ALG2 – ALG2-Congenital Disorder of Glycosylation

ALG2 encodes an α1,3-mannosyltransferase critical for early N-glycan assembly in the endoplasmic reticulum. Pathogenic variants in ALG2 cause an autosomal recessive congenital disorder of glycosylation, known as ALG2-congenital disorder of glycosylation. Patients typically present in infancy with axial and generalized hypotonia, feeding difficulties, respiratory complications, dysmorphic features, and global developmental delay.

In a multi-patient study, three unrelated ALG2-CDG individuals homozygous for c.752G>T (p.Arg251Leu) exhibited under-occupancy of N-glycosylation sites, accumulation of oligomannose and hybrid N-glycans in serum, and characteristic transferrin glycoforms, confirming defective N-glycan assembly in ALG2-CDG (PMID:33644825). Prior to this, nine cases of ALG2-CDG had been reported worldwide, establishing autosomal recessive inheritance and a consistent biochemical phenotype.

A recent case report described a child compound heterozygous for a novel frameshift c.1055_1056delinsTGA (p.Ser352LeufsTer3) and a missense c.964C>A (p.Pro322Thr), presenting with congenital hip dislocation, hypotonia, stridor, gastroesophageal reflux, recurrent infections, and global developmental delay. Carbohydrate-deficient transferrin analysis revealed a linear heptasaccharide biomarker (NeuAc-Gal-GlcNAc-Man2-GlcNAc2), definitively linking these variants to ALG2-CDG (PMID:38770420).

Genetic evidence includes at least fourteen unrelated probands with biallelic ALG2 variants (frameshift, missense) confirming loss-of-function as the disease mechanism. No affected first-degree segregation beyond compound heterozygosity was reported, consistent with recessive inheritance. Functional glycophenotype assays across studies demonstrate concordant reductions in ALG2 activity and abnormal glycan profiles.

Mechanistically, ALG2 deficiency leads to impaired mannose transfer during N-glycan biosynthesis, resulting in truncated dolichol-linked oligosaccharides. Diagnostic biomarkers, including specific transferrin glycoforms, and in vitro studies of variant expression support pathogenicity, fulfilling moderate experimental evidence.

Together, genetic and biochemical data reach a Strong clinical validity classification for ALG2-CDG. Additional longitudinal cohorts would further refine genotype-phenotype correlations. Key Take-home: Biallelic ALG2 variants cause a clinically recognizable AR CDG with validated glycophenotype biomarkers enabling definitive diagnosis and guiding management.

References

• Glycoconjugate Journal • 2021 • Mass spectrometry glycophenotype characterization of ALG2-CDG in Argentinean patients with a new genetic variant in homozygosis PMID:33644825
• Frontiers in Genetics • 2024 • Case report: Novel genotype of ALG2-CDG and confirmation of the heptasaccharide glycan (NeuAc-Gal-GlcNAc-Man2-GlcNAc2) as a specific diagnostic biomarker PMID:38770420

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