Genotype-phenotype correlations and clinical spectrum of ALG13-related developmental epileptic encephalopathy.

Background

Pathogenic variants in Asparagine-linked glycosylation 13 (ALG13) gene are associated with developmental and epileptic encephalopathy 36 (DEE36). The recurrent missense variant c.320A>G (p.Asn107Ser, N107S) represents the most frequently reported disease associated hotspot variant. However, genotype-phenotype correlations and factors associated with seizure and neurodevelopmental outcomes remain incompletely defined.

Methods

We performed a systematic literature review and pooled analysis of published cases pathogenic or likely pathogenic ALG13 variants, as classified according to ACMG/AMP criteria. Extracting clinical, electroencephalographic (EEG), and magnetic resonance imaging (MRI) features and inheritance pattern. Phenotypes were compared between N107S and non-N107S variants and within the N107S subgroup.

Results

Twenty eight publications (111 individuals) were identified, 100 patients were included after exclusions. The N107S variant accounted for 70% (70/100) of cases, with female predominance (79/97, 81.4%). Epilepsy was present in 87% (87/100) of the overall cohort, and in 98.6% (69/70) of individuals with N107S variant. Seizures typically began in infancy, with a median onset age of 6.0 months (IQR, 4.0-8.0) overall and 5.0 months (IQR, 4.0-6.0) in individuals with the N107S variant. Infantile epileptic spasms syndrome (IESS) was the most frequent epilepsy syndrome, occurring in 84.2% of the overall cohort and 88.5% of individuals with N107S. Hypsarrhythmia was observed in 84.9% of cases with available EEG data. Brain MRI was normal in approximately two-thirds of cases, whereas cerebral atrophy and benign enlargement of subarachnoid spaces (BESS) were the most common abnormalities. Among cases with available outcome data, 42.9% achieved seizure freedom, whereas 57.1% had drug resistant epilepsy (DRE). Compared with non-N107S variants, those with N107S more frequently presented with epilepsy, IESS, and de novo inheritance pattern. Earlier seizure onset was associated with more severe neurodevelopmental disorder (NDD) in both the overall cohort and the N107S subgroup.

Conclusions

This pooled analysis delineates the phenotypic spectrum of ALG13-related epilepsy and emphasizes the prominence of the N107S hotspot variant. Earlier seizure onset is associated with more severe neurodevelopmental outcomes. These findings refine the genotype-phenotype spectrum of ALG13-related disease and support early genetic testing and standardized long-term follow-up.