Carbohydrate-Deficient Glycoprotein Syndromes
Pamela Bean, Ph.D., MBA

The carbohydrate-deficient glycoprotein syndromes (CDGS) are a group of genetic multisystemic diseases characterized by the altered glycosylation of a wide range of serum and membrane-associated glycoproteins.1 The change in electrophoretic mobility or isoelectric point (pI) of serum transferrin is due to decreased sialylation of the transferrin molecules in the hepatocyte.2,3 Even though the exact nature of the glycoforms is controversial, a recent study demonstrates that the altered transferring glycoforms have lost one or both complete glycan side chains.4 Transferrin molecules with a low sialic acid content represent a convenient and reliable biochemical diagnosis of CDGS; the transferrin alterations can be detected in either serum or blood spots from Guthrie-type filter paper.5  With current techniques, circulating molecules of carbohydrate-deficient glycoproteins are detectable in serum between weeks 19 and 36 of gestation.6 Using a combination of online immunoaffinity-postconcentration-mass spectrometry, in conjunction with a blood spot cartridge, the relative quantities of the transferrin glycoforms present in CDGS can be determined using <5 mL blood in under 30 minutes.4,7

Because the CDGS present differently during various periods of life, a four stage grouping system by age was constructed.8,9 During infancy and early childhood, disease is characterized by failure to thrive, liver dysfunction, pericardial effusions, marked developmental delay and stroke-like episodes. In later childhood and adolescence, the most disabling constituents are stationary mental deficiency, ataxia, slowly progressive lower limb neuropathy, pigmentary retinal degeneration and secondary skeletal deformities.

A CDGS diagnosis should be considered in any unexplained neurological phenomenon including psychomotor retardation.  It is usually associated with combinations of features such as abnormal subcutaneous fat distribution, failure to thrive, protrusion of the thorax and/or kyphoscoliosis.  Also involved are pericardial effusion and/or cardiomyopathy, hepatomegaly, retinitis pigmentosa, cataracts and hypogonadism.10 Although the primary defect in CDGS is not identified, recent studies show that intracellular mannose is limited, suggesting that some patients might benefit by including mannose in their regular diets.11 Underlying the carbohydrate-deficient glycoprotein syndromes is a defect in phosphomannose isomerase (PMI), an enzyme of mannose metabolism.12   Indeed, an Asian girl who presented with failure to thrive, congenital hepatic fibrosis, protein losing enteropathy and hypoglycemia, showed reduced phosphomannose isomerase activity in skin fibroblasts and was homozygous for mutation D131N in the phosphomannose isomerase gene (PM1). This being a typical manifestation of CDGS, she responded well to treatment with oral mannose. 13


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