Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology
Authors: Elkhateeb Nour , Olivieri Giorgia , Siri Barbara , Stepien Karolina M. , Sharma Reena , Morris Andrew , Hartley Thomas , Crowther Laura , Grunewald Stephanie , Cleary Maureen , Mundy Helen , Chakrapani Anupam , Lachmann Robin , Murphy Elaine , Santra Saikat , Uudelepp Mari-Liis , Yeo Mildrid , Chan Alicia , Mills Philippa , Ridout Debora , Gissen Paul , Dionisi-Vici Carlo , Baruteau Julien 
Published: October 2022

ABSTRACTIntroductionArgininosuccinate lyase is integral to the urea cycle, which enables nitrogen waste and biosynthesis of arginine, a precursor of nitric oxide. Inherited argininosuccinate lyase deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy and movement disorder. Here we aim to characterise epilepsy, a common and neurodebilitating complication in argininosuccinic aciduria.Patients and MethodsWe conducted a retrospective study in seven tertiary metabolic centres in the UK, Italy and Canada from 2020 to 2022 to assess the phenotype of epilepsy in ASA and correlate it with clinical, biochemical, radiological and electroencephalographic data.ResultsThirty-seven patients aged 1 to 31 years old were included. Twenty-two (60%) patients presented epilepsy. Median age at epilepsy-onset was 24 months. Generalized tonic clonic and focal seizures were most common in early-onset patients whilst atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and 6 (27%) had partially controlled or refractory epilepsy. Epileptic patients presented with a severe neurodebilitating disease with higher rates of speech delay (p=0.04) and autism spectrum disorders (p=0.01) and more frequent arginine supplementation (p=0.01) compared to non-epileptic patients. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy-onset in early infancy (p=0.05) and electroencephalographic background asymmetry (p=0.0007) were significant predictors of partially controlled or refractory epilepsy.ConclusionsEpilepsy in argininosuccinic aciduria is frequent, polymorphic, associated with more frequent neurodevelopmental complications. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests roles of arginine toxicity and central dopamine deficiency.Key PointsEpilepsy in ASA is frequent, polymorphic, occurring in early childhood and associated with a more severe neurodevelopmental phenotype.Early-onset epilepsy and electroencephalographic background asymmetry are prognostic for pharmaco-resistance of epilepsy in ASA.Hyperammonaemia is suggested not to be the primary pathophysiological mechanism for epileptogenesis in ASA.Central dopamine deficiency is suggested to have a role in pathophysiology of epilepsy in ASA.Arginine-related neurotoxicity is suggested to be associated with increased in frequency and severity of epilepsy in ASA.