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https://ahro.austin.org.au/austinjspui/handle/1/27731| Title: | Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions. | Austin Authors: | Ng, Bobby G;Eklund, Erik A;Shiryaev, Sergey A;Dong, Yin Y;Abbott, Mary-Alice;Asteggiano, Carla;Bamshad, Michael J;Barr, Eileen;Bernstein, Jonathan A;Chelakkadan, Shabeed;Christodoulou, John;Chung, Wendy K;Ciliberto, Michael A;Cousin, Janice;Gardiner, Fiona;Ghosh, Suman;Graf, William D;Grunewald, Stephanie;Hammond, Katherine;Hauser, Natalie S;Hoganson, George E;Houck, Kimberly M;Kohler, Jennefer N;Morava, Eva;Larson, Austin A;Liu, Pengfei;Madathil, Sujana;McCormack, Colleen;Meeks, Naomi J L;Miller, Rebecca;Monaghan, Kristin G;Nickerson, Deborah A;Palculict, Timothy Blake;Papazoglu, Gabriela Magali;Pletcher, Beth A;Scheffer, Ingrid E ;Schenone, Andrea Beatriz;Schnur, Rhonda E;Si, Yue;Rowe, Leah J;Serrano Russi, Alvaro H;Russo, Rossana Sanchez;Thabet, Farouq;Tuite, Allysa;Villanueva, María Mercedes;Wang, Raymond Y;Webster, Richard I;Wilson, Dorcas;Zalan, Alice;Wolfe, Lynne A;Rosenfeld, Jill A;Rhodes, Lindsay;Freeze, Hudson H | Affiliation: | Department of Medicine, Columbia University, New York, New York, USA Department of Pediatrics, Columbia University, New York, New York, USA Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA Department of Pediatrics, Rutgers New Jersey Medical School, Newark, New Jersey, USA Department of Genome Sciences, University of Washington, Seattle, Washington, USA Department of Pediatrics, University of Washington, Seattle, Washington, USA Department of Pediatrics, Baystate Children's Hospital, University of Massachusetts Medical School - Baystate, Springfield, Massachusetts, USA Department of Human Genetics, Emory University, Atlanta, Georgia, USA Monash Children's Hospital, Melbourne, Australia GeneDx, Inc. Laboratory, Gaithersburg, Maryland, USA Baylor Genetics Laboratories, Houston, Texas, USA Inova Translational Medicine Institute Division of Medical Genomics Inova Fairfax Hospital Falls Church, Virginia, USA MercyOne Pediatric Neurology, Des Moines, Iowa, USA Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA Department of Pediatrics, University of California-Irvine, Orange, California, USA Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California, USA Keck School of Medicine, University of Southern California, Los Angeles, California, USA Division of Medical Genetics Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA Stanford University School of Medicine, Stanford, California, USA Chair of Pharmacology, Catholic University of Cordoba, Cordoba, Argentina, USA CEMECO-CONICET, Children Hospital, School of Medicine, National University of Cordoba, Cordoba, Argentina Department of Clinical Sciences, Lund, Pediatrics, Lund University, Lund, Sweden, USA Human Genetics Program, Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA Kids Neuroscience Centre, The Children's Hospital, Westmead, Australia T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital, Westmead, Australia Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Division of Pediatric Neurology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA Division of Pediatric Neurology, Department of Pediatrics, Connecticut Children's; University of Connecticut, Farmington, Connecticut, USA Department of Pediatrics Division of Pediatric Neurology, University of Florida College of Medicine, Gainesville, Florida, USA Section of Human Biochemical Genetics, National Human Genome Research Institute, Bethesda, Maryland, USA Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland, USA Nelson Mandela Children's Hospital, Johannesburg, South Africa, USA Netcare Sunninghill Hospital, Sandton, South Africa Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, USA University of Melbourne, Royal Children's Hospital, Florey and Murdoch Institutes, Melbourne, Australia Austin Health Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia Department of Paediatrics, University of Melbourne, Melbourne, Australia Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK, USA Metabolic Medicine Department, Great Ormond Street Hospital, Institute of Child Health University College London, NIHR Biomedical Research Center, London, UK, USA CEMECO-CONICET, Children Hospital, School of Medicine, National University of Cordoba, Cordoba, Argentina, USA Laboratorio de Neuroquimica "Dr. N. A. Chamoles"-FESEN, Buenos Aires, Argentina, USA |
Issue Date: | Nov-2020 | Date: | 2020-08-05 | Publication information: | Journal of Inherited Metabolic Disease 2020; 43(6): 1333-1348 | Abstract: | Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/27731 | DOI: | 10.1002/jimd.12290 | ORCID: | 0000-0003-0649-848X | Journal: | Journal of Inherited Metabolic Disease | PubMed URL: | 32681751 | Type: | Journal Article | Subjects: | N-linked glycosylation congenital disorders of glycosylation epilepsy whole exome sequencing |
| Appears in Collections: | Journal articles |
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