ALG13 – Developmental and Epileptic Encephalopathy 36

The X-linked gene ALG13 encodes a UDP-N-acetylglucosaminyltransferase essential for N-linked glycosylation. Pathogenic variants in ALG13 cause developmental and epileptic encephalopathy 36 (Developmental and Epileptic Encephalopathy 36), characterized by early-onset seizures, motor and speech delay, and intellectual disability.

Genetic studies have identified de novo ALG13 variants in over 60 unrelated individuals, including a male with c.1388A>G (p.Glu463Gly) (PMID:28777499) and 29 additional cases with diverse missense and in-frame deletion alleles (PMID:32681751; PMID:39311797). The inheritance is X-linked dominant, with hemizygous males and heterozygous females predominantly harboring de novo changes.

No multigenerational segregation has been reported for ALG13-related DEE36; all affected individuals carry de novo variants and there are no additional segregating relatives.

More than 20 distinct variants have been documented. The recurrent missense c.320A>G (p.Asn107Ser) is the most frequent (PMID:32681751), accompanied by other hotspot substitutions such as c.241G>A (p.Ala81Thr) and an in-frame Glu69 deletion.

Functional data demonstrate that yeast expressing human ALG13 p.Ala81Thr or p.Asn107Ser fails to rescue glycosylation defects (PMID:32681751). Patient fibroblasts with p.Glu463Gly show reduced ICAM-1 expression, which is normalized by D-galactose supplementation in vitro (PMID:28777499). Structural modeling of p.Asn107Ser reveals disruption of the UDP-GlcNAc binding site (PMID:35327592), and an ALG13/14 enzymatic assay confirms deficient transferase activity (PMID:36200043).

Clinically, ALG13-related DEE36 presents predominantly with infantile spasms/West syndrome, refractory seizures, global motor delay, delayed speech, and variable intellectual disability (PMID:32681751; PMID:33734437). Transferrin glycosylation is often normal or only subtly altered, underscoring the need for molecular testing (PMID:33734437; PMID:33807002).

Together, robust genetic and experimental data fulfill ClinGen criteria for a definitive ALG13–DEE36 association. Inclusion of ALG13 in diagnostic epilepsy panels is recommended, and functional assays may inform therapies such as ketogenic diet or D-galactose. Key take-home: ALG13 de novo missense variants define a recognizable X-linked DEE36 phenotype with discordant biochemical glycosylation markers.

References

• American journal of medical genetics. Part A • 2017 • ALG13-CDG in a male with seizures, normal cognitive development, and normal transferrin isoelectric focusing. PMID:28777499
• Journal of inherited metabolic disease • 2020 • Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions. PMID:32681751
• Children (Basel, Switzerland) • 2021 • The First Metabolome Analysis in Children with Epilepsy and ALG13-CDG Resulting from c.320A>G Variant. PMID:33807002
• Journal of inherited metabolic disease • 2021 • ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes. PMID:33734437
• Molecular genetics & genomic medicine • 2024 • Similarity of Phenotype in Three Male Patients With the c.320A>G Variant in ALG13: Possible Genotype-Phenotype Correlation. PMID:39311797
• Biomolecules • 2022 • Structural Analysis of the Effect of Asn107Ser Mutation on Alg13 Activity and Alg13-Alg14 Complex Formation and Expanding the Phenotypic Variability of ALG13-CDG. PMID:35327592
• Frontiers in cell and developmental biology • 2022 • An in vitro assay for enzymatic studies on human ALG13/14 heterodimeric UDP-N-acetylglucosamine transferase. PMID:36200043

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