Normal transferrin glycosylation does not rule out severe ALG1 deficiency.

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic diseases affecting protein function.
• ALG1-CDG results from a defect in the initial step of N-glycosylation, impacting protein stability and half-life.
• N-glycosylation is crucial for the proper function, stability, and lifespan of most proteins, making CDGs typically multisystemic.

Observation:

• A 3-year-old patient presented with severe neurological, cardiovascular, respiratory, musculoskeletal, and gastrointestinal symptoms.
• Exome sequencing and Western blot analysis suggested ALG1-CDG.
• Despite severe clinical manifestations and genetic diagnosis, serum transferrin glycoform analysis was normal.

Findings:

• Fibroblast analysis revealed decreased intercellular adhesion molecule 1 (ICAM1) but normal LAMP1/LAMP2 expression.
• Glycoproteomics identified an abnormal tetrasaccharide in fibroblasts.
• Only one other reported ALG1-CDG patient (out of 86) had normal transferrin analysis.

Implications:

• This case highlights the diagnostic challenges of ALG1-CDG.
• Normal serum transferrin glycosylation or other biomarkers can occur in ALG1-CDG patients.
• Multiple diagnostic methods are essential for accurate ALG1-CDG diagnosis, especially when standard biomarkers are normal.