Epilepsy expands the phenotype of L-arginine:glycine amidinotransferase deficiency

Objective: L-arginine:glycine amidinotransferase (AGAT) deficiency is a rare autosomal recessive disorder affecting creatine biosynthesis, leading to developmental delay, intellectual disabilities, and myopathy. Unlike other creatine deficiency disorders, its link to epilepsy remains uncertain. This study presents the first reported epilepsy cases in AGAT deficiency, analyzing seizure patterns and response to creatine monohydrate supplementation. Methods: We retrospectively analyzed two AGAT-deficient probands identified through a national collaboration. Biochemical assessments of creatine and guanidinoacetate (GAA) levels in plasma and urine were performed using electrospray ionization tandem mass spectrometry and high-performance liquid chromatography methods. Brain magnetic resonance spectroscopy was conducted to evaluate cerebral creatine levels pre- and postsupplementation. Results: Both probands carried the homozygous c.446G>A, p.(Trp149Ter) mutation in GATM, classified as pathogenic. The first, diagnosed at birth and treated with creatine from 4 months, had normal psychomotor development but developed focal epilepsy at 6 years, controlled with carbamazepine. The second, diagnosed at 5 years, presented with psychomotor delay, behavioral disturbances, and nocturnal seizures with unknown origin from age 4 years, later developing focal tonic seizures while awake. Initially the proband was unresponsive to carbamazepine; seizure control was achieved with valproate and lacosamide. Definitive conclusions on the role of creatine supplementation in epilepsy associated with AGAT deficiency cannot be drawn, as it was not modified after seizure onset in the first proband and introduced only after seizure control in the second. Significance: This study presents the first cases of epilepsy in AGAT deficiency, suggesting its prevalence may be underestimated. AGAT-related epilepsy appears to be part of the associated developmental encephalopathy, with focal seizures and minimal impact on psychomotor development. In AGAT deficiency, epilepsy is not linked to GAA accumulation as in other creatine deficiency disorders but rather to low brain creatine levels, which may affect γ-aminobutyric acidergic neurotransmission and seizure thresholds. The role of creatine supplementation in seizure control warrants further investigation.