplam (n = 6) or nusinersen (n = 1) was started by 15–39 days. Among 18 children enrolled, 17 sat, 15 walked, and 44% had motor delay (i.e., delay or failure to achieve prespecified milestones). Those on dual therapy sat but did not walk at an earlier age. 91% of muscle ultrasounds conducted within 60 postnatal days were normal but by 3–61 months, 94% showed echogenicity and/or fasciculation of at least one muscle group; these changes were indistinguishable between monotherapy and dual therapy cohorts. Five children with three SMN2 copies were treated with monotherapy in parallel: all sat and walked on time and had normal muscle sonograms at all time points. No child on dual therapy experienced treatment‐associated adverse events. All 11 participants who completed sensory testing (including six on dual therapy) had intact sural sensory responses. Interpretation: Preemptive dual therapy is well tolerated and may provide modest benefit for children at risk for severe spinal muscular atrophy but does not prevent widespread degenerative changes. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Blok, Lot Snijders, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot RF, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T, Hoischen, Alexander, Vissers, Lisenka ELM, Koemans, Tom S, Wissink-Lindhout, Willemijn, Eichler, Evan E, Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, van Bon, Bregje WM, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L, Van Dijck, Anke, Innes, A Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J, Henderson, Alex, Lynch, Sally A, Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Study, the DDD, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, van Gassen, Koen LI, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L, Pediaditakis, Igor, Haas, Stefan A, Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G, Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C, Stein, Quinn, Strauss, Kevin A, Brigatti, Karlla W, Keating, Katherine, Burton, Barbara K, Kim, Katherine H, Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D, Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M, van Roozendaal, Kees, Brunner, Han, Chung, Wendy K, Kooy, R Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G, Katsanis, Nicholas, and Kleefstra, Tjitske

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Intellectual and Developmental Disabilities (IDD), Human Genome, Clinical Research, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Amino Acid Substitution, Animals, Base Sequence, DEAD-box RNA Helicases, Embryo, Nonmammalian, Exome, Female, Gene Dosage, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Sequence Analysis, DNA, Sex Characteristics, Wnt Signaling Pathway, Zebrafish, DDD Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Published
2015

8. WiTNNess: An international natural history study of infantile‐onset TNNT1 myopathy.

Author

Strauss, Kevin A., Carson, Vincent J., Bolettieri, Emilienne, Everett, Mariah, Bollinger, Ashton, Bowser, Lauren E., Beiler, Keturah, Young, Millie, Edvardson, Simon, Fraenkel, Nitay, D'Amico, Adele, Bertini, Enrico, Lingappa, Lokesh, Chowdhury, Devyani, Lowes, Linda P., Iammarino, Megan, Alfano, Lindsay N., and Brigatti, Karlla W.

Subjects
NATURAL history, MUSCLE diseases, SKELETAL muscle, SURVIVAL rate, ARTIFICIAL respiration
Abstract

Objective: We created WiTNNess as a hybrid prospective/cross‐sectional observational study to simulate a clinical trial for infantile‐onset TNNT1 myopathy. Our aims were to identify populations for future trial enrollment, rehearse outcome assessments, specify endpoints, and refine trial logistics. Methods: Eligible participants had biallelic pathogenic variants of TNNT1 and infantile‐onset proximal weakness without confounding conditions. The primary endpoint was ventilator‐free survival. "Thriving" was a secondary endpoint defined as the ability to swallow and grow normally without non‐oral feeding support. Endpoints of gross motor function included independent sitting and standing as defined by the Word Health Organization, a novel TNNT1 abbreviated motor score, and video mapping of limb movement. We recorded adverse events, concomitant medications, and indices of organ function to serve as comparators of safety in future trials. Results: Sixteen children were enrolled in the aggregate cohort (6 prospective, 10 cross‐sectional; median census age 2.3 years, range 0.5–13.8). Median ventilator‐free survival was 20.2 months and probability of death or permanent mechanical ventilation was 100% by age 60 months. All six children (100%) in the prospective arm failed to thrive by age 12 months. Only 2 of 16 (13%) children in the aggregate cohort sat independently and none stood alone. Novel exploratory motor assessments also proved informative. Laboratory and imaging data suggest that primary manifestations of TNNT1 deficiency are restricted to skeletal muscle. Interpretation: WiTNNess allowed us to streamline and economize the collection of historical control data without compromising scientific rigor, and thereby establish a sound operational framework for future clinical trials. [ABSTRACT FROM AUTHOR]

Published
2023
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9. A recessive ataxia diagnosis algorithm for the next generation sequencing era

