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1. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

Author: Jonathan Li, Ryan G. Lim, Julia A. Kaye, Victoria Dardov, Alyssa N. Coyne, Jie Wu, Pamela Milani, Andrew Cheng, Terri G. Thompson, Loren Ornelas, Aaron Frank, Miriam Adam, Maria G. Banuelos, Malcolm Casale, Veerle Cox, Renan Escalante-Chong, J. Gavin Daigle, Emilda Gomez, Lindsey Hayes, Ronald Holewenski, Susan Lei, Alex Lenail, Leandro Lima, Berhan Mandefro, Andrea Matlock, Lindsay Panther, Natasha Leanna Patel-Murray, Jacqueline Pham, Divya Ramamoorthy, Karen Sachs, Brandon Shelley, Jennifer Stocksdale, Hannah Trost, Mark Wilhelm, Vidya Venkatraman, Brook T. Wassie, Stacia Wyman, Stephanie Yang, Jennifer E. Van Eyk, Thomas E. Lloyd, Steven Finkbeiner, Ernest Fraenkel, Jeffrey D. Rothstein, Dhruv Sareen, Clive N. Svendsen, Leslie M. Thompson, Hemali Phatnani, PhD, Justin Kwan, MD, Dhruv Sareen, PhD, James R. Broach, PhD, Zachary Simmons, MD, Ximena Arcila-Londono, MD, Edward B. Lee, MD, PhD, Vivianna M. Van Deerlin, MD, PhD, Neil A. Shneider, MD, PhD, Ernest Fraenkel, PhD, Lyle W. Ostrow, MD, PhD, Frank Baas, MD, PhD, Noah Zaitlen, PhD, James D. Berry, MD, MPH, Andrea Malaspina, MD, PhD, Pietro Fratta, MD, PhD, Gregory A. Cox, PhD, Leslie M. Thompson, PhD, Steve Finkbeiner, MD, PhD, Efthimios Dardiotis, MD, PhD, Timothy M. Miller, MD, PhD, Siddharthan Chandran, PhD, Suvankar Pal, MD, Eran Hornstein, MD, PhD, Daniel J. MacGowan, MD, Terry Heiman-Patterson, MD, Molly G. Hammell, PhD, Nikolaos.A. Patsopoulos, MD, PhD, Oleg Butovsky, PhD, Joshua Dubnau, PhD, Avindra Nath, MD, Robert Bowser, PhD, Matt Harms, MD, Mary Poss, DVM, PhD, Jennifer Phillips-Cremins, PhD, John Crary, MD, PhD, Nazem Atassi, MD, Dale J. Lange, MD, Darius J. Adams, MD, Leonidas Stefanis, MD, PhD, Marc Gotkine, MD, Robert H. Baloh, MD. PhD, Suma Babu, MBBS, MPH, Towfique Raj, PhD, Sabrina Paganoni, MD, PhD, Ophir Shalem, PhD, Colin Smith, MD, Bin Zhang, PhD, Brent Harris, MD, PhD, Iris Broce, PhD, Vivian Drory, MD, John Ravits, MD, Corey McMillan, PhD, Vilas Menon, PhD, Lani Wu, PhD, and Steven Altschuler, PhD
Subjects: Biological sciences, Neuroscience, Systems neuroscience, Systems biology, Omics, Science
Abstract: Summary: Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
Published: 2021
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2. Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Author: Oliver H. Tam, Nikolay V. Rozhkov, Regina Shaw, Duyang Kim, Isabel Hubbard, Samantha Fennessey, Nadia Propp, Delphine Fagegaltier, Brent T. Harris, Lyle W. Ostrow, Hemali Phatnani, John Ravits, Josh Dubnau, Molly Gale Hammell, Justin Kwan, Dhruv Sareen, James R. Broach, Zachary Simmons, Ximena Arcila-Londono, Edward B. Lee, Vivianna M. Van Deerlin, Neil A. Shneider, Ernest Fraenkel, Frank Baas, Noah Zaitlen, James D. Berry, Andrea Malaspina, Pietro Fratta, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Robert Bowser, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Robert Baloh, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, and Bin Zhang
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displays hallmarks of oxidative and proteotoxic stress. Another 19% of the samples shows predominant signatures of glial activation. Finally, a third group (20%) exhibits high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrate that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo. : Tam et al. present transcriptome profiling results from a large set of amyotrophic lateral sclerosis (ALS) patient cortex samples, finding 3 distinct groups. Two ALS subtypes are marked by gene pathways previously associated with ALS disease, while a third group shows elevated retrotransposon expression linked to TDP-43 pathology. Keywords: amyotrophic lateral sclerosis, retrotransposons, transposable elements, TDP-43, neurodegenerative disease, neurodegeneration, genetics and genomics of ALS
Published: 2019
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3. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Author: Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Huntington's Disease, Pathology, amyotrophic lateral sclerosis, Huntingtin, Neurology, 1702 Cognitive Sciences, International ALS/FTD Genomics Consortium, Neurodegenerative, frontotemporal dementia, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Psychology, Amyotrophic lateral sclerosis, Aetiology, Alzheimer's Disease Related Dementias (ADRD), NYGC ALS Consortium, Huntingtin Protein, DNA Repeat Expansion, General Neuroscience, Frontotemporal Dementia (FTD), International FTD Genetics Consortium, whole-genome sequencing, Frontotemporal Dementia, Neurological, Cognitive Sciences, Lewy body dementia, huntingtin, repeat expansions, Amyotrophic Lateral Sclerosis, Humans, Mutation, Whole Genome Sequencing, Frontotemporal dementia, Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, FALS Sequencing Consortium, Article, 03 medical and health sciences, Atrophy, Rare Diseases, American Genome Center, Clinical Research, mental disorders, Genetics, Acquired Cognitive Impairment, Dementia, PROSPECT Consortium, Neurology & Neurosurgery, Lewy body, business.industry, International LBD Genomics Consortium, Neurosciences, 3112 Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genomics England Research Consortium, 1701 Psychology, ALS, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract: Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
Published: 2020
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4. The infantile neuroaxonal dystrophy rating scale (INAD-RS)

Author: Darius J. Adams, Peter G. Milner, Frederic Heerinckx, Mark G. Midei, Paldeep S. Atwal, and Alex J. Fay
Subjects: Infantile neuroaxonal dystrophy rating scale (INAD-RS), Pediatrics, medicine.medical_specialty, Infantile neuroaxonal dystrophy, Infantile neuroaxonal dystrophy (INAD), Neuroaxonal Dystrophies, lcsh:Medicine, Neurological examination, Neurodegenerative, Rare Diseases, Clinical Research, Rating scale, Infantile neuroaxonal dystrophy rating scale, Clinical outcome assessment, medicine, Humans, PLA2G6-associated neurodegeneration, Pharmacology (medical), Peripheral Nerves, Spasticity, Cognitive decline, Child, Eye Disease and Disorders of Vision, Genetics (clinical), Pediatric, Genetics & Heredity, screening and diagnosis, Other Medical and Health Sciences, medicine.diagnostic_test, business.industry, Research, lcsh:R, Neurosciences, General Medicine, medicine.disease, Hypotonia, Brain Disorders, Detection, PLA2G6-associated neurodegeneration (PLAN), Clinical outcome assessment (COA), Neurological, Cohort, medicine.symptom, business, Developmental regression, 4.2 Evaluation of markers and technologies
Abstract: Background INAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6 months and 3 years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INAD. Methods We have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression. Results We show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p = 6.7 × 10− 07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset. Conclusion We have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.
Published: 2020
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5. Phenom: a prospective clinical study on the clinical impact of phenylketonuria in adults (307–902)

