After performing diagnostic testing on several thousand patients with seizure disorders, Courtagen's Clinical Team has described a variant in the ALG13 gene that directly causes infantile spasms, intellectual disability, and severe neurologic disease.
After reviewing the results of patients who were tested using either the epiSEEK® Comprehensive and the devSEEK® Comprehensive Next Generation sequencing panel, we found four female patients with a heterozygous c. 320A>G (p.N107S) variant. These patients all presented with one or more of the following conditions: infantile spasms, seizures, developmental delay. The ALG13 gene is located on the X chromosome and typically X-linked genes mostly affect males; however, this variant has only been found in females and is a cause of severe disease.
A review of the literature found 8 other cases where this variant was identified in female patients with a consistent phenotype of infantile spasms (with characteristic EEG), which may progress to other seizure types, and severe to profound intellectual disability, which often includes regression following the onset of seizures. Other common signs and symptoms include hypotonia, feeding issues, abnormal movement, visual impairment, atrophy on brain MRI and dysmorphic features. You can view a summary of our findings in the graphic below.
What does this finding mean?
This finding may have significant treatment implications because several patients in the literature were reported to respond to Adrenocorticotropic hormone (ACTH), also known as corticotropin.
This finding also has significant diagnostic implications. The ALG13 and ALG14 genes are a key step in the body’s N-linked glycosylation process. Glycosylation is the process by which a carbohydrate is attached to a proteins or lipids. This serves various functions, such as ensuring proteins fold correctly.
Loss of function mutations cause glycosylation defects in males, which can be identified through biochemical testing. However, two female patients in the literature had normal glycosylation results when tested. This suggests that biochemical testing for N-linked glycosylation defects caused by this variant may not be informative in females, and the diagnosis may be missed.
That is why we recommend considering molecular testing of ALG13 via gene panels for female patients with severe, early onset infantile spasms and global developmental delay with possible regression. If this variant is identified by genetic sequencing, it should be considered causative/pathogenic, as this variant may be more common in patients with severe neurological disease than previously expected.
The ALG13 gene is sequenced in a number of Next Generation Sequencing Panels offered by Courtagen, including:
- devSEEK® Triome
- epiSEEK® Triome
- epiSEEK Comprehensive
- epiSEEK® Spotlight Panel - Infantile Spasms
- epiSEEK® Spotlight Panel - EIEE
For more information about genetic testing services provided by Courtagen, please use the form on this page, and a representative will be in touch.