Author

Renaud, Mathilde, Tranchant, Christine, Martin, Juan Vicente Torres, Mochel, Fanny, Synofzik, Matthis, van de Warrenburg, Bart, Pandolfo, Massimo, Koenig, Michel, Kolb, Stefan A., Anheim, Mathieu, Alonso, Isabel, Azzedine, Hamid, Barbot, Clara, Bereau, Matthieu, Berkovic, Sam, Bernard, Geneviéve, Bindoff, Laurence A., Bompaire, Flavie, Bonneau, Dominique, Bonneau, Patrizia, Boycott, Kym M., Bras, Jose, Brais, Bernard, Brigatti, Karlla W., Cameron, Jillian, Chamova, Teodora, Choquet, Karine, Delague, Valérie, Denizeau, Philippe, Dotti, Maria Teresa, El‐Euch, Ghada, Elmalik, Salah A., Federico, Antonio, Fiskerstrand, Torunn, Gagnon, Cynthia, Guerreiro, Rita, Guissart, Claire, Hassin‐Baer, Sharon, Heimdal, Ketil Riddervold, Héron, Bénédicte, Isohanni, Pirjo, Kalaydijeva, Luba, Kawarai, Toshitaka, Koht, Jeanette Aimee, Lai, Szu‐Chia, Piana, Roberta La, Lecocq, Claire, Linnankivi, Tarja, Lönnqvist, Tuula, Lu, Chin‐Song, Maas, Roderick, Mahlaoui, Nizar, Mallaret, Martial, Marelli, Cecilia, Mariotti, Caterina, Mathieu, Jean, Méneret, Aurélie, Mignarri, Andrea, Monin, Marie Lorraine, Montaut, Solveig, Nanetti, Lorenzo, Nadjar, Yann, Poujois, Aurélia, Salih, Mustafa A., Sousa, Sergio, Stanier, Philip, Stoppa‐Lyonnet, Dominique, Strauss, Kevin, Tallaksen, Chantal, Tarnopolsky, Mark, Tinant, Nadége, Tournev, Ivailo, Topaloglu, Haluk, Varhaug, Kristin Nielsen, Woimant, France, Wolf, Nicole I., Yahalom, Gilad, Yoon, Grace, and Young, Millie

Published
2017
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10. Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Author

Grange, Laura J, Reynolds, John J, Ullah, Farid, Isidor, Bertrand, Shearer, Robert F, Latypova, Xenia, Baxley, Ryan M, Oliver, Antony W, Ganesh, Anil, Cooke, Sophie L, Jhujh, Satpal S, McNee, Gavin S, Hollingworth, Robert, Higgs, Martin R, Natsume, Toyoaki, Khan, Tahir, Martos-Moreno, Gabriel Á., Chupp, Sharon, Mathew, Christopher G., Parry, David, Simpson, Michael A., Nahavandi, Nahid, Yüksel, Zafer, Drasdo, Mojgan, Kron, Anja, Vogt, Petra, Jonasson, Annemarie, Seth, Saad Ahmed, Gonzaga-Jauregui, Claudia, Brigatti, Karlla W, Stegmann, Alexander P A, Kanemaki, Masato, Josifova, Dragana, Uchiyama, Yuri, Oh, Yukiko, Morimoto, Akira, Osaka, Hitoshi, Ammous, Zineb, Argente, Jesús, Matsumoto, Naomichi, Stumpel, Constance T.R.M., Taylor, Alexander M.R., Jackson, Andrew P., Bielinsky, Anja-Katrin, Mailand, Niels, Le Caignec, Cedric, Davis, Erica E., Stewart, Grant S., Grange, Laura J, Reynolds, John J, Ullah, Farid, Isidor, Bertrand, Shearer, Robert F, Latypova, Xenia, Baxley, Ryan M, Oliver, Antony W, Ganesh, Anil, Cooke, Sophie L, Jhujh, Satpal S, McNee, Gavin S, Hollingworth, Robert, Higgs, Martin R, Natsume, Toyoaki, Khan, Tahir, Martos-Moreno, Gabriel Á., Chupp, Sharon, Mathew, Christopher G., Parry, David, Simpson, Michael A., Nahavandi, Nahid, Yüksel, Zafer, Drasdo, Mojgan, Kron, Anja, Vogt, Petra, Jonasson, Annemarie, Seth, Saad Ahmed, Gonzaga-Jauregui, Claudia, Brigatti, Karlla W, Stegmann, Alexander P A, Kanemaki, Masato, Josifova, Dragana, Uchiyama, Yuri, Oh, Yukiko, Morimoto, Akira, Osaka, Hitoshi, Ammous, Zineb, Argente, Jesús, Matsumoto, Naomichi, Stumpel, Constance T.R.M., Taylor, Alexander M.R., Jackson, Andrew P., Bielinsky, Anja-Katrin, Mailand, Niels, Le Caignec, Cedric, Davis, Erica E., and Stewart, Grant S.

