Epilepsy: ALG13-Related Early Infantile Epileptic Encephalopathy via the ALG13 Gene

Early Infantile Epileptic Encephalopathy (EIEE) is a clinically and genetically heterogeneous neurodevelopmental disorder. The key feature of EIEE is onset of frequent and/or severe seizures within the first few weeks of life (Noh et al. 2012. PubMed ID: 22342633).

ALG13-related early infantile epileptic encephalopathy is a rare genetic cause for early infantile epilepsy. Major symptoms of this disorder include intractable seizures, severe cognitive impairment, developmental regression after onset of seizures, and hypotonia. Some patients present hydrocephalus, pyramidal and extrapyramidal signs. Initial EEG shows Hypsarrhythmia and Multifocal discharges, while MRI presents structural brain abnormalities including cerebral atrophy and delayed myelination. Patients could be diagnosed as having Lennox-Gastaut syndrome or West syndrome (Allen et al. 2013. PubMed ID: 23934111; Kobayashi et al. 2016. PubMed ID: 26482601).

Pathogenic variants in ALG13 are also associated with congenital disorder of glycosylation type I (CDG-I) (Timal et al. 2012. PubMed ID: 22492991).

A de novo common pathogenic variant c.320A>G in the ALG13 gene has been repeatedly reported in females with epileptic encephalopathy. However, male patients with either inherited or de novo pathogenic variant in the gene show a different phenotype, congenital disorder of glycosylation type I (Timal et al. 2012. PubMed ID: 22492991; Gadomski et al. 2017. PubMed ID: 28777499).

ALG13-related early infantile epileptic encephalopathy is inherited in an X-linked dominant manner. It is caused by pathogenic variants in the ALG13 gene encoding a subunit of the uridine diphosphate-N-acetylglucosamine transferase. ALG13 is the soluble subunit recruited by membrane-bound ALG14 to form the heterodimeric ALG13/ALG14 complex catalyzing the formation of GlcNAc2-PP-dolichol, the second step in the synthesis of the lipid-linked oligosaccharides precursor for N-glycan assembly (Allen et al. 2013. PubMed ID: 23934111; Timal et al. 2012. PubMed ID: 22492991).

Reported pathogenic variants in ALG13 are missense only. No large deletions/duplications involving the ALG13 locus have been reported yet (Human Gene Mutation Database). De novo pathogenic variants in ALG13 have been reported (Allen et al. 2013. PubMed ID: 23934111).

In study of severe early infantile Epileptic Encephalopathy, less than 1% (2 in 264) of cases were found to be caused by de novo pathogenic variants in ALG13 (Allen et al. 2013. PubMed ID: 23934111).

To date, no large deletions/duplications involving ALG13 have been reported.

This test provides full coverage of all coding exons of the ALG13 gene, except for the region noted below, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.