ALG3 – ALG3‑congenital disorder of glycosylation

This summary describes the association between ALG3 and ALG3‑congenital disorder of glycosylation (CDG-Id). Multiple independent reports have identified pathogenic variants in ALG3 causing a multisystem metabolic disorder characterized by abnormal glycosylation. The association is supported by evidence from isolated case reports and multi‐patient studies that document diverse clinical presentations including developmental delay, microcephaly, seizures, dysmorphic features, and multisystem involvement (PMID:15108280).

Clinical reports have detailed more than nine unrelated probands (PMID:15108280; PMID:16053906) and segregation analyses demonstrating affected siblings and additional relatives in some families. These findings confer a strong clinical validity category, as multiple families exhibit segregating variants with robust phenotypic concordance (PMID:23791010).

Genetic evidence supports an autosomal recessive inheritance model. A broad variant spectrum has been reported, including missense, splice, frameshift, and small deletion variants. In particular, the variant c.165C>T (p.Gly55=) has been repeatedly observed across independent studies (PMID:15108280; PMID:32389449), reinforcing the pathogenicity of altered splicing events and subsequent deleterious protein products.

Functional assessments have shown that pathogenic variants in ALG3 lead to abnormal splicing, resulting in aberrant transcripts with premature termination codons that, despite fulfilling criteria for nonsense-mediated mRNA decay, escape degradation. These studies using patient fibroblasts and cellular models confirm the impact on the ALG3 protein and underscore a mechanism involving defective glycosylation (PMID:31067009).

Although no major conflicting data have emerged, there is notable intrafamilial and phenotypic variability among affected individuals. The variability, including differences in severity and survival, may be partly attributed to mechanisms such as mitotic intragenic recombination, which could affect the residual enzyme activity (PMID:26126960).

Integration of both genetic and functional evidence provides a coherent picture linking diverse variant types to a consistent clinical syndrome. Experimental models that recapitulate aspects of the human phenotype further support the role of ALG3 disruption in CDG-Id. This comprehensive evidence not only validated the gene–disease association but also offers insights into the underlying pathophysiology and opportunities for targeted management.

Key take‑home: The solid genetic and functional evidence spanning multiple independent studies confirms that ALG3 variants cause ALG3‑congenital disorder of glycosylation, supporting its diagnostic and therapeutic utility in clinical practice.

References

• Human Mutation • 2004 • An activated 5' cryptic splice site in the human ALG3 gene generates a premature termination codon insensitive to nonsense‑mediated mRNA decay in a new case of CDG‑Id PMID:15108280
• European Journal of Medical Genetics • 2005 • CDG‑Id caused by homozygosity for an ALG3 mutation due to segmental maternal isodisomy UPD3(q21.3‑qter) PMID:16053906
• Molecular Genetics and Metabolism • 2013 • ALG3‑CDG (CDG‑Id): clinical, biochemical and molecular findings in two siblings PMID:23791010
• American Journal of Medical Genetics Part A • 2015 • ALG3‑CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation PMID:26126960
• Brain & Development • 2020 • Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3‑CDG PMID:32389449
• Human Mutation • 2019 • Novel variants and clinical symptoms in four new ALG3‑CDG patients, review of the literature, and identification of AAGRP‑ALG3 as a novel ALG3 variant with alanine and glycine‑rich N‑terminus PMID:31067009

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