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

Autor: Elsharkawi I; Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA.; Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Wongkittichote P; Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA., Daniel EJP; Palmieri Metabolic Disease Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Starosta RT; Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA., Ueda K; Division of Pediatric Neurology, Department of Neurology, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA., Ng BG; Human Genetics Program, Sanford Children's Health Research Center, La Jolla, California, USA., Freeze HH; Human Genetics Program, Sanford Children's Health Research Center, La Jolla, California, USA., He M; Palmieri Metabolic Disease Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Shinawi M; Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2023 Jan; Vol. 46 (1), pp. 92-100. Date of Electronic Publication: 2022 Oct 17.
DOI: 10.1002/jimd.12565
Abstrakt: 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 Man 0-5 GlcNAc 2, 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.
(© 2022 SSIEM.)
Databáze: MEDLINE
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