Abstract

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

Published
2022

11. Disease burden and management of Crigler-Najjar syndrome:Report of a world registry

Author

Aronson, Sem J., Junge, Norman, Trabelsi, Mediha, Kelmemi, Wided, Hubert, Aurelie, Brigatti, Karlla W., Fox, Michael D., de Knegt, Robert J., Escher, Johanna C., Ginocchio, Virginia M., Iorio, Raffaele, Zhu, Yan, Özçay, Figen, Rahim, Fakher, El-Shabrawi, Mortada H.F., Shteyer, Eyal, Di Giorgio, Angelo, D'Antiga, Lorenzo, Mingozzi, Federico, Brunetti-Pierri, Nicola, Strauss, Kevin A., Labrune, Philippe, Mrad, Ridha, Baumann, Ulrich, Beuers, Ulrich, Bosma, Piter J., Aronson, Sem J., Junge, Norman, Trabelsi, Mediha, Kelmemi, Wided, Hubert, Aurelie, Brigatti, Karlla W., Fox, Michael D., de Knegt, Robert J., Escher, Johanna C., Ginocchio, Virginia M., Iorio, Raffaele, Zhu, Yan, Özçay, Figen, Rahim, Fakher, El-Shabrawi, Mortada H.F., Shteyer, Eyal, Di Giorgio, Angelo, D'Antiga, Lorenzo, Mingozzi, Federico, Brunetti-Pierri, Nicola, Strauss, Kevin A., Labrune, Philippe, Mrad, Ridha, Baumann, Ulrich, Beuers, Ulrich, and Bosma, Piter J.

Published
2022

12. Additional file 1 of Clinical characterization of familial hypercholesterolemia due to an amish founder mutation in Apolipoprotein B

Author

Williams, Katie B., Horst, Michael, Young, Millie, Pascua, Christine, Puffenberger, Erik G., Brigatti, Karlla W., Gonzaga-Jauregui, Claudia, Shuldiner, Alan R., Gidding, Samuel, Strauss, Kevin A., and Chowdhury, Devyani

Abstract

Additional file 1. Supplemental Table 1: Plant sterols and fatty acids. Fasting plant sterol and fatty acid levels for ApoBR3500Q heterozygotes, homozygotes and age-matched sibling controls. Median (min-max) compared by the exact Wilcoxon rank-sum test.

Published
2022
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14. De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy

Author

Usmani, Muhammad A., primary, Ahmed, Zubair M., additional, Magini, Pamela, additional, Pienkowski, Victor Murcia, additional, Rasmussen, Kristen J., additional, Hernan, Rebecca, additional, Rasheed, Faiza, additional, Hussain, Mureed, additional, Shahzad, Mohsin, additional, Lanpher, Brendan C., additional, Niu, Zhiyv, additional, Lim, Foong-Yen, additional, Pippucci, Tommaso, additional, Ploski, Rafal, additional, Kraus, Verena, additional, Matuszewska, Karolina, additional, Palombo, Flavia, additional, Kianmahd, Jessica, additional, Martinez-Agosto, Julian A., additional, Lee, Hane, additional, Colao, Emma, additional, Motazacker, M. Mahdi, additional, Brigatti, Karlla W., additional, Puffenberger, Erik G., additional, Riazuddin, S. Amer, additional, Gonzaga-Jauregui, Claudia, additional, Chung, Wendy K., additional, Wagner, Matias, additional, Schultz, Matthew J., additional, Seri, Marco, additional, Kievit, Anneke J.A., additional, Perrotti, Nicola, additional, Klein Wassink-Ruiter, J.S., additional, van Bokhoven, Hans, additional, Riazuddin, Sheikh, additional, and Riazuddin, Saima, additional

Published
2021
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16. Disease burden and management of Crigler‐Najjar syndrome: Report of a world registry.

Author

Aronson, Sem J., Junge, Norman, Trabelsi, Mediha, Kelmemi, Wided, Hubert, Aurelie, Brigatti, Karlla W., Fox, Michael D., de Knegt, Robert J., Escher, Johanna C., Ginocchio, Virginia M., Iorio, Raffaele, Zhu, Yan, Özçay, Figen, Rahim, Fakher, El‐Shabrawi, Mortada H.F., Shteyer, Eyal, Di Giorgio, Angelo, D'Antiga, Lorenzo, Mingozzi, Federico, and Brunetti‐Pierri, Nicola

Subjects
SKIN cancer, DISEASE management, CYSTIC fibrosis transmembrane conductance regulator
Abstract

We found in 31 patients with liver fibrosis evaluation (liver histology or Fibroscan) five patients (16%) with signs of advanced liver fibrosis. Keywords: encephalopathy; liver transplantation; phototherapy; UGT1A1; unconjugated hyperbilirubinemia EN encephalopathy liver transplantation phototherapy UGT1A1 unconjugated hyperbilirubinemia 1593 1604 12 06/27/22 20220701 NES 220701 Abbreviations ALT alanine aminotransferase AST aspartate aminotransferase CB conjugated bilirubin CNS Crigler-Najjar syndrome GGT gamma glutamyl transpeptidase PB phenobarbital PT phototherapy TB total bilirubin UCB unconjugated bilirubin UGT1A1 uridine 5'-diphosphate glucuronosyltransferase ULN upper limit of normal Abstract Background and Aims Crigler-Najjar syndrome (CNS) is a disorder of bilirubin conjugation leading to brain damage and death without treatment. That in our small subcohort of fibrosis evaluated patients only patient with PT showed fibrosis is most likely caused because of the more severe phenotype in these patients but an association between long-term PT use and development of fibrosis cannot be excluded based on our data. Better detection and characterizing of liver fibrosis in CNS patients is necessary to gain an understanding of aetiology, to identify patients at risk, to develop individual treatment plans (e.g. LT vs. gene therapy in the future) and to probably find a way to avoid the development of fibrosis. [Extracted from the article]

