ALG11 – Congenital Disorder of Glycosylation

ALG11 has been repeatedly implicated in congenital disorders of glycosylation through studies that identified biallelic pathogenic variants in affected individuals. Patients present with a range of multisystemic features including muscular hypotonia, global developmental delay, seizures, and microcephaly. These clinical findings, consistently observed in independent reports, support a robust gene–disease association (PMID:20080937, PMID:30770273).

Multiple case reports have documented homozygous and compound heterozygous variants in ALG11 in patients with congenital disorder of glycosylation. For instance, one report identified the variant c.257T>C (p.Leu86Ser) in a patient presenting with hypotonia, seizures, and developmental retardation (PMID:20080937). Additional independent studies have revealed further variants such as c.1307G>T (p.Gly436Val) and c.1403G>A (p.Arg468His) that segregate with the disease phenotype in an autosomal recessive manner (PMID:39260222, PMID:35907674). This genetic evidence is bolstered by at least 17 documented cases spanning diverse populations (PMID:39260222).

Functional studies have provided critical insights into the pathogenicity of ALG11 variants. Experimental assays, including retroviral expression in patient fibroblasts and yeast complementation systems, have demonstrated that these mutations lead to decreased stability of the encoded mannosyltransferase, resulting in impaired N-glycosylation. The accumulation of immature dolichol-linked oligosaccharides in patient cells further confirms the molecular mechanism underlying the disease (PMID:20080937, PMID:22232241).

Segregation analyses in reported families have reinforced the autosomal recessive inheritance model. Although detailed counts of additional affected relatives were not consistently provided, the clustering of affected siblings and the demonstration of variant segregation in multi‑family studies underscore a coherent genetic etiology.

No substantial conflicting evidence has emerged; rather, the convergence of clinical, genetic, and functional data across independent studies supports a strong association between ALG11 mutations and congenital disorder of glycosylation. The reproducibility of both the molecular findings and the corresponding biochemical phenotypes adds to the diagnostic confidence in this association.

Integrating the genetic and experimental findings, the evidence indicates that pathogenic variants in ALG11 disrupt proper glycosylation pathways, leading to the severe multisystem manifestations observed in affected individuals. This association not only enhances the diagnostic armamentarium for congenital disorders of glycosylation but also informs targeted therapeutic and management strategies.

Key Take‑home sentence: The strong and multifaceted evidence linking ALG11 variants to congenital disorder of glycosylation supports its value as a diagnostic marker and invites further studies for improving patient care.

References

• Human molecular genetics • 2010 • A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11 leads to congenital disorder of glycosylation‑Ip PMID:20080937
• Pediatric neurology • 2019 • Arrest of Fetal Brain Development in ALG11‑Congenital Disorder of Glycosylation PMID:30770273
• Brain & development • 2022 • A case of ALG11‑congenital disorders of glycosylation diagnosed by post‑mortem whole exome sequencing PMID:35907674
• Seizure • 2024 • Identification of two novel variants in ALG11 causing congenital disorder of glycosylation PMID:39260222
• Genes • 2021 • Prevalence of Congenital Disorders of Glycosylation in Childhood Epilepsy and Effects of Anti‑Epileptic Drugs on the Transferrin Isoelectric Focusing Test PMID:34440401

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