Author: Amarilis Sanchez-Valle, Karen Gu, Jerry Vockley, David Neil, Cary O. Harding, Tarekegn Geberhiwot, Darius J. Adams, Haoling Weng, Avner Sandhu, and Roberto Bassi
Subjects: Pediatrics, medicine.medical_specialty, Endocrinology, business.industry, Endocrinology, Diabetes and Metabolism, Genetics, Prospective clinical study, Medicine, business, Molecular Biology, Biochemistry
Published: 2021
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6. GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Author: Arndt Rolfs, Douglas R. Smith, Hongjie Yuan, Markus Wolff, Eirik Frengen, Sarah E Parisotto, Mark A. Tarnopolsky, John Millichap, Katherine L. Helbig, Christian Korff, Lutz Dondit, Anna-Elina Lehesjoki, Alison M. Muir, Brad T. Tinkle, Heather C Mefford, Bodo Laube, Anne T. Berg, Wen-Hann Tan, Kelly L. Jones, Floor E. Jansen, Christine M. Stanley, Candace T. Myers, Isabelle De Bie, John A. Lawson, Henrike O. Heyne, Wenjuan Chen, David Neal Franz, Julie R. Jones, Elysa J. Marco, Nataliya Di Donato, Cyril Mignot, Jasper J. van der Smagt, Stephen F. Traynelis, Tarja Linnankivi, Tim M. Strom, Hirofumi Kusumoto, Rena Vanzo, Petter Strømme, Uffe Birk Jensen, Amy Lacroix, Darius J Adams, Chun Hu, Boris Keren, Sha Tang, Richard J. Leventer, Johannes R. Lemke, Levinus A. Bok, Helio Pedro, Rami Abou Jamra, Dianalee McKnight, Ethan M. Goldberg, Tony Roscioli, Lauren Brady, Konrad Platzer, Philippe Major, Amy Decker, Anup D. Patel, Marcia C. Willing, Ingrid E. Scheffer, Mark Mintz, Eva H. Brilstra, Carolina Courage, Lynette G. Sadleir, Alexander Winschel, William B. Dobyns, Stephanie Fox, Emmanuelle Ranza, Saskia Biskup, Dennis Döcker, Judith D. Ranells, Rikke S. Møller, Elaine H. Zackai, Hannah Schütz, Mieke M. van Haelst, Christel Depienne, Medicum, Research Programme for Molecular Neurology, Department of Medical and Clinical Genetics, Research Programs Unit, Neuroscience Center, Anna-Elina Lehesjoki / Principal Investigator, University of Helsinki, Children's Hospital, Clinicum, Lastenneurologian yksikkö, HUS Children and Adolescents, Amsterdam Reproduction & Development (AR&D), Human genetics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: 0301 basic medicine, INTELLECTUAL DISABILITY, Brain Diseases/drug therapy/genetics, Pathogenic GRIN2B mutations, AUTISM SPECTRUM DISORDERS, Cortical visual impairment, Bioinformatics, Clustering of missense variants, 3124 Neurology and psychiatry, Epilepsy, 0302 clinical medicine, Channelopathy, NMDA RECEPTORS, Receptors, Intellectual disability, Polymicrogyria, Genetics(clinical), Molecular Targeted Therapy, Genetics (clinical), ddc:618, biology, Epileptic encephalopathy, Precision medicine, 1184 Genetics, developmental biology, physiology, Magnetic Resonance Imaging, Memantine/therapeutic use, Hypotonia, 3. Good health, N-Methyl-D-Aspartate/antagonists & inhibitors/genetics/metabolism, Phenotype, medicine.symptom, Heterozygote, GENES, Mutation/genetics, MIGRATION, Clustering Of Missense Variants, Epileptic Encephalopathy, Pathogenic Grin2b Mutations, Precision Medicine, Encephalopathy, Neuroimaging, Article, 03 medical and health sciences, Journal Article, Genetics, medicine, Humans, NEURODEVELOPMENTAL DISORDERS, business.industry, 3112 Neurosciences, medicine.disease, INDIVIDUALS, 030104 developmental biology, DE-NOVO MUTATIONS, FOCAL EPILEPSY, SUBUNIT, biology.protein, Autism, GRIN2B, 3111 Biomedicine, business, 030217 neurology & neurosurgery
Abstract: BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
Published: 2017
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7. Treatment of infantile neuroaxonal dystrophy with RT001: A di-deuterated ethyl ester of linoleic acid: Report of two cases

Author: Mikhail S. Shchepinov, Peter G. Milner, Christina Flora, Robert J. Molinari, Darius J. Adams, Mark G. Midei, Frederic Heerinckx, Paldeep S. Atwal, Sarah Endemann, and Jahannaz Dastgir
Subjects: Research Report, medicine.medical_specialty, lcsh:QH426-470, Endocrinology, Diabetes and Metabolism, Linoleic acid, PLAN, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Biochemistry, Genetics and Molecular Biology (miscellaneous), PLA2G6, Infantile neuroaxonal dystrophy, Lipid peroxidation, chemistry.chemical_compound, Pharmacokinetics, Internal medicine, Internal Medicine, medicine, Adverse effect, lcsh:RC648-665, NBIA, business.industry, INAD, neurodegeneration, Research Reports, Ethyl ester, medicine.disease, Clinical trial, lcsh:Genetics, Endocrinology, chemistry, Arachidonic acid, business
Abstract: Background Infantile neuroaxonal dystrophy (INAD) is a rare, autosomal recessive disease due to defects in PLA2G6 and is associated with lipid peroxidation. RT001 is a di‐deuterated form of linoleic acid that protects lipids from oxidative damage. Methods We evaluated the pharmacokinetics (PK), safety, and effectiveness of RT001 in two subjects with INAD (subject 1: 34 months; subject 2: 10 months). After screening and baseline evaluations, subjects received 1.8 g of RT001 BD. PK analysis and clinical evaluations were made periodically. Main findings Plasma levels of deuterated linoleic acid (D2‐LA), deuterated arachidonic acid (D2‐AA), D2‐LA to total LA, and D2‐AA to total AA ratios were measured. The targeted plasma D2‐LA ratio (>20%) was achieved by month 1 and maintained throughout the study. RBC AA‐ratios were 0.11 and 0.18 at 6 months for subjects 1 and 2; respectively. No treatment‐related adverse events occurred. Limited slowing of disease progression and some return of lost developmental milestones were seen. Conclusions Oral RT001 was administered safely in two subjects with INAD. Early findings suggest that the compound was well tolerated, metabolized and incorporated in the RBC membrane. A clinical trial is underway to assess efficacy.
Published: 2019

8. Phenotype delineation of ZNF462 related syndrome

Author: Sarah Savage, Maximilian Muenke, Kym M. Boycott, Lynn Pais, Koen L.I. van Gassen, Julian A. Martinez-Agosto, Jacques C. Giltay, Eleina M. England, Oliver Bell, Stephanie Blaney, Nicole Fleischer, Maria Iascone, Pedro A. Sanchez-Lara, Sarah E. Mazzola, Tiong Yang Tan, Elizabeth C. Engle, Tommy Hu, Maria Francesca Bedeschi, Brenda J. Barry, Rebecca Signer, Marie-Ange Delrue, Sung-Kook Hong, Wilfredo Torres-Martinez, Esther Kinning, Charlotte W. Ockeloen, Elaine H. Zackai, Benjamin Cogné, Darius J. Adams, Betrand Isidor, Paul Kruszka, Julie Jurgens, and Kayla Treat
Subjects: Adult, Male, Adolescent, autism spectrum disorders, Nerve Tissue Proteins, Bioinformatics, Article, Craniosynostosis, corpus callosum, Dysgenesis, ptosis, Genetics, Humans, Medicine, Genetics(clinical), Child, Genetics (clinical), Loss function, business.industry, Facies, Infant, Syndrome, medicine.disease, Hypotonia, DNA-Binding Proteins, ZNF462, developmental delay, craniosynostosis, Phenotype, Palpebral fissure, Autism spectrum disorder, Child, Preschool, Noonan syndrome, Female, medicine.symptom, business, Haploinsufficiency, Transcription Factors, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Contains fulltext : 208539.pdf (Publisher’s version ) (Closed access) Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.
Published: 2019

9. Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features

Author: Jawad Ahmed, Christopher A. Walsh, Zehra Agha, Stylianos E. Antonarakis, Sayyed Fahim Shah, Justyna Iwaszkiewicz, Emmanuelle Ranza, Farid Ullah, Muhammad T. Sarwar, Sohail A. Paracha, Periklis Makrythanasis, Erica E. Davis, Muhammad Ansar, Azhar Ali Qaisar, Abbe Lai, Darius J. Adams, Francisca Millan, Lynn Pais, Emilie Falconnet, Nicholas Katsanis, Federico Santoni, and Vincent Zoete
Subjects: Adult, Intracranial Arteriovenous Malformations, Male, Microcephaly, Microarray, Protein Conformation, Dynein, Sequence Homology, Article, Craniofacial Abnormalities, 03 medical and health sciences, Young Adult, Intellectual Disability, Exome Sequencing, Genetics, medicine, Animals, Humans, Exome, Amino Acid Sequence, Allele, Craniofacial, Zebrafish, Gene, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, biology, 030305 genetics & heredity, Homozygote, Dyneins, Infant, biology.organism_classification, medicine.disease, Disease gene identification, Pedigree, Phenotype, Child, Preschool, Mutation, Female
Abstract: Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290(∗)) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.
Published: 2019

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

Author: Corrado Romano, Magnus Nordenskjöld, Tianyun Wang, Min Long, Suneeta Madan-Khetarpal, Evan E. Eichler, Jingping Zhao, Mengzhu Ou, Wei Xie, Yu Zhang, Kirsty McWalter, Chanika Phornphutkul, Kristin G. Monaghan, Koen L.I. van Gassen, Grazia M.S. Mancini, Zhengmao Hu, Madelyn A. Gillentine, Jessica Sebastian, Ying Li, Yaowen Zhang, Jieqiong Tan, Robert J. Hopkin, Kendra Hoekzema, Jozef Gecz, Lu Shen, Meilin Chen, Zhi-Qing David Xu, Carlos E. Prada, Alexander P.A. Stegmann, Judith D. Ranells, Hailun Ni, Ting Bai, Kuokuo Li, Tengfei Zhu, Joseph T. Shieh, Robert B. Hufnagel, Darius J. Adams, Lijuan Liu, Anna Lindstrand, Daryl A. Scott, Huidan Wu, Yingting Quan, Kun Xia, Melissa Racobaldo, J Peng, Mahshid Azamian, Raphael Bernier, Rongjuan Zhao, E. Haan, Fan Xia, Pengwei Peng, Nan Pang, Malin Kvarnung, Honghui Li, Xiangbin Jia, Seema R. Lalani, Jill A. Rosenfeld, Qiumeng Zhang, Susie Ball, Lin Han, Hui Guo, Ikeoluwa A. Osei-Owusu, Giuseppe Calabrese, Ornella Galesi, Tao Xu, Xiaobing Zou, Ann Nordgren, Yaning Liu, Pengfei Liu, Cenying Liu, Jonathan Pevsner, Bert B.A. de Vries, Peter M. van Hasselt, Clinical Genetics, MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output
Subjects: Male, Dendritic spine, Diseases and Disorders, RNA-binding protein, Synaptic Transmission, Synapse, Mice, 0302 clinical medicine, Child, Non-U.S. Gov't, Research Articles, Neurons, RISK, 0303 health sciences, Gene knockdown, ARCHITECTURE, Multidisciplinary, Research Support, Non-U.S. Gov't, SciAdv r-articles, RNA-Binding Proteins, MENTAL-RETARDATION PROTEIN, 3. Good health, Pedigree, Fragile X syndrome, DNA-Binding Proteins, DROSOPHILA, Phenotype, Child, Preschool, Female, MESSENGER-RNA, Research Article, GENES, Neurite, Adolescent, Neurogenesis, Neurotransmission, Biology, Research Support, behavioral disciplines and activities, N.I.H, 03 medical and health sciences, Young Adult, Research Support, N.I.H., Extramural, mental disorders, medicine, Journal Article, Animals, Humans, Genetic Predisposition to Disease, FRAGILE-X-SYNDROME, Autistic Disorder, Preschool, Genetic Association Studies, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, Animal, Genetic Variation, Extramural, Human Genetics, medicine.disease, Disease Models, Animal, DE-NOVO MUTATION, Genetic Loci, Synapses, Disease Models, Autism, TRANSLATION, Neuroscience, 030217 neurology & neurosurgery
Abstract: CSDE1 disruptive mutations are associated with autism., RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity–related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.
Published: 2019

11. Newborn screening for X-linked adrenoleukodystrophy in New York State: Diagnostic protocol, surveillance protocol and treatment guidelines

Author: Melissa P. Wasserstein, Gerald V. Raymond, David Kronn, Darius J. Adams, Joan E. Pellegrino, Richard W. Erbe, Chin-To Fong, A. Iglesias, Mark A. Morrissey, Beth Vogel, P. Parton, Joseph J. Orsini, Natasha Shur, S. E. Bradley, Michele Caggana, P. Levy, Carlos A. Saavedra-Matiz, and Kristin D'Aco
Subjects: Male, Pediatrics, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Genetic counseling, New York, Genetic Counseling, Disease, Biochemistry, Asymptomatic, Peroxisomal Disorders, Neonatal Screening, Endocrinology, X-linked adrenoleukodystrophy, Genetics, Humans, Medicine, Adrenoleukodystrophy, Peroxisomal Multifunctional Protein-2, Zellweger Syndrome, Molecular Biology, Protocol (science), Newborn screening, business.industry, Infant, Newborn, medicine.disease, Acyl-CoA Oxidase, medicine.symptom, business, Acyl-CoA oxidase deficiency, Algorithms, Adrenal Insufficiency
Abstract: Purpose To describe a diagnostic protocol, surveillance and treatment guidelines, genetic counseling considerations and long-term follow-up data elements developed in preparation for X-linked adrenoleukodystrophy (X-ALD) newborn screening in New York State. Methods A group including the director from each regional NYS inherited metabolic disorder center, personnel from the NYS Newborn Screening Program, and others prepared a follow-up plan for X-ALD NBS. Over the months preceding the start of screening, a series of conference calls took place to develop and refine a complete newborn screening system from initial positive screen results to long-term follow-up. Results A diagnostic protocol was developed to determine for each newborn with a positive screen whether the final diagnosis is X-ALD, carrier of X-ALD, Zellweger spectrum disorder, acyl CoA oxidase deficiency or D-bifunctional protein deficiency. For asymptomatic males with X-ALD, surveillance protocols were developed for use at the time of diagnosis, during childhood and during adulthood. Considerations for timing of treatment of adrenal and cerebral disease were developed. Conclusion Because New York was the first newborn screening laboratory to include X-ALD on its panel, and symptoms may not develop for years, long-term follow-up is needed to evaluate the presented guidelines.
Published: 2015
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12. An Absence of Cutaneous Neurofibromas Associated with a 3-bp Inframe Deletion in Exon 17 of the NF1 Gene (c.2970-2972 delAAT): Evidence of a Clinically Significant NF1 Genotype-Phenotype Correlation

