Journal article
Predominant and novel de novo variants in 29 individuals withALG13deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions
Journal of inherited metabolic disease, Vol.43(6), pp.1333-1348
11/01/2020
DOI: 10.1002/jimd.12290
PMCID: PMC7722193
PMID: 32681751
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 inALG13underlie 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 inALG13. 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.
Details
- Title: Subtitle
- Predominant and novel de novo variants in 29 individuals withALG13deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions
- Creators
- Bobby G. Ng - Discovery InstituteErik A. Eklund - Lund UniversitySergey A. Shiryaev - Discovery InstituteYin Y. Dong - University of OxfordMary-Alice Abbott - University of Massachusetts Medical SchoolCarla Asteggiano - National University of CórdobaMichael J. Bamshad - University of WashingtonEileen Barr - Emory UniversityJonathan A. Bernstein - Stanford UniversityShabeed Chelakkadan - Boston Children's HospitalJohn Christodoulou - University of SydneyWendy K. Chung - Columbia UniversityMichael A. Ciliberto - University of IowaJanice Cousin - National Institutes of HealthFiona Gardiner - University of MelbourneSuman Ghosh - University of FloridaWilliam D. Graf - University of ConnecticutStephanie Grunewald - Great Ormond Street HospitalKatherine Hammond - University of Alabama at BirminghamNatalie S. Hauser - Inova Fairfax HospitalGeorge E. Hoganson - University of Illinois at ChicagoKimberly M. Houck - Baylor College of MedicineJennefer N. Kohler - Stanford UniversityEva Morava - Mayo ClinicAustin A. Larson - University of Colorado Anschutz Medical CampusPengfei Liu - Baylor UniversitySujana Madathil - University of IowaColleen McCormack - Stanford UniversityNaomi J. L. Meeks - Univ Colorado, Dept Pediat, Sect Clin Genet & Metab, Anschutz Med Campus, Aurora, CO USARebecca Miller - Inova Fairfax HospitalKristin G. Monaghan - GeneDxDeborah A. Nickerson - University of WashingtonTimothy Blake Palculict - GeneDxGabriela Magali Papazoglu - National University of CórdobaBeth A. Pletcher - Rutgers, The State University of New JerseyIngrid E. Scheffer - University of MelbourneAndrea Beatriz Schenone - Lab Neuroquim Dr NA Chamoles FESEN, Buenos Aires, DF, ArgentinaRhonda E. Schnur - GeneDxYue Si - GeneDxLeah J. Rowe - University of Colorado Anschutz Medical CampusAlvaro H. Serrano Russi - University of Southern CaliforniaRossana Sanchez Russo - Emory UniversityFarouq Thabet - MercyOne Pediat Neurol, Des Moines, IA USAAllysa Tuite - Rutgers, The State University of New JerseyMaria Mercedes Villanueva - Lab Neuroquim Dr NA Chamoles FESEN, Buenos Aires, DF, ArgentinaRaymond Y. Wang - University of California, IrvineRichard Webster - Children's Hospital at WestmeadDorcas Wilson - Boston Children's HospitalAlice Zalan - University of Illinois at ChicagoLynne A. Wolfe - National Institutes of HealthJill A. Rosenfeld - National Institutes of HealthLindsay Rhodes - GeneDxHudson H. Freeze - Discovery InstituteUndiagnosed Diseases NetworkUniversity of Washington Center for Mendelian Genomics (UW-CMG)
- Resource Type
- Journal article
- Publication Details
- Journal of inherited metabolic disease, Vol.43(6), pp.1333-1348
- DOI
- 10.1002/jimd.12290
- PMID
- 32681751
- PMCID
- PMC7722193
- NLM abbreviation
- J Inherit Metab Dis
- ISSN
- 0141-8955
- eISSN
- 1573-2665
- Publisher
- Wiley
- Number of pages
- 16
- Grant note
- U01HG007708; U01HG010218 / NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA National Health and Medical Research Council of Australia NIH/NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) UM1 HG006493; U24 HG008956 / University of Washington Center for Mendelian Genomics through NHLBI March of Dimes Australian Epilepsy Research Fund Intramural Research Program of the National Human Genome Research Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) Health Research Council of New Zealand CURE Biocodex R01DK099551; U54 NS115198 / Rocket Fund, National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Eisai; Eisai Co Ltd Biomarin MR/S007180/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) GlaxoSmithKline SFARI JPB Foundation Region Skane, Sweden UCB; UCB Pharma SA University of Washington Center for Mendelian Genomics through NHGRI
- Language
- English
- Date published
- 11/01/2020
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Neurology (Pediatrics)
- Record Identifier
- 9984303012202771
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