Focal epilepsy with sensory seizures associated with arginine:glycine amidinotransferase deficiency: A clinical and advanced magnetic resonance imaging study

We aim to determine whether epilepsy can be considered part of the arginine:glycine amidinotransferase (AGAT) deficiency syndrome phenotype and to identify its associated electroclinical signatures. We reviewed clinical data from our center, identifying individuals with AGAT deficiency. Each individual underwent a dedicated epilepsy assessment with electroencephalography and 3-T brain magnetic resonance imaging (MRI). Additionally, 30 age- and sex-matched healthy controls (18 females, 28.2 ± 3.7 years old) were recruited for advanced MRI analysis. A family with four affected members carrying homozygous AGAT c.446>A:p.Trp149* variant was identified. Two individuals had focal epilepsy with sensory seizures characterized by a prominent "tingling" sensation. Three experienced febrile seizures plus and marked temperature sensitivity. Corpus callosum dysmorphisms were observed in three cases. Despite creatine supplementation, cortical thickness was significantly reduced across multiple brain regions compared to controls, as indicated by Z-scores. A brain map of AGAT mRNA expression revealed lower expression in the parieto-occipital areas. Our findings suggest that focal epilepsy with sensory seizures and temperature-related seizures may be part of the AGAT deficiency spectrum. Furthermore, significant brain atrophy was demonstrated, despite creatine supplementation. The sensory-predominant epilepsy phenotype aligns with observed atrophy and AGAT-mRNA regional expression patterns, supporting its biological plausibility.