TY - JOUR
T1 - Predominant and novel de novo variants in 29 individuals with ALG13 deficiency
T2 - Clinical description, biomarker status, biochemical analysis, and treatment suggestions
AU - Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics (UW-CMG)
AU - Ng, Bobby G.
AU - Eklund, Erik A.
AU - Shiryaev, Sergey A.
AU - Dong, Yin Y.
AU - Abbott, Mary Alice
AU - Asteggiano, Carla
AU - Bamshad, Michael J.
AU - Barr, Eileen
AU - Bernstein, Jonathan A.
AU - Chelakkadan, Shabeed
AU - Christodoulou, John
AU - Chung, Wendy K.
AU - Ciliberto, Michael A.
AU - Cousin, Janice
AU - Gardiner, Fiona
AU - Ghosh, Suman
AU - Graf, William D.
AU - Grunewald, Stephanie
AU - Hammond, Katherine
AU - Hauser, Natalie S.
AU - Hoganson, George E.
AU - Houck, Kimberly M.
AU - Kohler, Jennefer N.
AU - Morava, Eva
AU - Larson, Austin A.
AU - Liu, Pengfei
AU - Madathil, Sujana
AU - McCormack, Colleen
AU - Meeks, Naomi J.L.
AU - Miller, Rebecca
AU - Monaghan, Kristin G.
AU - Nickerson, Deborah A.
AU - Palculict, Timothy Blake
AU - Papazoglu, Gabriela Magali
AU - Pletcher, Beth A.
AU - Scheffer, Ingrid E.
AU - Schenone, Andrea Beatriz
AU - Schnur, Rhonda E.
AU - Si, Yue
AU - Rowe, Leah J.
AU - Serrano Russi, Alvaro H.
AU - Russo, Rossana Sanchez
AU - Thabet, Farouq
AU - Tuite, Allysa
AU - Villanueva, María Mercedes
AU - Wang, Raymond Y.
AU - Webster, Richard I.
AU - Wilson, Dorcas
AU - Zalan, Alice
AU - Wolfe, Lynne A.
N1 - Publisher Copyright:
© 2020 SSIEM
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - N-linked glycosylation
KW - congenital disorders of glycosylation
KW - epilepsy
KW - whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85088987006&partnerID=8YFLogxK
U2 - 10.1002/jimd.12290
DO - 10.1002/jimd.12290
M3 - Article
C2 - 32681751
AN - SCOPUS:85088987006
SN - 0141-8955
VL - 43
SP - 1333
EP - 1348
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 6
ER -