Congenital disorders of glycosylation are a large and rapidly expanding group of autosomal recessive inborn errors of metabolism.  Most often, they are severe multi-systemic disorders that affect several organs.  Currently prenatal diagnosis for this large group of diverse diseases is only possible when the molecular defect is known in the affected individual that first came to medical attention.
These conditions are currently divided in two groups.  The first group or CDG type I comprises defects in the initial metabolic step that entails adding complex sugars to a nascent protein.  Overall, during the last years, at least ten subtypes have been found (CDG-Ia to CDG-Ij) with CDG Ia, caused by a deficiency in the enzyme phosphomannomutase, the most common subtype.
The second group of CDG (CDG-II) comprises defects in the way the protein-linked complex sugars are handled in small compartments of the cell. Fewer patients have been reported within this group compared to the first group.

If both parents have already been identified as carriers of a recessive gene involved in this pathway, chorionic villous sampling or amniocentesis should be offered.  Chorionic villous sampling (CVS) is used for diagnosis in the first trimester and it could be best explained as a biopsy of the placenta.  Chorionic villi are aspirated in a syringe and cultured short-term and long-term in the laboratory.  There are two approaches.  Transcervical CVS is performed between 10 and 13 weeks of gestation.  Transabdominal CVS can be performed from the 10th week onwards.  The total fetal loss rate after 1st trimester CVS is not different from amniocentesis (0.5% above the 3% background fetal loss rate).  DNA can be extracted for molecular studies.  An error in diagnosis because of maternal cell contamination is rare when the techniques of the laboratory are good.
Amniocentesis is best performed at 15 to 17 weeks gestation when amniotic fluid is extracted with ultrasound guidance.  The primary advantage of CVS is that results are available earlier in pregnancy.

It should be stressed that although the initial diagnosis of CDG in children has relied upon the detection of abnormal glycosylation of serum proteins by the transferrin isoelectric focusing, prenatal diagnosis for CDG-Ia or other subtypes cannot be performed by this method or another method that could determine fetal protein glycosylation.  It has been demonstrated that an affected fetus with CDG Ia displayed a normal blood glycosylation pattern.

Now going back to the CDG subtypes, CDG Ia is caused by mutations in the PMM2 gene.  The clinical picture is that of a mild to moderate central nervous system disease with involvement of several organs.  No efficient treatment is known for this subtype. The frequency of the disease has been estimated as 1 in 20,000.  The enzyme that is deficient in this disease (phosphomannomutase) is deficient in cultured trophoblasts and amniocytes from the fetus.  However, the prenatal diagnosis by enzyme assay can give false positive results since low values for this enzyme have been obtained in poorly growing amniocytes when the fetus was not affected.  Some patients with severe disease could also show values in an intermediate range, making the interpretation difficult.  Therefore, prenatal testing should only be offered to families where mutations in the PMM2 gene have been documented and DNA analysis is the most reliable method for prenatal diagnosis in this subtype.

CDG type Ib: the clinical presentation is very different from the previous disorder and not as severe.  Patients can present with liver and small bowel disease with coagulation problems.  The liver disease can entail fibrosis of the liver.  Some patients have also presented low blood sugars with elevated insulin levels.  Because this disease is treatable with mannose and less frequent than the previous subtype, prenatal diagnosis has not been requested as often although potentially it could be done with DNA analysis if the mutation is known in the affected family member.

Other types of CDG-I and CDG-II
CDG-Ic and other types of CDG-I that affect the assembly of complex sugars in the cell have been discovered and are diagnosed by the analysis of metabolic intermediates that are assayed after cultured cells are radioactively labeled. However this type of analysis has never been carried out in amniocytes or trophoblasts.  Currently it is not advisable to use this approach for prenatal diagnosis, especially if the protein deficiency or the dNA defect is not know.  For these disorders, prenatal diagnosis is only accurate if the molecular defect is known in the affected child first.

Overall, the results of the direct DNA mutation analysis in the fetus should always be confirmed with linkage analysis which is a type of analysis that entails the use of DNA markers that would also detect contamination of fetal sample with maternal DNA, making the diagnosis more reliable.
When the direct DNA analysis is performed on DNA that has been extratcetd from non-cultured chorionic villi, the results could be available in one week.

Potentially, pre-implantation genetic diagnosis (using four-to-eight-cell stage embryos could be an option for CDG and this has already been offered in Europe for CDG-Ia and CDG-Ic.

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