"Hide and seek": Misleading transferrin variants in PMM2-CDG complicate diagnostics

Area of Science:

• Biochemistry
• Clinical Genetics
• Metabolic Disorders

Background:

• Congenital disorders of glycosylation (CDG) are a growing group of inborn errors of metabolism.
• Current CDG screening primarily uses serum transferrin (Tf) analysis, which can be confounded by common Tf protein variants.
• The diagnostic impact of Tf variants in CDG has been previously undocumented.

Purpose of the Study:

• To describe two cases of PMM2-CDG where transferrin (Tf) variants complicated the diagnostic process.
• To investigate the role of Tf variants in causing discrepancies between initial CDG screening and confirmation tests.

Main Methods:

• Utilized classical glycosylation screening (capillary electrophoresis, isoelectric focusing, HPLC of Tf) and advanced confirmation techniques (2D electrophoresis, Western blot, N-glycome, UPLC-MS).
• Identified Tf variants by analyzing patterns after neuraminidase treatment.
• Performed PMM2 gene sequencing for definitive diagnosis.

Main Results:

• Both patients initially showed CDG-II patterns on Tf screening, but subsequent analyses indicated CDG-I.
• Tf variants were identified in both patients, explaining the observed discrepancies.
• Causative PMM2 variants were confirmed in both individuals.

Conclusions:

• Transferrin (Tf) variants can lead to misinterpretation of CDG screening results.
• Neuraminidase treatment should be considered during initial Tf analysis when a typical CDG pattern is observed.
• Accurate CDG diagnosis requires careful consideration of Tf variants alongside genetic testing.