Author: S. Giovannini, Susan M Huson, D G R Evans, Nadia Chuzhanova, Rachel K. Hachen, J. P. Van Biervliet, Hua Li, A. Barnicoat, David A. Stevenson, Dave Viskochil, M. Davies, Conxi Lázaro, Darius J. Adams, E. Howard, Vincent M. Riccardi, Nicholas Stuart Tudor Thomas, Sian Wyn Griffiths, Diana Baralle, Bronwyn Kerr, Peter D. Turnpenny, Meena Upadhyaya, Claudia Consoli, Lucy Side, Ludwine Messiaen, Eric Haan, Mary Ella M Pierpont, and P. Wallace
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Neurofibromatosis 1, Skin Neoplasms, Adolescent, Genotype, Biology, medicine.disease_cause, Article, Exon, Genetics, medicine, Humans, Neurofibroma, Genetics(clinical), Child, Genetics (clinical), Watson syndrome, Sequence Deletion, Legius syndrome, Mutation, Neurofibromin 1, Exons, Sequence Analysis, DNA, Middle Aged, medicine.disease, Phenotype, Pedigree, nervous system diseases, biology.protein, Female
Abstract: Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA--ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.
Published: 2007
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13. Newborn screening for Krabbe disease in New York State: the first eight years' experience

Author: Patricia Galvin-Parton, David A. Wenger, Melissa P. Wasserstein, Denise M. Kay, Joan E. Pellegrino, Lea M. Krein, David Kronn, Carlos A. Saavedra-Matiz, Michele Caggana, Richard W. Erbe, Jennifer M. Kwon, Maria L. Escolar, Alejandro D. Iglesias, Chad K. Biski, Natasha Shur, Monica Martin, Georgianne L. Arnold, Joseph J. Orsini, Paul A. Levy, Matthew Nichols, Joanne Kurtzberg, Darius J. Adams, and Patricia K. Duffner
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, medicine.medical_treatment, New York, Neurological examination, Hematopoietic stem cell transplantation, Asymptomatic, Polymorphism, Single Nucleotide, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, Neonatal Screening, Predictive Value of Tests, Medicine, Humans, Genetics (clinical), Newborn screening, medicine.diagnostic_test, business.industry, Leukodystrophy, Hematopoietic Stem Cell Transplantation, Infant, Newborn, medicine.disease, Leukodystrophy, Globoid Cell, Transplantation, 030104 developmental biology, Treatment Outcome, Predictive value of tests, Krabbe disease, Dried Blood Spot Testing, medicine.symptom, business, 030217 neurology & neurosurgery, Algorithms, Galactosylceramidase
Abstract: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006. Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination. Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease. The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms. Genet Med 18 3, 239–248.
Published: 2015

14. Common genetic and epigenetic syndromes

Author: Darius J. Adams and David A. Clark
Subjects: Williams Syndrome, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Beckwith-Wiedemann Syndrome, Genetic syndromes, Trisomy 13 Syndrome, Turner Syndrome, Chromosome Disorders, Genetic Counseling, Trisomy, Classical Lissencephalies and Subcortical Band Heterotopias, Bioinformatics, Epigenesis, Genetic, Klinefelter Syndrome, WAGR Syndrome, DiGeorge Syndrome, Medicine, Humans, Epigenetics, Imprinting (psychology), Psychiatry, Chromosomes, Human, Pair 13, business.industry, Clinical course, DNA Methylation, Alagille Syndrome, Pediatrics, Perinatology and Child Health, DNA methylation, Angelman Syndrome, Chromosome Deletion, Down Syndrome, Smith-Magenis Syndrome, business, Chromosomes, Human, Pair 18, Prader-Willi Syndrome, Trisomy 18 Syndrome
Abstract: Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes.
Published: 2015

15. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain

Author: H. Hattig, C. Delli Pizzi, M. C. Addonizio, Michelle Davis, A. R. Giovagnoli, L. Florensa, M. Roth, J. de Kruijk, Francisco Lacruz, Ph. Dewailly, A. Toygar, C. Avendano, P.P. De Deyn, J. F. Hurtevent, F. Lomeila, T. W. Wong, Gordon T. Plant, M. Bud, H. J. Willison, DH Miller, D. W. Langdon, R. Cioni, J. Servan, A. Kaygisiz, E. Racadot, D. B. Schens, E. Picciola, L. Falip, C. Bouchard, J. Jotova, A. Jorge-Santamaria, P. Misra, A. Dufour, C. P. Panagopoulos, A. Venneri, B. Sredni, B. Angelard, M. Janelidze, M. Carreno, J. Obenberger, J. Pouget, H. W. Moser, R. Kaufmann, J. A. Molina, D. Linden, A. Martin Urda, E. Uvestad, A. Krone, J. P. Cochin, J. Mallecourt, A. Cambon-Thomsen, K. Violleau, P. Osschmann, A. M. Durocher, E. Bussaglia, D. M. Danielle, H. Efendi, C. Van Broeckhoven, K. G. Jordan, W. Rautenberg, C. Iniguez, J. M. Delgado, Graham Watson, M. Lawden, Gareth J. Barker, K. Stiasny, James T. Becker, G. Campanella, E. Peghi, A. Poli, A. Haddad, T. Yamawaki, Giacomo P. Comi, S. Sotgiu, B. Ersmark, A. Pomes, M. Ziegler, P. Ferrante, P. Ruppi, H. KuÇukoglu, R. Bouton, U. K. Rinne, P. Vieregge, M. Dary, P. Giunti, Peter J. Goadsby, S. Jung, E. Secor, A. Steinberg, N. Vila, M. A. Hernandez, M. Cursi, A. Enqelhardt, A. Engelhardt, J. Veitch, F. Di Silverio, F. Arnaud, B. Neundörfer, R. Brucher, Dominique Caparros-Lefebvre, B. Meyer, Marianne Dieterich, M. H. Snidaro, R. Gomez, R. Cerbo, M. Ragno, J. M. Vance, S. Nemni, A. Caliskan, F. Barros, I. Velcheva, D. Ceballos-Baumann, V. Barak, A. Avila, N. Antonova, F. Resche, S. Pappata, L. Varela, S. R. Silveira Santos, A. Cammarota, L. Naccache, Y. Nara, E. Tournier-Lasserves, R. Mobner, T. Chase, A. Ensenyat, J. Ulrich, G. Giegerich, M. Rother, M. Revilla, N. Nitschke, K. Honczarenko, E. Basart Tarrats, J. Blin, B. Jacob, J. Santamaria, S. Knezevic, J. L. Castillo, M. Antem, J. Colomer, O. Busse, Didier Hannequin, S. Carrier, J. B. Ruidavets, C. Rozman, J. Bogoussslavsky, J. Pascual Calvet, E. Monros, J. M. Polo, M. Zucconl, Javier Muruzabal, R. R. Allen, R. Rivolta, K. Haugaard, A. Nespolo, K. Hoang-Xuang, G. Bussone, T. Avramidis, E. Corsini, Christiana Franke, T. Vinogradova, H. Boot, K. Vestergaard, G. H. Jansen, N. Argentino, M. Raltzig, W. Linssen, Mark B. Pepys, P. Roblot, L. Lauritzen, E. Fainardi, D. Morin, T. X. Arbizu Urdiain, J. Wollenhaupt, S. Bostantjopoulou, G. Pavesi, A. D. Forman, Giovanni Fabbrini, D. Jean, J. J. Archelos, M. I. Blanchs, M. Del Gobbo, Anna Carla Turconi, Ch. Derouesné, Elio Scarpini, A. Visbeck, P. Castejon, J. P. Renou, F. Mounier-Vehier, G. Potagas, Ch. Duyckaerts, A. Filla, R. Schneider, G. Ronen, K. Nagata, J. P. Vedel, A. Henneberg, G. van Melle, C. Baratti, H. Knott, M. C. Prevett, A. Bes, B. Metin, Jos V. Reempts, L. Martorell, Mefkure Eraksoy, H. O. Handwerker, D. S. Younger, O. Oktem, D. Frongillo, C. Soriano-Soriano, L. Niehaus, F. Zipp, A. Tartaro, S Newman, R. H. Browne, P. Davous, R. Sanchez, M. Muros, M. E. Kornhuber, A. Lavarone, M. Mohr, M. R. Garcia, S. Russell, H. Kellar-Wood, M. R. Tola, B. Ostermeyer, Ch. Tzekov, K. Sartor, E. B. Ringelstein, P. P. Gazzaniga, Paul Krack, H. Fidaner, H. Rico, T. Dbaiss, F. Alameda, E. Torchiana, L. Rumbach, I. Charques, J. M. Bogaard, C. D. Frith, L. J. Rappelle, R. Brenner, A. Joutel, K. Fuxe, G. HÄcker, M. J. Blaser, J. Valls-SolÇ, G. Ulm, M. Alberdi, A. Bock, F. W. Bertelsmann, U. Wieshmann, J. Visa, J. R. Lupski, D. D'Amico, L. M. P. Ramos, A. A. Vanderbark, R. Horn, M. Warmuth, Dietmar Kühne, Mark S. Palmer, C. Ehrenheim, E. Canga, S. Viola, O. Scarpino, P. Naldi, R. Almeida, A. A. Raymond, J. Gamez, Stephan Arnold, A. DiGiovanni, J. Dalmau, C. C. Chari, H. F. Beer, J. C. Koetsier, J. Iriarte, E. Yunis, J. Casadevall, E. Le Guern, E. Stenager, S. R. Benbadis, J. M. Warter, F. Burklin, I. Theodorou, L. Johannesen, G. A. Graveland, X. Leclerc, I. Vecchio, L. Ozelius, G. Nicoletti, R. K. Gherardi, E. Esperet, M. L. Delodovici, F. Cattin, F. Paiau, Giorgio Sacilotto, C. A. J. Broere, D. Chavdarov, J. P. Willmer, C. H. Hawkes, Th. Naegele, E. Ellie, E. Dartigues, M. J. Guardiola, S. Hesse, Z. Levic, Marco Rovaris, P. Saugeir-Veber, B. A. Yaqub, H. F. Durwen, R. Larumbe, J. Ballabrina, M. Sendtner, J. Röther, M. Horstink, C. Kluglein, M.P. Montesi, H. Apaydin, J. Montoya, E. Waubant, Ch. Verellen-Dunoulin, A. Nicolai, J. Lopez-Delval, R. Lemon, G. Cantinho, E. Granieri, A. Zeviani, Wolfgang H. Oertel, U. Ficola, V. Di Piero, V. Fragola, K. Sabev, M. V. Guitera, I. Turki, F. Bolgert, P. Ingrand, J. M. Gobernado, L. M. E. Grimaldi, S. Baybas, B. Eymard, Y. Rolland, Y. Robitaille, Ta. Pampols, P. J. Koehler, A. Carroacedo, J. Vilchez, S. Di Vittorio, I. R. Rise, T. Nagy, M. Kuffner, E. Palazzini, A. Ott, J. Pruim, T. X. Arbizu, E. Manetti, C. Cervera, S. Felber, G. Gursoy, J. Scholz, G. A. Buscaino, M. S. Chen, A. Pascual, J. Hazan, J. U. Gajda, J. G. Cea, G. Bottini, G. Damalik, F. Le Doze, G. Bonaldi, J. M. Hew, C. Messina, A. M. Kennedy, J. M. Carney, N. M. F. Murray, M. Parent, M. Koepp, V. Dimova, D. De Leo, K. Jellinger, G. Salemi, S. Mientus, M. L. Hansen, F. Mazzucchelli, J. Vieth, M. Mauri, E. Bartels, L. Johannsen, C. Humphreys, J. Emile, D. N. Landon, E. Kansu, R. Sanchez-Pernaute, Rsj Frackowiak, M. Gonzalez Torres, L. Oller, C. Machedo, J. Kother, M. Billiard, H. Durak, T. Schindler, A. Frank, A. Uncini, A. Sbriccoli, C. Farinas, D. W. Paty, N. Fast, A. T. Zangaladze, A. Kerkhofs, J. M. Pino Garcia, I. De la Fuente, B. Marini, L. Gomez, I. Rubio, Alessandra Bardoni, C. Brodie, P. Acin, U. Sliwka, S. A. Hawkins, S. Tardieu, F. Vitullo, J. M. Pereira Monteino, R. Gagliardi, T. Jezewski, A. Cano, T. Lempert, F. Abad Alegria, G. Rotondo, D. Ince, C. Martinez Parra, Y. Huang, H. Luders, Y. Steinvil, F. G. A. Van Der Meche, R. Bianchi, A. Sanchez, T. Sevilla, J. M. Ketelslegers, A. Domzal-Stryga, M. Pandolfo, M. O. Josse, K. W. Neff, I. Blanco, G. W. Bruyn, O. W. Witte, J. L. Thibault, G. Andersen, J. Pariset, A. Marcone, R. J. M. 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Garcia de Yebenes, N. K. Olsen, P. Hitzenberger, S. Einius, Aj Thompson, Ch. J. Vecht, T. Crepin-Leblond, Klaus L. Leenders, A. Di Muzio, L. Georgieva, René Spiegel, K. Sabey, D. Ménégalli, J. Meulstee, U. Liszka, P. Giral, C. Sunol, J. M. Espadaler, A. D. Crockar, K. Varli, G. Giraud, P. J. Hülser, A. Benazzouz, A. Reggio, M. Salvatore, K. Genc, M. Kushnir, S. Barbieri, J. Ph. Azulay, M. Gianelli, N. Bathien, A. AlMemar, F. Hentati, I. Ragueneau, F. Chiarotti, R. C. F. Smits, A. K. Asbury, F. Lacruz, B. Muller, Alan J. Thompson, Gordon Smith, K. Schmidt, C. Daems Monpeun, Juergen Weber, A. Arboix, G. R. Fink, A. M. Cobo, M. Ait Kaci Ahmed, E. Gencheva, Israel-Biet, G. Schlaug, P. De Jonghe, Philip Scheltens, K. Toyka, P. Gonzalez-Porque, A. Cila, J. M. Fernandez, P. Augustin, J. Siclia, S. Medaglini, D. E. Ziogas, A. Feve, L. Kater, G. J. E. Rinkel, D. Leppert, Rüdiger J. Seitz, S. Ried, C. Turc-Carel, G. Smeyers, F. Godinho, M. Czygan, M. Rijntjes, E. Aversa, M. Frigo, Leif Østergaard, J. L. Munoz Blanco, A. Cruz-Matinez, J. De Reuck, C. Theillet, T. Barroso, V. Oikonen, Florence Lebert, M. Kilinc, C. Cordon-Cardon, G. Stoll, E. Thiery, F. Pulcinelli, J. Solski, M. Schmiegelow, L. J. Polman, P. Fernandez-Calle, C. Wikkelso, M. Ben Hamida, M. Laska, E. Kott, W. Sulkowski, C. Lucas, N. M. Bornstein, D. Schmitz, M. W. Lammers, A. de Louw, R. J. S. Wise, P. A. van Darn, C. Antozzi, P. Villanueva, P. H. E. Hilkens, C. Constantin, W. Ricart, A. Wolf, M. Gamba, P. Maguire, Alessandro Padovani, B. M. Patten, Marie Sarazin, H. Ackermann, L. Durelli, S. Timsit, Sebastian Jander, B. W. Scheithauer, G. Demir, J. P. Neau, P. Barbanti, A. Brand, N. AraÇ, V. Fischer-Gagnepain, R. Marchioli, G. Serratrice, C. Maugard-Louboutin, G. T. Spencer, D. Lücke, G. Mainardi, K. Harmant Van Rijckevorsel, G. B. Creel, R. Manzanares, Francesco Fortunato, A. May, J. Workman, K. Johkura, E. Fernandez, Carlo Colosimo, L. Calliauw, L. Bet, Félix F. Cruz-Sánchez, M. Dhib, H. Meinardi, F. Carrara, J. Kuehnen, C. Peiro, H. Lassmann, K. Skovgaard Olsen, A. McDonald, L. Sciulli, A. Cobo, A. Monticelli, B. Conrad, J. Bagunya, J. Benitez, V. Desnizza, B. Dupont, O. Delrieu, D. Moraes, J. J. Heimans, F. Garcia Rio, M. Matsumto, A. Fernandez, R. Nermni, R. Chalmers, M. J. Marchau, F. Aguado, P. Velupillai, P. J. Martin, P. Tassan, V. Demarin, A. Engelien, T. Gerriets, Comar, J. L. Carrasco, J. P. Pruvo, A. Lopez de Munain, D. Pavitt, J. Alarcon, Chris H. Polman, B. Guldin, N. Yeni, Hartmut Brückmann, N. Wilczak, H. Szwed, R. Causaran, G. Kyriazis, M. E. Westarp, M. Gasparini, N. Pecora, J. M. Roda, E. Lang, V. Scaioli, David R. Fish, D. Caputo, O. Gratzl, R. Mercelis, A. Perretti, G. Steimetz, I. Link, C. Rigoletto, A. Catafau, G. Lucotte, M. Buti, G. Fagiolari, A. Piqueras, C. Godinot, J. C. Meurice, Erodriguez J. Dominigo, F. Lionnet, H. Grzelec, David J. Brooks, P. M. G. Munro, F. X. Weilbach, M. Maiwald, W. Split, B. Widjaja-Cramer, V. Ozturk, J. Colas, E. Brizioli, J. Calleja, L. Publio, M. Desi, R. Soffietti, P. Cortinovis-Tourniaire, E. F. Gonano, G. Cavaletti, S. Uselli, K. Westerlind, H. Betuel, C. O. Dhiver, H. Guggenheim, M. Hamon, R. Fazio, P. Lehikoinen, A. Esser, B. Sadzot, G. Fink, Angelo Antonini, D. Bendahan, V. Di Carlo, G. Galardi, A. F. Boller, M. Aksenova, Del Fiore, V. de la Sayette, H. Chabriat, A. Nicoletti, A. Dilouya, M. L. Harpin, E. Rouillet, J. Stam, A. Wolters, M. R. Delgado, Eduardo Tolosa, G. Said, A. J. Lees, L. Rinaldi, A. Schulze-Bonhage, MA Ron, C. Lefebvre, E. W. Radü, R. Alvarez, M. L. Bots, P. Reganati, S. Palazzi, A. Poggi, N. J. Scolding, V. Sazdovitch, T. Moreau, E. Maes, M. A. Estelies, P. Petkova, Jose-Felix Marti-Masso, G De La Meilleure, N. Mullatti, M. Rodegher, N. C. Notermans, T. A. T. Warner, S. Aktan, J. P. Louboutin, L. Volpe, C. Scheidt, W. Aust, C. M. Wiles, U. Schneider, S. K. Braekken, W. R. Willems, K. Usuku, Peter M. Rothwell, C. Talamon, M. L. Sacchetti, A. Codina, M. H. Marion, A. Santoro, J. Roda, A. Bordoni, D. J. Taylor, S. Ertas, H. H. Emmen, J. Vichez, V. BesanÇon, R. E. Passingham, M. L. Malosio, A. Vérier, M. Bamberg, A. W. Hansen, E. Mostacero, G. Gaudriault, Marie Vidailhet, B. Birebent, K. Strijckmans, F. Giannini, T. Kammer, I. Araujo, J. Nowicki, E. Nikolov, A. Hutzelmann, R. Gherardi, J. Verroust, L. Austoni, A. Scheller, A. Vazquez, S. Matheron, H. Holthausen, J. M. Gerard, M. Bataillard, S. Dethy, V. H. Patterson, V. Ivanez, N. P. Hirsch, F. Ozer, M. Sutter, C. Jacomet, M. Mora, Bruno Colombo, A. Sarropoulos, T. H. Papapetropoulos, M. Schwarz, D. S. Dinner, N. Acarin, B. Iandolo, J. O. Riis, P. R. J. Barnes, F. Taroni, J. Kazenwadel, L. Torre, A. Lugaresi, I. L. Henriques, S. Pauli, S. Alfonso, Pedro Quesada, A. S. T. Planting, J. M. Castilla, Thomas Gasser, M. Van der Linden, A. Alfaro, E. Nobile-Orazio, G. Popova, W. Vaalburg, F. G. A. van der Mech, L. Williams, F. Medina, J. P. Vernant, J. Yaouanq, B. Storch-Hagenlocher, A. Potemkowski, R. Riva, M. H. Mahagne, M. Ozturk, Ve. Drory, N. Konic, C. Jungreis, A. Pou Serradell, J. L. Gauvrit, G. J. Chelune, S. Hermandez, T. Dingus, L. Hewer, Ch. Koch, M. N. Metz-Lutz, G. Parlato, M. Sinaki, Charles Pierrot-Deseilligny, H. C. Diener, J. Broeckx, J. Weill-Fulazza, M. L. Villar, M. Rizzo, O. Ganslandt, C. Duran, N. A. Fletcher, G. Di Giovacchino, Susan T. Iannaccone, C. Kolig, N. Fabre, H. A. Crockard, Rita Bella, M. Tazir, E. Papagiannuli, K. Overgaard, Emma Ciafaloni, I. Lorenzetti, F. Viader, P. A. H. Millac, I. Montiel, L. H. Visser, M. Palomar, P. L. Murgia, H. Pedersen, Rafael Blesa, S. Seddigh, W. O. Renier, I. Lemahieu, H. M. L. Jansen, L. Rosin, J. Galofre, K. Mattos, M. Pondal, G. M. Hadjigeorgiou, D. Francis, L. Cantin, D. Stegeman, M. Rango, A. B. M. F. Karim, S. Schraff, B. Castellotti, I. Iriarte, E. Laborde, T. J. Tjan, R. Mutani, D. Toni, B. Bergaasco, J. G. Young, C. Klotzsch, A. Zincone, X. Ducrocq, M. Uchuya, O. J. Kolar, A. Quattrone, T. Bauermann, Nereo Bresolin, J. Vallée, B. C. Jacobs, A. Campos, Werner Poewe, J. A. Villanueva, A. W. Kornhuber, A. Malafosse, E. Diez-Tejedor, G. Jungreia, M. J. A. Puchner, A. Komiyama, O. Saribas, V. Volpini, L. Geremia, S. Bressi, A. Nibbio, Timothy E. Bates, T. z. Tzonev, E. Ideman, G. A. Damlacik, G. Martino, G. Crepaldi, T. Martino, Kjell Någren, E. Idiman, D. Samuel, J. M. Perez Trullen, Y. van der Graaf, J. O. Thorell, M. J. M. Dupuis, E. Sieber, R. D'Alessandro, C. Cazzaniga, J. Faiss, A. Tanguy, A. Schick, I. Hoksergen, A. Cardozo, R. Shakarishvili, G. K. Wennlng, J. L. Marti-Vilalta, J. Weissenbach, I. L. Simone, Amalia C. Bruni, Darius J. Adams, C. Weiller, A. Pietrangeli, F. Croria, C. Vigo-Pelfrey, Patricia Limousin, A. Ducros, G. Conti, O. Lindvall, E. Richter, M. Zuffi, A. Nappo, T. Riise, J. Wijdenes, M. J. Fernandez, J. Rosell, P. Vermersh, S. Servidei, M. S. C. Verdugo, F. Gouttiere, W. Solbach, M. Malbezin, I. S. Watanabe, A. Tumac, W. I. McDonald, D. A. Butterfield, P. P. Costa, F. deRino, F. Bamonti, J. M. Cesar, C. H. Lahoz, I. Mosely, M. Starck, M. H. Lemaitre, K. M. Stephan, S. Tex, R. Bokonjic, I. Mollee, L. Pastena, M. Gutierrez, F. Boiler, M. C. Martinez-Para, M. Velicogna, O. Obuz, A. Grinspan, M. Guarino, L. M. Cartier, E. Ruiz, D. Gambi, S. Messina, M. Villa, Michael G. Hanna, J. Valk, Leone Pascual, M. Clanet, Z. Argov, B. Ryniewicz, E. Magni, B. Berlanga, K. S. Wong, C. Gellera, C. Prevost, F. Gonzalez-Huix, R. Petraroli, J. E. G. Benedikz, I. Kojder, C. Bommelaer, L. Perusse, M. R. Bangioanni, Guy M. McKhann, A. Molina, C. Fresquet, E. Sindern, Florence Pasquier, M. J. Rosas, M. Altieri, O. Simoncini, M. Koutroumanidis, C. A. F. Tulleken, M. Dary-Auriol, S. Oueslati, H. Kruyer, I. Nishisho, C. R. Horning, A. Vital, G. V. Czettritz, J. Ph. Neau, B. Mihout, A. Ameri, M. Francis, S. Quasthoff, D. Taussig, S. Blunt, P. Valentin, C. Y. Gao, O. Heinzlef, H. d'Allens, C. Coudero, M. Erfas, G. Borghero, P. J. Modrego Pardo, M. C. Patrosso, N. L. Gershfeld, P. A. J. M. Boon, O. Sabouraud, M. Lara, J. Svennevig, G. L. Lenzi, A. Barrio, H. Villaroya, JosÇ M. Manubens, O. Boespflug-Tanguy, M. Carreras, D. A. Costiga, J. P. Breux, S. Lynn, C. Oliveras Ley, A. G. Herbaut, J. Nos, C. Tornali, Y. A. Hekster, J. L. Chopard, J. M. Manubens, P. Chemouilli, A. Jovicic, F. Dworzak, S. Smirne, S. E. Soudain, B. Gallano, D. Lubach, G. Masullo, G. Izquierdo, A. Pascual Leone Pascual, A. Sessa, V. Freitas, O. Crambes, L. Ouss, G. W. Van Dijk, P. Marchettini, P. Confalonieri, M. Donaghy, A. Munnich, M. Corbo, and M. E. L. van der Burg
Subjects: Neurology, business.industry, Media studies, Library science, Medicine, Neurology (clinical), business
Published: 1994
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16. Tetrahydrobiopterin therapy for phenylketonuria in infants and young children

