Abstract
Introduction: Protein N-glycosylation is a post-translational modification with a significant influence on protein function and stability. Disorders of this pathway lead to highly heterogeneous and multi-systemic clinical findings.
ALG13 gene localized on X chromosome encodes a highly conserved transferase which catalyzes one of the first steps in the N-glycosylation pathway. Pathogenic variants in ALG13 (particularly variant c.320A>G) are associated with early infantile epileptic encephalopathy (EIEE36) and congenital disorder of glycosylation (ALG13-CDG).
Patient: The index case was born to non-consanguineous healthy Caucasian parents with unremarkable family history. Currently, he is a 4-year-old male, born prematurely at 33rd GW by C-section due to premature rupture of membranes.
Physical examination showed the distinct dysmorphic features - bilateral anotia associated with low set rudiments of the ears; plagiocephaly; frontal bossing; wide root and depressed nasal bridge. Other malformations included pectus excavatum, simian crease in the left palm, clinodactyly of the 5th finger and hepatosplenomegaly.
Haematological and biochemical examination detected thrombocytopenia and neutropenia. Transferrin isoeletric focusing was normal.
In the first year, the patient presented with necrotizing enterocolitis (with subsequent short bowel syndrome) and several sepses. Intractable epileptic seizures (mainly infantile spasms) developed during 6th month.
EEG recording was significantly abnormal - multifocal discharges above the posterior quadrants while awake and intermittent burst - suppression activity during sleep. Psychomotor development was delayed from birth with subsequent regression to newborn level evident from the age of 6 months (in connection with epilepsy) Methods: DNA was extracted from peripheral blood lymphocytes by standard extraction procedures (Magcore assay).
Whole exome sequencing was followed by bioinformatics analysis utilising the TRIO mode function. Filtration and interpretation of NGS data were performed using the software VarAFT.
Sanger DNA sequencing was used for the verification of the detected variant. Conclusion: Recurrent de novo variant c.320A>G within gene ALG13 has been mainly described in females (34 cases) but only in 2 males.
Manifestation of this pathogenic variant in males is slightly more pronounced, especially in facial dysmorphism and hearing loss. The mechanism of the pathogenicity is unclear.
We found this variant in another male patient with developmental delay, epileptic encephalopathy, hearing loss and facial dysmorphism. Manifestation of disorder is consistent with the description of another male patient by Galama et al., 2017.