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Screening for congenital disorders of glycosylation
Results are reported as the mono-oligosaccharide/di-oligosaccharide transferrin ratio, the a-oligosaccharide/di-oligosaccharide transferrin ratio, the tri-sialo/di-oligosaccharide transferrin ratio, the apolipoprotein CIII-1/apolipoprotein CIII-2 ratio and the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio.
Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndrome, are a group of over 75 inherited metabolic disorders affecting several steps of the pathway involved in the glycosylation of proteins. CDG are currently classified into 2 main groups. Type I CDG is characterized by defects in the assembly or transfer of the dolichol-linked glycan, while type II involves processing defects of the glycan. Apolipoprotein CIII (Apo-CIII) isoforms, a protein with a single core 1 mucin type O-glycosylate protein, is a complementary evaluation for the CDG type II profile. This analysis will evaluate mucin type O-glycosylation, a defect that happens in the Golgi apparatus, and will change the ratios, increasing the asialo or monoisalo forms and decreasing the fully sialilate (disialo) forms.
CDG typically present as multisystemic disorders with a broad clinical spectrum including developmental delay, hypotonia, with or without neurological abnormalities, abnormal magnetic resonance imaging findings, skin manifestations, and coagulopathy. There is considerable variation in the severity of this group of diseases ranging from a mild presentation in adults to severe multiorgan dysfunctions causing infantile lethality. In some subtypes, MPI-CDG (CDG-Ib) in particular, intelligence is not compromised. CDG should be suspected in all patients with neurological abnormalities including developmental delay and seizures, brain abnormalities such as cerebellar atrophy or hypoplasia as well as unexplained liver dysfunction. Abnormal subcutaneous fat distribution and chronic diarrhea each may or may not be present. The differential diagnosis of abnormal transferrin patterns also includes liver disease not related to CDG including uncontrolled galactosemia, hereditary fructose intolerance in acute crisis, and liver disease of unexplained etiology.
Transferrin and apolipoprotein CIII isoform analysis test is the initial screening test for CDG. The results of the transferrin and apolipoprotein CIII isoform analysis should be correlated with the clinical presentation to determine the most appropriate follow-up testing strategy including enzyme, molecular, and research-based testing. Enzymatic analysis for phosphomannomutase and phosphomannose isomerase in leukocytes (PMMIL / Phosphomannomutase [PMM] and Phosphomannose Isomerase [PMI], Leukocytes) or fibroblasts (PMMIF / Phosphomannomutase [PMM] and Phosphomannose Isomerase [PMI], Fibroblasts) should be performed if either PMM2-CDG (CDG-Ia) or MPI-CDG (CDG-Ib) are suspected.
Transferrin Mono-oligo/Di-oligo Ratio
< or =0.06
> or =0.10
Transferrin A-oligo/Di-oligo Ratio
< or =0.011
> or =0.022
Transferrin Tri-sialo/Di-oligo Ratio
< or =0.05
> or =0.13
Apo CIII-1/Apo CIII-2 Ratio
< or =2.91
> or =3.69
Apo CIII-0/Apo CIII-2 Ratio
< or =0.48
> or =0.69
Positive test results could be due to a genetic or nongenetic condition; additional confirmatory testing is required.
Results are reported as the mono-oligosaccharide/di-oligosaccharide transferrin ratio, the a-oligosaccharide/di-oligosaccharide transferrin ratio, the tri-sialo/di-oligosaccharide transferrin ratio, and the apolipoprotein CIII-1/apolipoprotein CIII-2 ratio, and the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio. The report will include the quantitative results and an interpretation.
The congenital disorders of glycosylation (CDG) profiles are categorized in 4 types:
-CDG type I profile. Mono-oligosaccharide/di-oligosaccharide transferrin ratio, and/or the a-oligosaccharide/di-oligosaccharide transferrin ratio are abnormal. This group should have the apolipoprotein C-III profile within the normal ranges, because the Golgi system is not affected in CDG type I.
-CDG type II profile. The tri-sialo/di-oligosaccharide transferrin ratio is abnormal. In this category, the apolipoprotein C-III profile will have 2 scenarios:
-The apolipoprotein CIII-1/apolipoprotein CIII-2 ratio and/or the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio will be abnormal when the defect is most likely glycan processing in the Golgi apparatus, therefore the CDG defect is likely.
-The apolipoprotein CIII-1/apolipoprotein CIII-2 ratio and/or the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio are normal, in this case most likely the defects do not involve the Golgi system, thus the molecular defect is different.
-CDG mixed type profile (type I and II together). In this type of profile one can have abnormal tri-sialo/di-oligosaccharide transferrin ratio with the mono-oligosaccharide/di-oligosaccharide transferrin ratio and/or the a-oligosaccharide/di-oligosaccharide transferrin ratio abnormal, and may have the apolipoprotein CIII-1/apolipoprotein CIII-2 ratio and the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio normal or abnormal, depending if the defects involve Golgi apparatus.
When the profile cannot be categorized following the above classification, all the abnormal transferrin and/or Apo-CIII species will be reported descriptively according to the molecular mass stating the possible structures.
Reports of abnormal results will include recommendations for additional biochemical and molecular genetic studies to more precisely identify the correct form of CDG. Treatment options, the name and telephone number of contacts who may provide studies at Mayo Clinic or elsewhere, and a telephone number for one of the laboratory directors (if the referring physician has additional questions) will be provided.
Other conditions such as acute crisis of hereditary fructose intolerance, metabolically decompensate galactosemia, and acute liver disease may have a congenital disorders of glycosylation (CDG) profile that is indistinguishable from any other true CDG type I cases. Relevant clinical information and the indication for the analysis should be provided with the specimen, in particular for nonpediatric patients.
Transferrin glycosylation patterns may normalize so repeat testing is warranted in patients with significant clinical suspicion.
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