Published
2022
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17. A recurring NFS1 pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes

Author

Hershkovitz, Tova, primary, Kurolap, Alina, additional, Tal, Galit, additional, Paperna, Tamar, additional, Mory, Adi, additional, Staples, Jeffrey, additional, Brigatti, Karlla W., additional, Gonzaga-Jauregui, Claudia, additional, Dumin, Elena, additional, Saada, Ann, additional, Mandel, Hanna, additional, and Baris Feldman, Hagit, additional

Published
2021
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18. De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation

Author

Mendoza-Ferreira, Natalia, Karakaya, Mert, Cengiz, Nur, Beijer, Danique, Brigatti, Karlla W., Gonzaga-Jauregui, Claudia, Fuhrmann, Nico, Hoelker, Irmgard, Thelen, Maximilian P., Zetzsche, Sebastian, Rombo, Roman, Puffenberger, Erik G., De Jonghe, Peter, Deconinck, Tine, Zuchner, Stephan, Strauss, Kevin A., Carson, Vincent, Schrank, Bertold, Wunderlich, Gilbert, Baets, Jonathan, Wirth, Brunhilde, Mendoza-Ferreira, Natalia, Karakaya, Mert, Cengiz, Nur, Beijer, Danique, Brigatti, Karlla W., Gonzaga-Jauregui, Claudia, Fuhrmann, Nico, Hoelker, Irmgard, Thelen, Maximilian P., Zetzsche, Sebastian, Rombo, Roman, Puffenberger, Erik G., De Jonghe, Peter, Deconinck, Tine, Zuchner, Stephan, Strauss, Kevin A., Carson, Vincent, Schrank, Bertold, Wunderlich, Gilbert, Baets, Jonathan, and Wirth, Brunhilde

Abstract

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.

Published
2020

20. Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades

Author

Strauss, Kevin A., primary, Williams, Katie B., additional, Carson, Vincent J., additional, Poskitt, Laura, additional, Bowser, Lauren E., additional, Young, Millie, additional, Robinson, Donna L., additional, Hendrickson, Christine, additional, Beiler, Keturah, additional, Taylor, Cora M., additional, Haas-Givler, Barbara, additional, Hailey, Jennifer, additional, Chopko, Stephanie, additional, Puffenberger, Erik G., additional, Brigatti, Karlla W., additional, Miller, Freeman, additional, and Morton, D. Holmes, additional

Published
2020
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21. De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation

Author

Mendoza-Ferreira, Natalia, primary, Karakaya, Mert, additional, Cengiz, Nur, additional, Beijer, Danique, additional, Brigatti, Karlla W., additional, Gonzaga-Jauregui, Claudia, additional, Fuhrmann, Nico, additional, Hölker, Irmgard, additional, Thelen, Maximilian P., additional, Zetzsche, Sebastian, additional, Rombo, Roman, additional, Puffenberger, Erik G., additional, De Jonghe, Peter, additional, Deconinck, Tine, additional, Zuchner, Stephan, additional, Strauss, Kevin A., additional, Carson, Vincent, additional, Schrank, Bertold, additional, Wunderlich, Gilbert, additional, Baets, Jonathan, additional, and Wirth, Brunhilde, additional

Published
2020
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22. RSRC1 loss-of-function variants cause mild to moderate autosomal recessive intellectual disability

Author

Scala, Marcello, primary, Mojarrad, Majid, primary, Riazuddin, Saima, primary, Brigatti, Karlla W, primary, Ammous, Zineb, primary, Cohen, Julie S, primary, Hosny, Heba, primary, Usmani, Muhammad A, primary, Shahzad, Mohsin, primary, Riazuddin, Sheikh, primary, Stanley, Valentina, primary, Eslahi, Atiye, primary, Person, Richard E, primary, Elbendary, Hasnaa M, primary, Comi, Anne M, primary, Poskitt, Laura, primary, Salpietro, Vincenzo, primary, Genomics, Queen Square, primary, Rosenfeld, Jill A, primary, Williams, Katie B, primary, Marafi, Dana, primary, Xia, Fan, primary, Biderman Waberski, Marta, primary, Zaki, Maha S, primary, Gleeson, Joseph, primary, Puffenberger, Erik, primary, Houlden, Henry, primary, and Maroofian, Reza, primary

Published
2020
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23. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes

Author

Strauss, Kevin A., primary, Carson, Vincent J., additional, Soltys, Kyle, additional, Young, Millie E., additional, Bowser, Lauren E., additional, Puffenberger, Erik G., additional, Brigatti, Karlla W., additional, Williams, Katie B., additional, Robinson, Donna L., additional, Hendrickson, Christine, additional, Beiler, Keturah, additional, Taylor, Cora M., additional, Haas-Givler, Barbara, additional, Chopko, Stephanie, additional, Hailey, Jennifer, additional, Muelly, Emilie R., additional, Shellmer, Diana A., additional, Radcliff, Zachary, additional, Rodrigues, Ashlin, additional, Loeven, KaLynn, additional, Heaps, Adam D., additional, Mazariegos, George V., additional, and Morton, D. Holmes, additional

