Congenital disorder of glycosylation

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, are a large and rapidly expanding group of rare inherited metabolic disorders caused by defects in the synthesis or processing of glycans (sugar chains) that are attached to proteins and lipids throughout the body. Glycosylation is one of the most fundamental and complex post-translational modifications, and because glycoproteins and glycolipids play critical roles in virtually every organ system, CDG can affect nearly any part of the body. The group encompasses over 160 distinct subtypes, broadly classified into disorders of N-linked glycosylation, O-linked glycosylation, glycosphingolipid and glycosylphosphatidylinositol (GPI) anchor glycosylation, and multiple pathway defects. The most common subtype is PMM2-CDG (CDG-Ia), caused by mutations in the PMM2 gene encoding phosphomannomutase 2. Clinical features across CDG subtypes are highly variable but frequently include neurological involvement such as intellectual disability, cerebellar hypoplasia, hypotonia, seizures, and ataxia. Other commonly affected systems include the liver (elevated transaminases, hepatomegaly, liver fibrosis), the gastrointestinal tract (failure to thrive, feeding difficulties, protein-losing enteropathy), the heart (cardiomyopathy, pericardial effusions), the eyes (strabismus, retinitis pigmentosa), the skeletal system (skeletal dysplasia), the coagulation system (both thrombotic and bleeding tendencies due to abnormal clotting factors), and the endocrine system (hypothyroidism, hypogonadism). Characteristic physical features in some subtypes include inverted nipples, abnormal fat distribution, and dysmorphic facial features. Currently, treatment for most CDG subtypes remains largely supportive and symptomatic, including physical therapy, nutritional support, anti-epileptic medications, and management of organ-specific complications. However, a few subtypes have specific targeted therapies: MPI-CDG (CDG-Ib) can be effectively treated with oral mannose supplementation, SLC35C1-CDG (CDG-IIc) may respond to oral fucose, and PIGM-CDG has shown response to butyrate therapy. Research into additional targeted therapies, including substrate supplementation and gene therapy approaches, is ongoing. Early diagnosis through transferrin isoelectric focusing or mass spectrometry-based glycan analysis, followed by genetic confirmation, is essential for appropriate management and genetic counseling.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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