Insights into ALG3-CDG: A case study combining glycan profiling and genetic analysis.

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Congenital disorders of glycosylation (CDG) are rare inherited metabolic diseases affecting protein glycosylation.
• Defects in glycosylation pathways lead to significant clinical manifestations and altered glycoprofiles.
• Early diagnosis is critical for timely intervention and improved patient outcomes.

Purpose of the Study:

• To investigate the underlying cause of complex clinical symptoms in a pediatric patient.
• To characterize the N-glycan profile and identify genetic variants associated with the disorder.
• To highlight the diagnostic utility of glycomic and genetic analyses in CDG.

Main Methods:

• LC-ESI-MS analysis of RapiFluor-labelled N-glycans from serum glycoproteins.
• Whole exome sequencing to identify genetic mutations.
• Clinical phenotyping including developmental, neurological, and cardiac assessments.

Main Results:

• The patient presented with developmental delay, epilepsy, microcephaly, dysmorphism, and cardiac abnormalities.
• N-glycan analysis revealed increased truncated mannosylated structures and decreased higher-order mannose structures.
• Compound heterozygous variants (c.165C>T and c.1060C>T) in the ALG3 gene were identified, confirming ALG3-CDG.

Conclusions:

• Glycan profiling is a valuable tool for diagnosing CDG.
• Genetic analysis, specifically whole exome sequencing, is essential for pinpointing causative variants.
• This case underscores the importance of integrated diagnostic approaches for rare metabolic disorders like ALG3-CDG.