Published
2020
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24. Crigler‐Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier

Author

Strauss, Kevin A., primary, Ahlfors, Charles E., additional, Soltys, Kyle, additional, Mazareigos, George V., additional, Young, Millie, additional, Bowser, Lauren E., additional, Fox, Michael D., additional, Squires, James E., additional, McKiernan, Patrick, additional, Brigatti, Karlla W., additional, Puffenberger, Erik G., additional, Carson, Vincent J., additional, and Vreman, Hendrik J., additional

Published
2020
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25. Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy.

Author

Carson, Vincent J., Young, Millie, Brigatti, Karlla W., Robinson, Donna L., Reed, Robert M., Sohn, Jihee, Petrillo, Marco, Farwell, Wildon, Miller, Freeman, and Strauss, Kevin A.

Abstract

Introduction/Aims: Intrathecal administration of nusinersen is challenging in patients with spinal muscular atrophy (SMA) who have spine deformities or fusions. We prospectively studied the safety and efficacy of nusinersen administration via an indwelling subcutaneous intrathecal catheter (SIC) for SMA patients with advanced disease. Methods: Seventeen participants commenced nusinersen therapy between 2.7 and 31.5 years of age and received 9 to 12 doses via SIC. Safety was assessed in all participants. A separate efficacy analysis comprised 11 nonambulatory, treatment‐naive SMA patients (18.1 ± 6.8 years) with three SMN2 copies and complex spine anatomy. Results: In the safety analysis, 14 treatment‐related adverse events (AEs) occurred among 12 (71%) participants; all were related to the SIC and not nusinersen. Device‐related AEs interfered with 2.5% of nusinersen doses. Four SICs (24%) required surgical revision due to mechanical malfunction with or without cerebrospinal fluid leak (n = 2), and one (6%) was removed due to Staphylococcus epidermidis meningitis. In the efficacy analysis, mean performance on the nine‐hole peg test improved in dominant (15.9%, P = 0.012) and nondominant (19.0%, P = 0.008) hands and grip strength increased by 44.9% (P = 0.031). We observed no significant changes in motor scales, muscle force, pulmonary function, or SMA biomarkers. All participants in the efficacy cohort reported one or more subjective improvement(s) in endurance, purposeful hand use, arm strength, head control, and/or speech. Discussion For SMA patients with complex spine anatomy, the SIC allows for reliable outpatient administration of nusinersen that results in meaningful improvements in upper limb function, but introduces risks of technical malfunction and iatrogenic infection. [ABSTRACT FROM AUTHOR]

Published
2022
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27. Cortical Overgrowth in a Preclinical Forebrain Organoid Model of CNTNAP2-Associated Autism Spectrum Disorder

Author

de Jong, Job O., primary, Llapashtica, Ceyda, additional, Strauss, Kevin, additional, Provenzano, Frank, additional, Sun, Yan, additional, Cortese, Giuseppe P., additional, Brigatti, Karlla W., additional, Corneo, Barbara, additional, Migliori, Bianca, additional, Kushner, Steven A., additional, Kellendonk, Christoph, additional, Javitch, Jonathan A., additional, Xu, Bin, additional, and Markx, Sander, additional

Published
2019
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28. Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier

Author

Bowser, Lauren E., primary, Young, Millie, additional, Wenger, Olivia K., additional, Ammous, Zineb, additional, Brigatti, Karlla W., additional, Carson, Vincent J., additional, Moser, Teresa, additional, Deline, James, additional, Aoki, Kazuhiro, additional, Morlet, Thierry, additional, Scott, Ethan M., additional, Puffenberger, Erik G., additional, Robinson, Donna L., additional, Hendrickson, Christine, additional, Salvin, Jonathan, additional, Gottlieb, Steven, additional, Heaps, Adam D., additional, Tiemeyer, Michael, additional, and Strauss, Kevin A., additional

Published
2019
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29. Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay

Author

Morimoto, Marie, primary, Waller-Evans, Helen, additional, Ammous, Zineb, additional, Song, Xiaofei, additional, Strauss, Kevin A., additional, Pehlivan, Davut, additional, Gonzaga-Jauregui, Claudia, additional, Puffenberger, Erik G., additional, Holst, Charles R., additional, Karaca, Ender, additional, Brigatti, Karlla W., additional, Maguire, Emily, additional, Coban-Akdemir, Zeynep H., additional, Amagata, Akiko, additional, Lau, C. Christopher, additional, Chepa-Lotrea, Xenia, additional, Macnamara, Ellen, additional, Tos, Tulay, additional, Isikay, Sedat, additional, Nehrebecky, Michele, additional, Overton, John D., additional, Klein, Matthew, additional, Markello, Thomas C., additional, Posey, Jennifer E., additional, Adams, David R., additional, Lloyd-Evans, Emyr, additional, Lupski, James R., additional, Gahl, William A., additional, and Malicdan, May Christine V., additional

