A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged...

Two clinical phenotypes are associated with GLUL mutations, from different inheritance mode. Recessive forms are associated with congenital glutamine deficiency, manifesting with severe brain malformation, multiorgan failure, and early death. A dominant form has recently been described, which involves dysregulated glutamine synthetase stability and manifests as developmental and epileptic encephalopathy (DEE). All reported dominant mutations are within the start codon or the 5 ^' UTR. Here, we report a DEE patient with a de novo variant, c.522_536dup, in the catalytic domain of GLUL. Her brain MRI demonstrated involvement of the white matter signal-intensity alterations and markedly enlarged perivascular spaces. In vitro overexpression assays revealed no difference in protein expression or enzyme activity between the mutant and wild-type under normal glutamine conditions. However, under either low or high glutamine concentrations, the mutant exhibited significantly higher enzyme activity than the wild-type, indicating disrupted regulation of glutamine synthetase activity. This study expands the spectrum of variants, provides further evidence for the role of enzyme stability in gain-of-function variants, and highlights enlarged perivascular spaces as a diagnostic clue in GLUL-related disorders.