ALG6 – ALG6-Congenital Disorder of Glycosylation 1C

Pathogenic variants in the alpha-1,3-glucosyltransferase gene ALG6 cause ALG6-congenital disorder of glycosylation 1C, an autosomal recessive glycosylation defect. The condition manifests in infancy with psychomotor retardation, hypotonia, and multisystem involvement.

Multiple variant classes have been reported, including the common founder missense c.998C>T (p.Ala333Val) present in over half of CDG-Ic patients and the less frequent c.391T>C (p.Tyr131His) (PMID:14517965). Splice‐site mutations (e.g., IVS7+2T>G) and small indels leading to frameshifts have also been described.

Segregation analysis in the initial family demonstrated cosegregation of ALG6 mutations with disease in four affected relatives (3 additional carriers) (PMID:10359825). A subsequent cohort study identified seven additional unrelated CDG-Ic patients, confirming the multi-allelic origin (PMID:10914684).

Functional assays support a loss-of-function mechanism: mutant ALG6 cDNAs fail to complement an alg6 yeast strain (PMID:10359825), and wild-type ALG6 delivered to patient fibroblasts via lentiviral vector restores normal glycosylation (PMID:16007612).

Clinically, affected individuals present with developmental delay (HP:0001263), hypotonia (HP:0001252), and seizures (HP:0001250) in ≥70% of cases (HP:0200134) (PMID:36756224). Strabismus (HP:0000486) and feeding difficulties (HP:0011968) are common, while rare adult presentations include deep venous thrombosis (HP:0002625) and dilated cardiomyopathy (HP:0001644).

This definitive gene–disease association underpins targeted genetic testing in suspected CDG-Ic, with inclusion of the recurrent c.998C>T (p.Ala333Val) variant in diagnostic panels enhancing detection and enabling early intervention.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1999 • A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic. PMID:10359825
• Human Genetics • 2000 • Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic. PMID:10914684
• Human Mutation • 2003 • Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic. PMID:14517965
• American Journal of Medical Genetics. Part A • 2005 • Clinical and molecular characterization of the first adult congenital disorder of glycosylation (CDG) type Ic patient. PMID:16007612
• Orphanet Journal of Rare Diseases • 2010 • A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report. PMID:20398363
• Child Neurology Open • 2023 • A Case of ALG6-CDG with Explosive Onset of Intractable Epilepsy During Infancy. PMID:36756224

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