Published
2018
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30. Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease

Author

Williams, Katie B, primary, Brigatti, Karlla W, additional, Puffenberger, Erik G, additional, Gonzaga-Jauregui, Claudia, additional, Griffin, Laurie B, additional, Martinez, Erick D, additional, Wenger, Olivia K, additional, Yoder, Mark A, additional, Kandula, Vinay V R, additional, Fox, Michael D, additional, Demczko, Matthew M, additional, Poskitt, Laura, additional, Furuya, Katryn N, additional, Reid, Jeffrey G, additional, Overton, John D, additional, Baras, Aris, additional, Miles, Lili, additional, Radhakrishnan, Kadakkal, additional, Carson, Vincent J, additional, Antonellis, Anthony, additional, Jinks, Robert N, additional, and Strauss, Kevin A, additional

Published
2018
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33. Genomic diagnostics within a medically underserved population: efficacy and implications

Author

Strauss, Kevin A., primary, Gonzaga-Jauregui, Claudia, additional, Brigatti, Karlla W., additional, Williams, Katie B., additional, King, Alejandra K., additional, Van Hout, Cristopher, additional, Robinson, Donna L., additional, Young, Millie, additional, Praveen, Kavita, additional, Heaps, Adam D., additional, Kuebler, Mindy, additional, Baras, Aris, additional, Reid, Jeffrey G., additional, Overton, John D., additional, Dewey, Frederick E., additional, Jinks, Robert N., additional, Finnegan, Ian, additional, Mellis, Scott J., additional, Shuldiner, Alan R., additional, and Puffenberger, Erik G., additional

Published
2018
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34. Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease.

Author

Williams, Katie B, Brigatti, Karlla W, Puffenberger, Erik G, Gonzaga-Jauregui, Claudia, Griffin, Laurie B, Martinez, Erick D, Wenger, Olivia K, Yoder, Mark A, Kandula, Vinay V R, Fox, Michael D, Demczko, Matthew M, Poskitt, Laura, Furuya, Katryn N, Reid, Jeffrey G, Overton, John D, Baras, Aris, Miles, Lili, Radhakrishnan, Kadakkal, Carson, Vincent J, and Antonellis, Anthony

Published
2019
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35. Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant

Author

Di Donato, Nataliya, primary, Jean, Ying Y., additional, Maga, A. Murat, additional, Krewson, Briana D., additional, Shupp, Alison B., additional, Avrutsky, Maria I., additional, Roy, Achira, additional, Collins, Sarah, additional, Olds, Carissa, additional, Willert, Rebecca A., additional, Czaja, Agnieszka M., additional, Johnson, Rachel, additional, Stover, Jessi A., additional, Gottlieb, Steven, additional, Bartholdi, Deborah, additional, Rauch, Anita, additional, Goldstein, Amy, additional, Boyd-Kyle, Victoria, additional, Aldinger, Kimberly A., additional, Mirzaa, Ghayda M., additional, Nissen, Anke, additional, Brigatti, Karlla W., additional, Puffenberger, Erik G., additional, Millen, Kathleen J., additional, Strauss, Kevin A., additional, Dobyns, William B., additional, Troy, Carol M., additional, and Jinks, Robert N., additional

Published
2016
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38. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Snijders Blok, Lot, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot R F, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T., Hoischen, Alexander, Vissers, Lisenka E L M, Koemans, Tom S., Wissink-Lindhout, Willemijn, Eichler, Evan E., Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, Van Bon, Bregje W M, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L., Van Dijck, Anke, Innes, A. Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J., Henderson, Alex, Lynch, Sally A., Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, Van gassen, Koen L I, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L., Pediaditakis, Igor, Haas, Stefan A., Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G., Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C., Stein, Quinn, Strauss, Kevin A., Brigatti, Karlla W., Keating, Katherine, Burton, Barbara K., Kim, Katherine H., Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D., Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M., Van Roozendaal, Kees, Brunner, Han, Chung, Wendy K., Kooy, R. Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G., Katsanis, Nicholas, Kleefstra, Tjitske, Snijders Blok, Lot, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot R F, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T., Hoischen, Alexander, Vissers, Lisenka E L M, Koemans, Tom S., Wissink-Lindhout, Willemijn, Eichler, Evan E., Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, Van Bon, Bregje W M, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L., Van Dijck, Anke, Innes, A. Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J., Henderson, Alex, Lynch, Sally A., Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, Van gassen, Koen L I, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L., Pediaditakis, Igor, Haas, Stefan A., Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G., Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C., Stein, Quinn, Strauss, Kevin A., Brigatti, Karlla W., Keating, Katherine, Burton, Barbara K., Kim, Katherine H., Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D., Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M., Van Roozendaal, Kees, Brunner, Han, Chung, Wendy K., Kooy, R. Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G., Katsanis, Nicholas, and Kleefstra, Tjitske

