CDG-Id in two siblings with partially different phenotypes

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic diseases.
• CDG type Id is specifically linked to defects in the ALG3 gene, crucial for N-glycan synthesis.

Observation:

• Two siblings presented with severe global developmental delay, failure to thrive, seizures, microcephaly, axial hypotonia, and disaccharidase deficiency.
• Clinical manifestations varied, with one sibling experiencing more severe digestive issues and the other more pronounced neurological impairment.

Findings:

• Both siblings were compound heterozygous for a novel mutation and a known mutation in the ALG3 gene.
• These mutations resulted in the synthesis of a severely truncated oligosaccharide precursor for N-glycans.
• Functional studies demonstrated that introducing a normal ALG3 cDNA corrected the observed defect.

Implications:

• This study highlights the critical role of the ALG3 gene in normal development and glycosylation.
• Congenital disorder of glycosylation (CDG) type Id should be considered in the differential diagnosis of infants presenting with severe seizures and failure to thrive.
• Gene therapy targeting the ALG3 gene holds promise for treating CDG type Id.