Author: John I. Malone, Kayt D. Marra, Barbara K. Burton, Darius J. Adams, Laurie Sprietsma, Kathleen T. Swan, Elaina Jurecki, Heather Bausell, and Dorothy K. Grange
Subjects: Male, medicine.medical_specialty, Pediatrics, Side effect, Phenylalanine hydroxylase, Phenylalanine, Blood phenylalanine, Diet Records, Internal medicine, Phenylketonurias, medicine, Humans, In patient, biology, business.industry, Patient Selection, Infant, Tetrahydrobiopterin, Biopterin, Endocrinology, Treatment Outcome, El Niño, Child, Preschool, Pediatrics, Perinatology and Child Health, biology.protein, Female, business, medicine.drug
Abstract: Objective To describe patient selection, treatment administration, response evaluation, and side effect management associated with sapropterin therapy in infants and children aged Study design Six case reports are presented from 4 US metabolic clinics treating phenylketonuria with sapropterin in patients aged 7 months to 4 years. Outcomes included blood phenylalanine (Phe) levels before and during treatment. For 3 of 6 cases, diet records were used to monitor changes in dietary Phe. Results Severity of phenylketonuria ranged from mild to severe (classic). Treatment with sapropterin was safe and generally well tolerated. Blood Phe levels were reduced, or maximum dietary Phe tolerance was increased in patients with blood Phe that was well controlled by diet. Conclusions Given the increasing evidence that maintaining blood Phe levels below 360 μmol/L is important for the normal development of neurocognitive and behavioral function, sapropterin can be combined with a Phe-restricted diet to control blood Phe levels in young patients responsive to sapropterin therapy.
Published: 2010

17. Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects

Author: Joyce A. Kobori, Fernando Scaglia, Ayman W. El-Hattab, Erica Wahl, Joseph J. Shen, Lee-Jun C. Wong, Berkley R. Powell, Brett H. Graham, Erawati V. Bawle, Darius J. Adams, and Fangyuan Li
Subjects: Adult, medicine.medical_specialty, Organic Cation Transport Proteins, Physiology, SLC22A5, Asymptomatic, Infant, Newborn, Diseases, Neonatal Screening, Pregnancy, Internal medicine, Carnitine, Systemic primary carnitine deficiency, medicine, Humans, Mass Screening, Family, Solute Carrier Family 22 Member 5, Maternal-Fetal Exchange, Genetics (clinical), Mass screening, Newborn screening, biology, Infant, Newborn, Infant, medicine.disease, Endocrinology, Child, Preschool, Mutation, biology.protein, Female, medicine.symptom, Primary Carnitine Deficiency, medicine.drug
Abstract: Background: Systemic primary carnitine deficiency is an autosomal recessive disorder of the carnitine cycle caused by mutations in the SLC22A5 gene that encodes the carnitine transporter, organic cation transporter. Systemic primary carnitine deficiency typically presents in childhood with either metabolic decompensation or cardiomyopathy. We report five families in which low free carnitine levels in the infants’ newborn screening have led to the diagnosis of maternal systemic primary carnitine deficiency. Methods: Blood samples from the infants and /or their family members were used to extract the DNA. The entire coding regions of the SLC22A5 gene were sequenced. The clinical data were obtained from the referring metabolic specialists. Result: Sequencing the SLC22A5 gene allowed molecular confirmation with identification of three novel mutations: c.1195CT (p.R399W), c.1324_1325GCAT (p.A442I), and c.43GT (p.G15W). All infants were asymptomatic at the time of diagnosis, and one was found to have systemic primary carnitine deficiency. Three mothers are asymptomatic, one had decreased stamina during pregnancy, and one has mild fatigability and developed preeclampsia. Discussion: These findings provide further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from a metabolic decompensation in infancy to an asymptomatic adult. The maternal systemic primary carnitine deficiency was uncovered by the newborn screening results supporting the previous notion that newborn screening can identify some of the maternal inborn errors of metabolism. It also emphasizes the importance of maternal evaluation after identification of a low free carnitine level in the newborn screening. Genet Med 2010:12(1):19–24.
Published: 2009

18. Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State

Author: Patricia Galvin-Parton, Matthew Nichols, Melissa P. Wasserstein, Joan E. Pellegrino, Richard W. Erbe, David Kronn, Shideh Mofidi, Paul A. Levy, Carlos A. Saavedra-Matiz, Darius J. Adams, Ellen DeVincentis, Georgianne L. Arnold, and Michele Caggana
Subjects: Male, Pediatrics, medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, New York, Hypoglycemia, Biochemistry, Asymptomatic, Lethargy, Endocrinology, Neonatal Screening, Acyl-CoA Dehydrogenases, Carnitine, Genetics, medicine, Humans, Sibling, Molecular Biology, Newborn screening, business.industry, Hypoketotic hypoglycemia, Fatty Acids, Infant, Newborn, Medium-Chain Acyl-CoA Dehydrogenase Deficiency, medicine.disease, Prognosis, Phenotype, Mutation, Female, medicine.symptom, business, Metabolism, Inborn Errors
Abstract: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome.All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms.We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p0.012). Four infants had initial C8 level30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985AG mutation was rarely found in non-Caucasians.No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.
Published: 2009

19. Newborn screening for Krabbe disease: the New York State model

Author: Darius J. Adams, Emma Ciafaloni, David A. Wenger, Joseph J. Orsini, Jill Miller-Horn, David Kronn, Stanley J. Rothman, Marc C. Patterson, Joanne Kurtzberg, Mary R. Andriola, Patricia Galvin-Parton, Maria L. Escolar, Laura Helton, James M. Provenzale, Alexandra Djukic, Michele Caggana, Jennifer M. Kwon, Paul A. Levy, Georgianne L. Arnold, Patricia K. Duffner, Barry E. Kosofsky, Melissa P. Wasserstein, Joan E. Pellegrino, Richard W. Erbe, Carl J. Crosley, Edwin H. Kolodny, Thomas P. Naidich, and Alan M. Aron
Subjects: Gerontology, Pediatrics, medicine.medical_specialty, medicine.medical_treatment, DNA Mutational Analysis, Neural Conduction, New York, Disease, Hematopoietic stem cell transplantation, Risk Assessment, Degenerative disease, Neonatal Screening, Developmental Neuroscience, Galactosylceramidase, medicine, Evoked Potentials, Auditory, Brain Stem, Humans, Sphingolipidosis, Referral and Consultation, Neurologic Examination, Newborn screening, business.industry, Hematopoietic Stem Cell Transplantation, Infant, Newborn, medicine.disease, Magnetic Resonance Imaging, Leukodystrophy, Globoid Cell, Transplantation, Treatment Outcome, Neurology, Models, Organizational, Pediatrics, Perinatology and Child Health, Krabbe disease, Evoked Potentials, Visual, Neurology (clinical), business, Follow-Up Studies
Abstract: Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.
Published: 2008

20. Specific Congenital Metabolic Disorders

Author: Angel Rios and Darius J. Adams
Subjects: business.industry, Medicine, business
Published: 2008
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21. Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy

Author: Kevin E. Bove, Erin E. Baldwin, Charles L. Hoppel, Nancy D. Leslie, Darius J. Adams, Beverly B. Dahms, Nada Yazigi, Ignacio Gonzalez-Gomez, Eric S. Schmitt, Jing Wang, Qing Zhang, Douglas S. Kerr, Lee-Jun C. Wong, Michelle Puchowicz, Nicola Brunetti-Pierri, Ping Chieh Chou, Richard G. Boles, Cavatina K. Truong, and William J. Craigen
Subjects: Male, medicine.medical_specialty, Pathology, Mitochondrial DNA, Biology, DGUOK, medicine.disease_cause, DNA, Mitochondrial, White People, Internal medicine, medicine, Humans, Genetic Testing, MPV17, Inner mitochondrial membrane, Pathological, Mutation, Hepatology, Infant, Newborn, Infant, Membrane Proteins, Hispanic or Latino, medicine.disease, Texas, Pedigree, Electron Transport Chain Complex Proteins, Liver, Mitochondrial DNA depletion syndrome, Cancer research, Disease Progression, Female, Liver Failure
Abstract: MPV17 is a mitochondrial inner membrane protein of unknown function recently recognized as responsible for a mitochondrial DNA depletion syndrome. The aim of this study is to delineate the specific clinical, pathological, biochemical, and molecular features associated with mitochondrial DNA depletion due to MPV17 gene mutations. We report 4 cases from 3 ethnically diverse families with MPV17 mutations. Importantly, 2 of these cases presented with isolated liver failure during infancy without notable neurologic dysfunction. Conclusion: We therefore propose that mutations in the MPV17 gene be considered in the course of evaluating the molecular etiology for isolated, rapidly progressive infantile hepatic failure. (HEPATOLOGY 2007.)
Published: 2007

22. Recognizing the clinical features of Trisomy 13 syndrome

Author: David A. Clark, Darius J. Adams, Angel Rios, and Susan A Furdon
Subjects: Pediatrics, medicine.medical_specialty, Numerical Chromosomal Abnormality, Trisomy 13 Syndrome, Prenatal diagnosis, Chromosome Disorders, Trisomy, Prosencephalon, Holoprosencephaly, Pregnancy, Prenatal Diagnosis, Medicine, Humans, Abnormalities, Multiple, Genetic testing, Chromosome Aberrations, medicine.diagnostic_test, Chromosomes, Human, Pair 13, business.industry, Genetic disorder, Infant, Newborn, General Medicine, Syndrome, medicine.disease, Prognosis, Magnetic Resonance Imaging, Pediatrics, Perinatology and Child Health, Female, Abnormality, business
Abstract: Recognition of the clinical features of Trisomy 13 syndrome, a common autosomal trisomy, provides the basis for diagnostic testing and counseling of families. This article provides a systematic guide to physical assessment and photographs to enhance recognition of this genetic disorder. The principles of numerical chromosomal abnormalities as related to trisomies are reviewed. An abnormal development of the forebrain, holoprosencephaly, is the most common cranial abnormality in infants with Trisomy 13. The embryology and implications of holoprosencephaly are described. A discussion of antenatal diagnosis of Trisomy 13 and delivery room management is also provided. The diagnosis of Trisomy 13 is confirmed antenatally or after delivery with genetic testing. Prognosis of infants with Trisomy 13 and implications for the infants development are described.
Published: 2004

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22 results on '"Darius J. Adams"'

1. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients

2. Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

3. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

4. The infantile neuroaxonal dystrophy rating scale (INAD-RS)

5. Phenom: a prospective clinical study on the clinical impact of phenylketonuria in adults (307–902)

6. GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

7. Treatment of infantile neuroaxonal dystrophy with RT001: A di-deuterated ethyl ester of linoleic acid: Report of two cases

8. Phenotype delineation of ZNF462 related syndrome

9. Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features

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

11. Newborn screening for X-linked adrenoleukodystrophy in New York State: Diagnostic protocol, surveillance protocol and treatment guidelines

12. An Absence of Cutaneous Neurofibromas Associated with a 3-bp Inframe Deletion in Exon 17 of the NF1 Gene (c.2970-2972 delAAT): Evidence of a Clinically Significant NF1 Genotype-Phenotype Correlation

13. Newborn screening for Krabbe disease in New York State: the first eight years' experience

14. Common genetic and epigenetic syndromes

15. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain

16. Tetrahydrobiopterin therapy for phenylketonuria in infants and young children

17. Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects

18. Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State

19. Newborn screening for Krabbe disease: the New York State model

20. Specific Congenital Metabolic Disorders

21. Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy

22. Recognizing the clinical features of Trisomy 13 syndrome

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22 results on '"Darius J. Adams"'

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