Novel mutation and severe respiratory failure in congenital disorders of glycosylation Type Ix

Congenital glycosylation disorders (CDG) are a group of rare hereditary metabolic diseases that result from abnormal protein and lipid glycosylation. Virtually all organ systems can be affected, and neurological involvement is particularly severe and disabling. More than 100 CDG types have been reported to date and those numbers are rapidly increasing. Each type is very rare, and the clinical characteristics of each subtype are difficult to determine. There are large numbers of biochemically unresolved cases defined as CDG-Ix. In this report, we present a 5-year-old boy who had dysmorphic features, hypotonia, developmental and mental delay, epileptic spasms, recurrent apnea and respiratory failure that led to the diagnosis of an unreported mutation of a rare form of CDG-Ix. This mutation in the STT3B gene affects the catalytic subunit of the oligosaccharyltransferase and the recipient substrate properties, which in part have the same functions in N-glycosylation. A novel homozygous mutation in the STT3B presence of c.38C>G that encodes p.S13W (p.Ser13Trp) was detected with next generation sequencing. The CDG clinical spectrum can be unusual, ranging from dysfunction of certain organs to severe multiple system disorders. Respiratory failure has rarely been reported in these cases. Increased types and numbers of patients constitute symptom variety. The identification of new genes and genotype-phenotype relationships may expand the family of CDG.

PDF

___

1.Freeze HH, Chong JX, Bamshad MJ, Ng BG. Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet 2014; 94: 161-175.

2.Varki A. New and updated glycoscience-related resources at NCBI. Glycobiology 2017; 27: 993.

3.Fang J, Peters V, Assmann B, Körner C, Hoffmann GF. Improvement of CDG diagnosis by combined examination of several glycoproteins. J Inherit Metab Dis 2004; 27: 581-590.

4.Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta 2009; 1792: 825-826.

5.McKenzie FA, Fietz M, Fletcher J, Smith RLL, Wright IMR, Jaeken J. A previously undescribed form of congenital disorder of glycosylation with variable presentation in siblings: early fetal loss with hydrops fetalis, and infant death with hypoproteinemia. Am J Med Genet A 2007; 143A: 2029-2034.

6.Morava E, Wosik H, Kártezi J, et al. Congenital disorder of glycosylation Type Ix: review of clinical spectrum and diagnostic steps. J Inherit Metab Dis 2008; 31: 450-456.

7.Lefeber DJ, Schönberg J, Morava E, et al. Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. Am J Hum Genet 2009; 85: 76-86.

8.Sinha MD, Horsfield C, Komaromy D, Booth CJ, Champion MP. Congenital disorders of glycosylation: a rare cause of nephrotic syndrome. Nephrol Dial Transplant 2009; 24: 2591-2594.

9.Jaeken J, Hennet T, Freeze HH, Matthijs G. On the nomenclature of congenital disorders of glycosylation (CDG). J Inherit Metab Dis 2008; 31: 669-672.

10.Jaeken J. Congenital disorders of glycosilation (CDG): it’s all in it! J Inherit Metab Dis 2003; 26: 99-118.

11.Dupré T, Vuillaumier-Barrot S, Chantret I, et al. Guanosine diphosphate-mannose: GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations. J Med Genet 2010; 47: 729-735.

12.Jiang L, Zhu X, Chen J, Yang D, Zhou C, Hong Z. Two conserved oligosaccharyltransferase catalytic subunits required for N-glycosylation exist in Spartina alterniflora. Bot Stud 2015; 56: 31.

13.Kitajima T, Xue W, Liu YS, et al. Construction of green fluorescence protein mutant to monitor STT3B-dependent N-glycosylation. FEBS J 2018; 285: 915-928.

14.Sato T, Sako Y, Sho M, et al. STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein. Mol Cell 2012; 47: 99-110.

15.Moriconi C, Ordonez A, Lupo G, et al. Interactions between N-linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum. FEBS J 2015; 282: 4565-4579.

16.Shrimal S, Trueman SF, Gilmore R. Extreme C-terminal sites are posttranslocationally glycosylated by the STT3B isoform of the OST. J Cell Biol 2013; 201: 81-95.

17.Shrimal S, Ng BG, Losfeld ME, Gilmore R, Freeze HH. Mutations in STT3A and STT3B cause two congenital disorders of glycosylation. Hum Mol Genet 2013; 22: 4638-4645.

18.Varki A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 1993; 3: 97-130.

19.Rymen D, Jaeken J. Skin manifestations in CDG. J Inherit Metab Dis 2014; 37: 699-708.

20.Sparks SE, Krasnewich DM. Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview. In: GeneReviews® [Internet]. University of Washington, Seattle; 2005.