Male proband with intractable seizures and a de novo start codon disrupting variant in GLUL.

Abstract

Biallelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females all with a de novo single nucleotide variant within the start codon or the 5'UTR region of GLUL that truncate 17 amino acids of the protein product, including its critical N-terminal degron sequence, resulting in a disorder of abnormal glutamine synthetase stability and manifesting as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.