Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.
N-linked glycosylation
congenital disorders of glycosylation
epilepsy
whole exome sequencing
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
21
05
2020
revised:
03
07
2020
accepted:
09
07
2020
pubmed:
19
7
2020
medline:
8
10
2021
entrez:
19
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32681751
doi: 10.1002/jimd.12290
pmc: PMC7722193
mid: NIHMS1636829
doi:
Substances chimiques
Biomarkers
0
Transferrin
0
ALG13 protein, human
EC 2.4.1.-
N-Acetylglucosaminyltransferases
EC 2.4.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1333-1348Subventions
Organisme : NINDS NIH HHS
ID : U54 NS115198
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007708
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG010218
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006493
Pays : United States
Organisme : Medical Research Council
ID : MR/S007180/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK099551
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
Informations de copyright
© 2020 SSIEM.
Références
Ann Hum Genet. 2018 Jan;82(1):35-47
pubmed: 28940310
Hum Mol Genet. 2012 Oct 1;21(19):4151-61
pubmed: 22492991
Epilepsia Open. 2017 May 04;2(2):236-243
pubmed: 29588952
Brain Dev. 2016 Mar;38(3):285-92
pubmed: 26482601
Brain. 2013 Mar;136(Pt 3):944-56
pubmed: 23404334
Epilepsy Res. 2015 Jan;109:81-9
pubmed: 25524846
Hum Mutat. 2016 Jul;37(7):653-60
pubmed: 26931382
Seizure. 2016 Feb;35:83-7
pubmed: 26803281
Clin Genet. 2016 Feb;89(2):198-204
pubmed: 26138355
J Biol Chem. 2007 Oct 5;282(40):29081-8
pubmed: 17686769
Neuroscience. 2019 Jun 15;409:204-221
pubmed: 30872163
JIMD Rep. 2018;40:11-16
pubmed: 28887793
Mol Cell Proteomics. 2013 Mar;12(3):825-31
pubmed: 23266961
Hum Mol Genet. 2014 Sep 15;23(18):4846-58
pubmed: 24781210
Nature. 2013 Sep 12;501(7466):217-21
pubmed: 23934111
Am J Hum Genet. 2018 Oct 4;103(4):553-567
pubmed: 30290151
J Biol Chem. 2005 Oct 28;280(43):36254-62
pubmed: 16100110
Clin Chem. 2001 Mar;47(3):513-8
pubmed: 11238305
JIMD Rep. 2015;22:95-8
pubmed: 25732998
Genet Med. 2019 Nov;21(11):2496-2503
pubmed: 31056551
Yeast. 2002 Mar 15;19(4):351-71
pubmed: 11870858
Neurology. 2017 Aug 15;89(7):657-664
pubmed: 28733338
Front Neurol. 2019 May 21;10:434
pubmed: 31164858
Eur J Med Genet. 2017 Oct;60(10):541-547
pubmed: 28778787
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):845-9
pubmed: 12538870
Dev Med Child Neurol. 2020 May;62(5):581-586
pubmed: 31850517
Nature. 2017 Feb 23;542(7642):433-438
pubmed: 28135719
J Biol Chem. 2008 Nov 21;283(47):32534-41
pubmed: 18809682
Epilepsy Behav. 2016 Mar;56:50-3
pubmed: 26828692
Indian J Pediatr. 2019 Nov;86(11):1072-1073
pubmed: 31444733
PLoS One. 2017 Nov 30;12(11):e0188978
pubmed: 29190809
Pediatr Neurol. 2020 Jul;108:54-64
pubmed: 32305143
J Inherit Metab Dis. 2017 Mar;40(2):195-207
pubmed: 28108845
J Biol Chem. 2005 Oct 14;280(41):34500-6
pubmed: 16100113
Epilepsia. 1983 Apr;24(2):135-58
pubmed: 6299719
Brain Dev. 2001 Nov;23(7):539-41
pubmed: 11701251
Trends Genet. 2018 Jun;34(6):466-476
pubmed: 29606283
Cell. 2013 Jul 3;154(1):169-84
pubmed: 23827681
N Engl J Med. 2012 Nov 15;367(20):1921-9
pubmed: 23033978
JIMD Rep. 2019;44:85-92
pubmed: 30117111
Protein Pept Lett. 2013 Sep;20(9):1002-8
pubmed: 22973843
Structure. 2008 Jun;16(6):965-75
pubmed: 18547528
Mol Biol Cell. 2008 May;19(5):2169-78
pubmed: 18337470