Published
2015

39. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Snijders Blok, Lot, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot R F, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T., Hoischen, Alexander, Vissers, Lisenka E L M, Koemans, Tom S., Wissink-Lindhout, Willemijn, Eichler, Evan E., Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, Van Bon, Bregje W M, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L., Van Dijck, Anke, Innes, A. Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J., Henderson, Alex, Lynch, Sally A., Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, Van gassen, Koen L I, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L., Pediaditakis, Igor, Haas, Stefan A., Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G., Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C., Stein, Quinn, Strauss, Kevin A., Brigatti, Karlla W., Keating, Katherine, Burton, Barbara K., Kim, Katherine H., Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D., Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M., Van Roozendaal, Kees, Brunner, Han, Chung, Wendy K., Kooy, R. Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G., Katsanis, Nicholas, Kleefstra, Tjitske, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Snijders Blok, Lot, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot R F, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T., Hoischen, Alexander, Vissers, Lisenka E L M, Koemans, Tom S., Wissink-Lindhout, Willemijn, Eichler, Evan E., Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, Van Bon, Bregje W M, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L., Van Dijck, Anke, Innes, A. Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J., Henderson, Alex, Lynch, Sally A., Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, Van gassen, Koen L I, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L., Pediaditakis, Igor, Haas, Stefan A., Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G., Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C., Stein, Quinn, Strauss, Kevin A., Brigatti, Karlla W., Keating, Katherine, Burton, Barbara K., Kim, Katherine H., Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D., Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M., Van Roozendaal, Kees, Brunner, Han, Chung, Wendy K., Kooy, R. Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G., Katsanis, Nicholas, and Kleefstra, Tjitske

Published
2015

40. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Snijders Blok, Lot, primary, Madsen, Erik, additional, Juusola, Jane, additional, Gilissen, Christian, additional, Baralle, Diana, additional, Reijnders, Margot R.F., additional, Venselaar, Hanka, additional, Helsmoortel, Céline, additional, Cho, Megan T., additional, Hoischen, Alexander, additional, Vissers, Lisenka E.L.M., additional, Koemans, Tom S., additional, Wissink-Lindhout, Willemijn, additional, Eichler, Evan E., additional, Romano, Corrado, additional, Van Esch, Hilde, additional, Stumpel, Connie, additional, Vreeburg, Maaike, additional, Smeets, Eric, additional, Oberndorff, Karin, additional, van Bon, Bregje W.M., additional, Shaw, Marie, additional, Gecz, Jozef, additional, Haan, Eric, additional, Bienek, Melanie, additional, Jensen, Corinna, additional, Loeys, Bart L., additional, Van Dijck, Anke, additional, Innes, A. Micheil, additional, Racher, Hilary, additional, Vermeer, Sascha, additional, Di Donato, Nataliya, additional, Rump, Andreas, additional, Tatton-Brown, Katrina, additional, Parker, Michael J., additional, Henderson, Alex, additional, Lynch, Sally A., additional, Fryer, Alan, additional, Ross, Alison, additional, Vasudevan, Pradeep, additional, Kini, Usha, additional, Newbury-Ecob, Ruth, additional, Chandler, Kate, additional, Male, Alison, additional, Dijkstra, Sybe, additional, Schieving, Jolanda, additional, Giltay, Jacques, additional, van Gassen, Koen L.I., additional, Schuurs-Hoeijmakers, Janneke, additional, Tan, Perciliz L., additional, Pediaditakis, Igor, additional, Haas, Stefan A., additional, Retterer, Kyle, additional, Reed, Patrick, additional, Monaghan, Kristin G., additional, Haverfield, Eden, additional, Natowicz, Marvin, additional, Myers, Angela, additional, Kruer, Michael C., additional, Stein, Quinn, additional, Strauss, Kevin A., additional, Brigatti, Karlla W., additional, Keating, Katherine, additional, Burton, Barbara K., additional, Kim, Katherine H., additional, Charrow, Joel, additional, Norman, Jennifer, additional, Foster-Barber, Audrey, additional, Kline, Antonie D., additional, Kimball, Amy, additional, Zackai, Elaine, additional, Harr, Margaret, additional, Fox, Joyce, additional, McLaughlin, Julie, additional, Lindstrom, Kristin, additional, Haude, Katrina M., additional, van Roozendaal, Kees, additional, Brunner, Han, additional, Chung, Wendy K., additional, Kooy, R. Frank, additional, Pfundt, Rolph, additional, Kalscheuer, Vera, additional, Mehta, Sarju G., additional, Katsanis, Nicholas, additional, and Kleefstra, Tjitske, additional

Published
2015
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41. Frataxin levels in peripheral tissue in Friedreich ataxia

