General summary
Authors: Jaeken Jaak , Stibler Helena , Hagberg Bengt 
Published: January 2008

Carbohydrate‐deficient glycoprotein (CDG) syndrome clearly represents a new type of distinct disease entity(ies), from both a clinical and a biochemical point of view. It is most probably a disorder of glycoprotein metabolism with autosomal recessive inheritance, and presents with unique and complex clinical, biochemical and ultra‐structural features. This supplement is based on 29 biochemically verified Scandinavian and Belgian patients. In addition to these, seven of their siblings have died in a clinically identical condition, and another 21 patients have come to our knowledge within a short period of time, including a few non‐European cases. The patients represent altogether eight nationalities.

Severe symptoms from the nervous system were present in all patients. The neurological and neuropathological characteristics were a combination of mental retardation, olivopontocerebellar atrophy (OPCA) and peripheral neuropathy with systemic manifestations including retinal pigmental degeneration, hepatopathy, nephropathy, osseous changes with secondary skeletal deformities, pericardial effusions, female hypogonadism, abnormalities of adipose tissue and skin together with discrete but characteristic dysmorphic features.

The clinical expression and course were variable with respect to the degree of psychomotor retardation and the severity of complications. Failure to thrive and floppiness were major symptoms during infancy, when dramatic complications often occurred such as acute hepatopathy with oedema, coagulation abnormalities, pericardial effusions and severe infections, which continued to occur during childhood. A number of patients were affected by sudden and sometimes repeated stuporous or stroke‐like episodes. Thoracic deformities developed in many cases. From school age the disease was usually rather stationary with persistent psychomotor retardation of variable severity, at most an IQ level of 50–60, and locomotion with rollator aid. The motor disability was that of a combined cerebellar ataxia and peripheral neuropathy. From early childhood only the peripheral neuropathy and retinal degeneration were slowly progressive. At adult age hypogonadism in female patients and premature aging developed. Analysis of life expectancy revealed that early mortality was substantially increased.

The biochemical changes were dominated by a complex carbohydrate deficiency in a number of serum glycoproteins and by hypoalbuminemia, hypo‐betalipoproteinemia and low thyroxine‐binding globulin (TBG). The carbohydrate defect was most readily observed in serum and liver transferrin, which partly lacked two or all four of its terminal trisaccharides, consisting of N‐acetylglucosamine, galactose and sialic acid. The result of this defect was the presence of abnormal isoforms of several glycoproteins, particularly of transferrin in serum as well as in the liver. Due to this unique molecular deficiency, CDG syndrome can be diagnosed biochemically either by isoelectric focusing of serum transferrin or by quantitative analysis of “carbohydrate‐deficient transferrin” (CDT) by means of a rapid micro anion exchange chromatography assay.

The ultrastructural findings in CDG syndrome were also unique. In fibroblasts, Schwann cells and hepatocytes, usually membrane‐bounded lamellar, fibrillary and multivacuolated inclusions were found, suggesting a defect in macromolecular metabolism. These observations, together with the studies of glycoprotein metabolism carried out to date suggest an abnormality in the turnover of glycoproteins.

Although the genetic defect has not yet been identified, indirect prenatal diagnosis may be possible by analysis of isoforms of transferrin and other glycoproteins, such as alpha1 ‐fetoprotein in amniotic fluid or fetal serum. Immune isoelectric focusing of these proteins and the CDT assay were applicable to both body fluids, and reference values for CDT during gestation were established. Preliminary findings have demonstrated that neonatal diagnosis is possible by analysis of transferrin isoforms, and that blood eluted from Guthrie cards (PKU filter paper blood spots) used in neonatal metabolic screening programs can be utilized for this purpose. Moreover, reduced levels of T4 due to low concentration of TBG combined with neurological disease should arouse the suspicion of CDG syndrome.

We suggest that this new inborn error of glycoprotein metabolism should be considered in infants with combinations of failure to thrive, floppiness, lipoatrophic changes, developmental delay, strabismus, early hepatopathy or pericardial effusions. In older children and in adults the combination of mental retardation, OPCA, peripheral neuropathy and retinal pigmental degeneration is strongly suggestive of CDG syndrome.

During the course of this work we have observed two clinical and biochemical variants of this syndrome, suggesting that CDG syndrome may represent a group of new disorders of glycoprotein metabolism.