DDOST-CDG: Clinical and molecular characterization of a third patient with a milder and a predominantly movement disorder phenotype

Ibrahim Elsharkawi, Parith Wongkittichote, Earnest James Paul Daniel, Rodrigo Tzovenos Starosta, Keisuke Ueda, Bobby G. Ng, Hudson H. Freeze, Miao He, Marwan Shinawi

Research output: Contribution to journalArticlepeer-review

Abstract

Congenital disorders of glycosylation (CDG) are a group of heterogeneous inherited metabolic disorders affecting posttranslational protein modification. DDOST-CDG, caused by biallelic pathogenic variants in DDOST which encodes dolichyl-diphospho-oligosaccharide-protein glycosyltransferase, a subunit of N-glycosylation oligosaccharyltransferase (OST) complex, is an ultra-rare condition that has been described in two patients only. The main clinical features in the two reported patients include profound developmental delay, failure to thrive, and hypotonia. In addition, both patients had abnormal transferrin glycosylation. Here, we report an 18-year-old male who presented with moderate developmental delay, progressive opsoclonus, myoclonus, ataxia, tremor, and dystonia. Biochemical studies by carbohydrate deficient transferrin analysis showed a type I CDG pattern. Exome sequencing identified compound heterozygous variants in DDOST: a maternally inherited variant, c.1142dupT (p.Leu381Phefs*11), and a paternally inherited variant, c.661 T > C (p.Ser221Pro). Plasma N-glycan profiling showed mildly increased small high mannose glycans including Man0-5GlcNAc2, a pattern consistent with what was previously reported in DDOST-CDG or defects in other subunits of OST complex. Western blot analysis on patient's fibroblasts revealed decreased expression of DDOST and reduced intracellular N-glycosylation, as evident by the biomarkers ICAM-1 and LAMP2. Our study highlights the clinical variability, expands the clinical and biochemical phenotypes, and describes new genotype, which all are essential for diagnosing and managing patients with DDOST-CDG.

Original languageEnglish
JournalJournal of Inherited Metabolic Disease
DOIs
StateAccepted/In press - 2022

Keywords

  • congenital disorders of glycosylation
  • movement disorders
  • N-glycans
  • tremor
  • type I CDG

Fingerprint

Dive into the research topics of 'DDOST-CDG: Clinical and molecular characterization of a third patient with a milder and a predominantly movement disorder phenotype'. Together they form a unique fingerprint.

Cite this