Author

Lazaropoulos, Michael, primary, Dong, Yina, additional, Clark, Elisia, additional, Greeley, Nathaniel R., additional, Seyer, Lauren A., additional, Brigatti, Karlla W., additional, Christie, Carlton, additional, Perlman, Susan L., additional, Wilmot, George R., additional, Gomez, Christoper M., additional, Mathews, Katherine D., additional, Yoon, Grace, additional, Zesiewicz, Theresa, additional, Hoyle, Chad, additional, Subramony, Sub H., additional, Brocht, Alicia F., additional, Farmer, Jennifer M., additional, Wilson, Robert B., additional, Deutsch, Eric C., additional, and Lynch, David R., additional

Published
2015
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42. Friedreich Ataxia Clinical Outcome Measures

Author

Regner, Sean R., primary, Wilcox, Nicholas S., additional, Friedman, Lisa S., additional, Seyer, Lauren A., additional, Schadt, Kim A., additional, Brigatti, Karlla W., additional, Perlman, Susan, additional, Delatycki, Martin, additional, Wilmot, George R., additional, Gomez, Christopher M., additional, Bushara, Khalaf O., additional, Mathews, Katherine D., additional, Subramony, S. H., additional, Ashizawa, Tetsuo, additional, Ravina, Bernard, additional, Brocht, Alicia, additional, Farmer, Jennifer M., additional, and Lynch, David R., additional

Published
2012
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44. Disease burden and management of Crigler‐Najjar syndrome: Report of a world registry

Author

Sem J. Aronson, Norman Junge, Mediha Trabelsi, Wided Kelmemi, Aurelie Hubert, Karlla W. Brigatti, Michael D. Fox, Robert J. de Knegt, Johanna C. Escher, Virginia M. Ginocchio, Raffaele Iorio, Yan Zhu, Figen Özçay, Fakher Rahim, Mortada H. F. El-Shabrawi, Eyal Shteyer, Angelo Di Giorgio, Lorenzo D'Antiga, Federico Mingozzi, Nicola Brunetti-Pierri, Kevin A. Strauss, Philippe Labrune, Ridha Mrad, Ulrich Baumann, Ulrich Beuers, Piter J. Bosma, CureCN Consortium, Aronson, Sem J., Junge, Norman, Trabelsi, Mediha, Kelmemi, Wided, Hubert, Aurelie, Brigatti, Karlla W., Fox, Michael D., de Knegt, Robert J., Escher, Johanna C., Ginocchio, Virginia M., Iorio, Raffaele, Zhu, Yan, Özçay, Figen, Rahim, Fakher, El-Shabrawi, Mortada H. F., Shteyer, Eyal, Di Giorgio, Angelo, D'Antiga, Lorenzo, Mingozzi, Federico, BRUNETTI PIERRI, Nicola, Strauss, Kevin A., Labrune, Philippe, Mrad, Ridha, Baumann, Ulrich, Beuers, Ulrich, Bosma, Piter J., Consortium, Curecn, Gastroenterology & Hepatology, Pediatrics, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology

Subjects
Registrie, Hepatology, liver transplantation, Bilirubin, encephalopathy, Cost of Illne, unconjugated hyperbilirubinemia, Cost of Illness, Humans, Registries, UGT1A1, Glucuronosyltransferase, Human, Crigler-Najjar Syndrome, phototherapy
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45. A recurring NFS1 pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes.

Author

Hershkovitz T, Kurolap A, Tal G, Paperna T, Mory A, Staples J, Brigatti KW, Gonzaga-Jauregui C, Dumin E, Saada A, Mandel H, and Baris Feldman H

Abstract

Iron‑sulfur clusters (FeSCs) are vital components of a variety of essential proteins, most prominently within mitochondrial respiratory chain complexes I-III; Fe-S assembly and distribution is performed via multi-step pathways. Variants affecting several proteins in these pathways have been described in genetic disorders, including severe mitochondrial disease. Here we describe a Christian Arab kindred with two infants that died due to mitochondrial disorder involving Fe-S containing respiratory chain complexes and a third sibling who survived the initial crisis. A homozygous missense variant in NFS1 : c.215G>A; p.Arg72Gln was detected by whole exome sequencing. The NFS1 gene encodes a cysteine desulfurase, which, in complex with ISD11 and ACP, initiates the first step of Fe-S formation. Arginine at position 72 plays a role in NFS1-ISD11 complex formation; therefore, its substitution with glutamine is expected to affect complex stability and function. Interestingly, this is the only pathogenic variant ever reported in the NFS1 gene, previously described once in an Old Order Mennonite family presenting a similar phenotype with intra-familial variability in patient outcomes. Analysis of datasets from both populations did not show a common haplotype, suggesting this variant is a recurrent de novo variant. Our report of the second case of NFS1-related mitochondrial disease corroborates the pathogenicity of this recurring variant and implicates it as a hot-spot variant. While the genetic resolution allows for prenatal diagnosis for the family, it also raises critical clinical questions regarding follow-up and possible treatment options of severely affected and healthy homozygous individuals with mitochondrial co-factor therapy or cysteine supplementation., Competing Interests: JS and CG-J are full-time employees of the Regeneron Genetics Center and receive stock options as part of compensation. All other authors have no conflicts to declare., (© 2020 The Authors.)

Published
2020
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