Ferretti Alessandro, Battini Roberta, Gagliardo Olga, Verrigni Daniela, Manca Maria Beatrice, Ferrari Anna Rita, Salerno Gerardo, Boccia Rosanna, Polese Daniela, Cocco Chiara, Zampogna Stefania, Di Nardo Giovanni, Evangelisti Melania, Pagani Jacopo, Bruni Oliviero, Romano Andrea, Piastra Marco, Simmaco Maurizio, Rocco Monica, Novelli Antonio, Carducci Claudia, Bozzao Alessandro, Parisi Pasquale
Pediatrics Unit, Neuroscience, Mental Health, and Sensory Organs Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Epilepsia. 2025 Jul 17. doi: 10.1111/epi.18565.
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.
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.
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.
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.
L-精氨酸：甘氨酸脒基转移酶（AGAT）缺乏症是一种罕见的常染色体隐性疾病，会影响肌酸生物合成，导致发育迟缓、智力障碍和肌病。与其他肌酸缺乏症不同，其与癫痫的关联仍不明确。本研究报告了首例AGAT缺乏症相关的癫痫病例，分析了发作模式及对一水肌酸补充治疗的反应。
我们回顾性分析了通过全国合作确定的两名AGAT缺乏症先证者。采用电喷雾电离串联质谱法和高效液相色谱法对血浆和尿液中的肌酸和胍乙酸（GAA）水平进行生化评估。进行脑磁共振波谱分析以评估补充肌酸前后的脑肌酸水平。
两名先证者均在GATM基因中携带纯合的c.446G>A、p.（Trp149Ter）突变，被归类为致病性突变。第一名先证者出生时被诊断出，并在4个月时开始接受肌酸治疗，其精神运动发育正常，但在6岁时出现局灶性癫痫，使用卡马西平控制。第二名先证者在5岁时被诊断出，表现为精神运动发育迟缓、行为障碍，4岁起出现不明原因的夜间发作，后来在清醒时出现局灶性强直发作。起初，该先证者对卡马西平无反应；使用丙戊酸盐和拉科酰胺实现了癫痫控制。由于第一名先证者在癫痫发作后未改变治疗方案，而第二名先证者在癫痫得到控制后才开始补充肌酸，因此无法就补充肌酸在AGAT缺乏症相关癫痫中的作用得出明确结论。
本研究报告了首例AGAT缺乏症相关的癫痫病例，提示其患病率可能被低估。AGAT相关癫痫似乎是相关发育性脑病的一部分，表现为局灶性发作，对精神运动发育影响最小。在AGAT缺乏症中，癫痫不像其他肌酸缺乏症那样与GAA蓄积有关，而是与脑肌酸水平低有关，这可能会影响γ-氨基丁酸能神经传递和癫痫阈值。补充肌酸在癫痫控制中的作用值得进一步研究。
