Argininosuccinate neurotoxicity and prevention by creatine in argininosuccinate lyase deficiency: An in vitro study in rat three‐dimensional organotypic brain cell cultures

Dı́ez-Fernández, Carmen; Hertig, Damian; Loup, Marc; Diserens, Gaëlle; Henry, Hugues; Vermathen, Peter; Nuoffer, Jean‐Marc; Häberle, Johannes; Braissant, Olivier

doi:10.1002/jimd.12090

Cited by 13 publications

(16 citation statements)

References 30 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Argininosuccinic acid is a precursor to fumarate in the citric acid cycle via argininosuccinate lyase. Argininosuccinic acid is particularly toxic to astrocytes and neurons in organotypic cell cultures by decreasing their viability [98]. In the knockout mice model of argininosuccinic aciduria, increased brain levels of nitrite, nitrate, and nitrotyrosine indicated that oxidative/nitrative stress are involved in neurotoxicity [99,100].…”

Section: Candidate Biomarkers Of Occupational Exposure To Cr(vi)mentioning

confidence: 99%

HBM4EU Chromates Study: Urinary Metabolomics Study of Workers Exposed to Hexavalent Chromium

et al. 2022

View full text Add to dashboard Cite

Exposure to hexavalent chromium Cr(VI) may occur in several occupational activities, placing workers in many industries at risk for potential related health outcomes. Untargeted metabolomics was applied to investigate changes in metabolic pathways in response to Cr(VI) exposure. We obtained our data from a study population of 220 male workers with exposure to Cr(VI) and 102 male controls from Belgium, Finland, Poland, Portugal and the Netherlands within the HBM4EU Chromates Study. Urinary metabolite profiles were determined using liquid chromatography mass spectrometry, and differences between post-shift exposed workers and controls were analyzed using principal component analysis. Based on the first two principal components, we observed clustering by industrial chromate application, such as welding, chrome plating, and surface treatment, distinct from controls and not explained by smoking status or alcohol use. The changes in the abundancy of excreted metabolites observed in workers reflect fatty acid and monoamine neurotransmitter metabolism, oxidative modifications of amino acid residues, the excessive formation of abnormal amino acid metabolites and changes in steroid and thyrotropin-releasing hormones. The observed responses could also have resulted from work-related factors other than Cr(VI). Further targeted metabolomics studies are needed to better understand the observed modifications and further explore the suitability of urinary metabolites as early indicators of adverse effects associated with exposure to Cr(VI).

show abstract

Section: Candidate Biomarkers Of Occupational Exposure To Cr(vi)mentioning

confidence: 99%

HBM4EU Chromates Study: Urinary Metabolomics Study of Workers Exposed to Hexavalent Chromium

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Developing alternatives models with induced pluripotent stem cells derived neurons or neuronal or organotypic cultures will provide surrogates to better study the complex pathophysiology of this disorder. 49,50…”

Section: Discussionmentioning

confidence: 99%

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

et al. 2023

View full text Add to dashboard Cite

Objective: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide.Inherited ASL 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 characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. Methods:We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of | 1613 ELKHATEEB et al. | INTRODUCTIONArgininosuccinate lyase (ASL) is the only enzyme in mammals enabling endogenous arginine synthesis. 1 This cytosolic enzyme, which breaks down argininosuccinic acid into arginine and fumarate, is integral to the citrulline-nitric oxide (NO) cycle, which enables NO synthesis from arginine, and the urea cycle, a liver-based pathway enabling nitrogen wasting through clearance of neurotoxic ammonia. 1 ASL deficiency causes argininosuccinic aciduria (ASA) (OMIM#207900), an autosomal recessive metabolic disease and the second most common urea cycle disorder with a prevalence of one in 110 000 live births. 2 Patients present acute hyperammonemia either in the neonatal period defined as early-onset phenotype, or later in life in late-onset presentation. 3 Most patients will present a multisystemic phenotype with chronic neurological, hepatic, and gastrointestinal conditions, and anemia and high blood pressure. 4 The neurological phenotype entails intellectual and motor disability, behavioral changes, and epilepsy, which can occur in the absence epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data.Results: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. 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 = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy.Significance: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic...

show abstract

“…Analysing metabolites from cerebrospinal fluid and MRI spectroscopy with prospective monitoring will provide better tools to understand the pathophysiology of the epilepsy and neurological disease in ASA. Developing alternatives models with induced pluripotent stem cells derived neurons or neuronal or organotypic cultures will provide surrogates to better study the complex pathophysiology of this disorder (43,44).…”

Section: Discussionmentioning

confidence: 99%

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology

Elkhateeb

Olivieri

Stępień

et al. 2022

Preprint

View full text Add to dashboard Cite

IntroductionArgininosuccinate 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.

show abstract

Argininosuccinate neurotoxicity and prevention by creatine in argininosuccinate lyase deficiency: An in vitro study in rat three‐dimensional organotypic brain cell cultures

Cited by 13 publications

References 30 publications

HBM4EU Chromates Study: Urinary Metabolomics Study of Workers Exposed to Hexavalent Chromium

HBM4EU Chromates Study: Urinary Metabolomics Study of Workers Exposed to Hexavalent Chromium

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology

Contact Info

Product

Resources

About