Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

Bobby G Ng; Erik A Eklund; Sergey A Shiryaev; Yin Y Dong; Mary-Alice Abbott; Carla Asteggiano; Michael J Bamshad; Eileen Barr; Jonathan A Bernstein; Shabeed Chelakkadan; John Christodoulou; Wendy K Chung; Michael A Ciliberto; Janice Cousin; Fiona Gardiner; Suman Ghosh; William D Graf; Stephanie Grunewald; Katherine Hammond; Natalie S Hauser; George E Hoganson; Kimberly M Houck; Jennefer N Kohler; Eva Morava; Austin A Larson; Pengfei Liu; Sujana Madathil; Colleen McCormack; Naomi J L Meeks; Rebecca Miller; Kristin G Monaghan; Deborah A Nickerson; Timothy Blake Palculict; Gabriela Magali Papazoglu; Beth A Pletcher; Ingrid E Scheffer; Andrea Beatriz Schenone; Rhonda E Schnur; Yue Si; Leah J Rowe; Alvaro H Serrano Russi; Rossana Sanchez Russo; Farouq Thabet; Allysa Tuite; María Mercedes Villanueva; Raymond Y Wang; Richard I Webster; Dorcas Wilson; Alice Zalan; Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics (UW-CMG); Lynne A Wolfe; Jill A Rosenfeld; Lindsay Rhodes; Hudson H Freeze

doi:10.1002/jimd.12290

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

J Inherit Metab Dis. 2020 Nov;43(6):1333-1348. doi: 10.1002/jimd.12290. Epub 2020 Aug 5.

Authors

Bobby G Ng¹, Erik A Eklund^{1

2}, Sergey A Shiryaev¹, Yin Y Dong³, Mary-Alice Abbott⁴, Carla Asteggiano^{5

6}, Michael J Bamshad^{7

8}, Eileen Barr⁹, Jonathan A Bernstein^{10

11}, Shabeed Chelakkadan¹², John Christodoulou^{13

14

15}, Wendy K Chung^{16

17}, Michael A Ciliberto¹⁸, Janice Cousin¹⁹, Fiona Gardiner²⁰, Suman Ghosh²¹, William D Graf²², Stephanie Grunewald²³, Katherine Hammond²⁴, Natalie S Hauser²⁵, George E Hoganson²⁶, Kimberly M Houck²⁷, Jennefer N Kohler^{10

28}, Eva Morava²⁹, Austin A Larson³⁰, Pengfei Liu^{31

32}, Sujana Madathil¹⁸, Colleen McCormack^{10

28}, Naomi J L Meeks³⁰, Rebecca Miller²⁵, Kristin G Monaghan³³, Deborah A Nickerson⁸, Timothy Blake Palculict³³, Gabriela Magali Papazoglu⁵, Beth A Pletcher³⁴, Ingrid E Scheffer^{20

35}, Andrea Beatriz Schenone³⁶, Rhonda E Schnur³³, Yue Si³³, Leah J Rowe³⁰, Alvaro H Serrano Russi^{37

38}, Rossana Sanchez Russo⁹, Farouq Thabet³⁹, Allysa Tuite³⁴, María Mercedes Villanueva³⁶, Raymond Y Wang^{40

41}, Richard I Webster^{42

43}, Dorcas Wilson^{44

45}, Alice Zalan²⁶; Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics (UW-CMG); Lynne A Wolfe⁴⁶, Jill A Rosenfeld^{31

32}, Lindsay Rhodes³³, Hudson H Freeze¹

Affiliations

¹ Human Genetics Program, Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
² Department of Clinical Sciences, Lund, Pediatrics, Lund University, Lund, Sweden.
³ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁴ Department of Pediatrics, Baystate Children's Hospital, University of Massachusetts Medical School - Baystate, Springfield, Massachusetts, USA.
⁵ CEMECO-CONICET, Children Hospital, School of Medicine, National University of Cordoba, Cordoba, Argentina.
⁶ Chair of Pharmacology, Catholic University of Cordoba, Cordoba, Argentina.
⁷ Department of Pediatrics, University of Washington, Seattle, Washington, USA.
⁸ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
⁹ Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
¹⁰ Stanford University School of Medicine, Stanford, California, USA.
¹¹ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA.
¹² Monash Children's Hospital, Melbourne, Australia.
¹³ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
¹⁴ Department of Paediatrics, University of Melbourne, Melbourne, Australia.
¹⁵ Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, Australia.
¹⁶ Department of Pediatrics, Columbia University, New York, New York, USA.
¹⁷ Department of Medicine, Columbia University, New York, New York, USA.
¹⁸ Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
¹⁹ Section of Human Biochemical Genetics, National Human Genome Research Institute, Bethesda, Maryland, USA.
²⁰ University of Melbourne, Austin Health, Melbourne, Australia.
²¹ Department of Pediatrics Division of Pediatric Neurology, University of Florida College of Medicine, Gainesville, Florida, USA.
²² Division of Pediatric Neurology, Department of Pediatrics, Connecticut Children's; University of Connecticut, Farmington, Connecticut, USA.
²³ Metabolic Medicine Department, Great Ormond Street Hospital, Institute of Child Health University College London, NIHR Biomedical Research Center, London, UK.
²⁴ Division of Pediatric Neurology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁵ Inova Translational Medicine Institute Division of Medical Genomics Inova Fairfax Hospital Falls Church, Virginia, USA.
²⁶ Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, USA.
²⁷ Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
²⁸ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
²⁹ Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.
³⁰ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
³¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
³² Baylor Genetics Laboratories, Houston, Texas, USA.
³³ GeneDx, Inc. Laboratory, Gaithersburg, Maryland, USA.
³⁴ Department of Pediatrics, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
³⁵ University of Melbourne, Royal Children's Hospital, Florey and Murdoch Institutes, Melbourne, Australia.
³⁶ Laboratorio de Neuroquimica "Dr. N. A. Chamoles"-FESEN, Buenos Aires, Argentina.
³⁷ Division of Medical Genetics Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA.
³⁸ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
³⁹ MercyOne Pediatric Neurology, Des Moines, Iowa, USA.
⁴⁰ Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California, USA.
⁴¹ Department of Pediatrics, University of California-Irvine, Orange, California, USA.
⁴² T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital, Westmead, Australia.
⁴³ Kids Neuroscience Centre, The Children's Hospital, Westmead, Australia.
⁴⁴ Netcare Sunninghill Hospital, Sandton, South Africa.
⁴⁵ Nelson Mandela Children's Hospital, Johannesburg, South Africa.
⁴⁶ Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland, USA.

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.

Keywords: N-linked glycosylation; congenital disorders of glycosylation; epilepsy; whole exome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Child, Preschool
Congenital Disorders of Glycosylation / diagnosis
Congenital Disorders of Glycosylation / genetics*
Diet, Ketogenic
Female
Glycosylation
Humans
Infant
Male
Mutation
N-Acetylglucosaminyltransferases / chemistry
N-Acetylglucosaminyltransferases / deficiency*
N-Acetylglucosaminyltransferases / genetics*
Spasms, Infantile / diagnosis
Spasms, Infantile / genetics*
Transferrin / metabolism

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

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