ALG13 – X-linked Developmental and Epileptic Encephalopathy

ALG13, encoding an X-linked UDP-N-acetylglucosaminyltransferase, is implicated in developmental and epileptic encephalopathy (DEE36; [MONDO:0100062]). Pathogenic variants, notably the recurrent de novo c.320A>G (p.Asn107Ser), cause early-onset, pharmacoresistant epilepsy with West syndrome and severe neurodevelopmental impairment, transmitted in an X-linked dominant fashion.

Three unrelated males with de novo hemizygous c.320A>G (p.Asn107Ser) share infantile spasms, drug-resistant seizures, intellectual disability, dysmorphic features, recurrent infections, skeletal anomalies, brain malformations, and movement disorders ([PMID:39311797]). A larger series of 38 females and one male bearing the identical variant exhibited West syndrome, epileptic spasms, hypsarrhythmia, severe to profound developmental delay, sparse purposeful hand use, and dyskinetic movements ([PMID:33410528]).

Beyond p.(Asn107Ser), 29 additional individuals with de novo ALG13 variants (including p.(Ala81Thr), p.(Glu69del), p.(Ile17Asn), p.(Gly972Val)) display overlapping DEE phenotypes and West syndrome features, expanding the variant spectrum ([PMID:32681751]). All cases are de novo; no affected relatives are reported.

Functional assays demonstrate that yeast expressing ALG13 hotspot variants (p.(Ala81Thr), p.(Asn107Ser)) rescue growth defects but fail to restore normal glycosylation in an ALG13-deficient strain, indicating impaired enzyme activity ([PMID:32681751]). A quantitative liquid chromatography–mass spectrometry GnTase assay of the human ALG13/ALG14 heterodimer confirms that pathogenic alleles markedly reduce UDP-GlcNAc transferase activity, establishing a loss-of-function mechanism ([PMID:36200043]).

No significant alternative inheritance or non-epileptic phenotypes have been associated with these recurrent variants in DEE cohorts. Normal serum transferrin glycosylation patterns in most affected individuals suggest tissue-specific glycosylation defects in neural cells.

Overall, the evidence meets ClinGen criteria for a Strong gene-disease association, supported by >70 unrelated de novo cases with consistent clinical features and concordant functional data. Genetic evidence is Strong (41 recurrent p.(Asn107Ser) and 29 other de novo cases), and functional evidence is Moderate (yeast complementation and in vitro GnTase assays). Key Take-home: ALG13 pathogenic variants, particularly c.320A>G (p.Asn107Ser), reliably cause X-linked DEE36 and should be included in epilepsy gene panels.

References

• 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
• Epilepsia • 2021 • The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy. PMID:33410528
• 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
• 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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