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Argininosuccinic aciduria
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Jc Baruteau – One of the best experts on this subject based on the ideXlab platform.
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Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects.
Journal of Inherited Metabolic Disease, 2019Co-Authors: Jc Baruteau, Sandesh C S Nagamani, Ayelet Erez, Carmen Diez-fernandez, Shaul Lerner, Giusy Ranucci, Paul Gissen, Carlo Dionisi-vici, Johannes HäberleAbstract:The first patients affected by Argininosuccinic aciduria (ASA) were reported 60 years ago. The clinical presentation was initially described as similar to other urea cycle defects, but increasing evidence has shown overtime an atypical systemic phenotype with a paradoxical observation, that is, a higher rate of neurological complications contrasting with a lower rate of hyperammonaemic episodes. The disappointing long-term clinical outcomes of many of the patients have challenged the current standard of care and therapeutic strategy, which aims to normalize plasma ammonia and arginine levels. Interrogations have raised about the benefit of newborn screening or liver transplantation on the neurological phenotype. Over the last decade, novel discoveries enabled by the generation of new transgenic argininosuccinate lyase (ASL)-deficient mouse models have been achieved, such as, a better understanding of ASL and its close interaction with nitric oxide metabolism, ASL physiological role outside the liver, and the pathophysiological role of oxidative/nitrosative stress or excessive arginine treatment. Here, we present a collaborative review, which highlights these recent discoveries and novel emerging concepts about ASL role in human physiology, ASA clinical phenotype and geographic prevalence, limits of current standard of care and newborn screening, pathophysiology of the disease, and emerging novel therapies. We propose recommendations for monitoring of ASA patients. Ongoing research aims to better understand the underlying pathogenic mechanisms of the systemic disease to design novel therapies.
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Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer
Nature Communications, 2018Co-Authors: Jc Baruteau, Dany P. Perocheau, Joanna Hanley, Rajvinder Karda, Natalie Suff, Maëlle Lorvellec, Eridan Rocha-ferreira, Juan Antinao Diaz, Ahad A. RahimAbstract:Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and the citrulline-nitric oxide (NO) cycle producing NO. ASL-deficient patients present Argininosuccinic aciduria characterised by hyperammonaemia, multiorgan disease and neurocognitive impairment despite treatment aiming to normalise ammonaemia without considering NO imbalance. Here we show that cerebral disease in Argininosuccinic aciduria involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intravenous injection of AAV8 vector into adult or neonatal ASL-deficient mice demonstrates long-term correction of the hepatic urea cycle and the cerebral citrulline-NO cycle, respectively. Cerebral disease persists if ammonaemia only is normalised but is dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This correlates with behavioural improvement and reduced cortical cell death. Thus, neuronal oxidative/nitrosative stress is a distinct pathophysiological mechanism from hyperammonaemia. Disease amelioration by simultaneous brain and liver gene transfer with one vector, to treat both metabolic pathways, provides new hope for hepatocerebral metabolic diseases.
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Gene therapy in Argininosuccinic aciduria
bioRxiv, 2018Co-Authors: Jc Baruteau, Dany P. Perocheau, Joanna Hanley, Eridan Rocha Ferreira, Rajvinder Karda, Jo Ng, Natalie Suff, Ahad A. Rahim, Michael Hughes, Blerida BanushiAbstract:Argininosuccinate lyase (ASL) belongs to the liver-based urea cycle detoxifying ammonia, and the citrulline-nitric oxide cycle synthesising nitric oxide (NO). ASL-deficient patients present Argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with neurocognitive impairment. Current therapeutic guidelines aim to control ammonaemia without considering the systemic NO imbalance. Here, we observed a neuronal disease with oxidative/nitrosative stress in ASL-deficient mouse brains. A single systemic injection of gene therapy mediated by an adeno-associated viral vector serotype 8 (AAV8) in adult or neonatal mice demonstrated the long-term correction of the urea cycle and the citrulline-NO cycle in the brain, respectively. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This was correlated with behavioural improvement and a decrease of the cortical cell death rate. Thus, the cerebral disease in Argininosuccinic aciduria involves neuronal oxidative/nitrosative stress not mediated by hyperammonaemia, which is reversed by AAV gene transfer targeting the brain and the liver, acting on two different metabolic pathways via a single vector delivered systemically. This approach provides new hope for hepatocerebral metabolic diseases.
Ayelet Erez – One of the best experts on this subject based on the ideXlab platform.
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Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects.
Journal of Inherited Metabolic Disease, 2019Co-Authors: Jc Baruteau, Sandesh C S Nagamani, Ayelet Erez, Carmen Diez-fernandez, Shaul Lerner, Giusy Ranucci, Paul Gissen, Carlo Dionisi-vici, Johannes HäberleAbstract:The first patients affected by Argininosuccinic aciduria (ASA) were reported 60 years ago. The clinical presentation was initially described as similar to other urea cycle defects, but increasing evidence has shown overtime an atypical systemic phenotype with a paradoxical observation, that is, a higher rate of neurological complications contrasting with a lower rate of hyperammonaemic episodes. The disappointing long-term clinical outcomes of many of the patients have challenged the current standard of care and therapeutic strategy, which aims to normalize plasma ammonia and arginine levels. Interrogations have raised about the benefit of newborn screening or liver transplantation on the neurological phenotype. Over the last decade, novel discoveries enabled by the generation of new transgenic argininosuccinate lyase (ASL)-deficient mouse models have been achieved, such as, a better understanding of ASL and its close interaction with nitric oxide metabolism, ASL physiological role outside the liver, and the pathophysiological role of oxidative/nitrosative stress or excessive arginine treatment. Here, we present a collaborative review, which highlights these recent discoveries and novel emerging concepts about ASL role in human physiology, ASA clinical phenotype and geographic prevalence, limits of current standard of care and newborn screening, pathophysiology of the disease, and emerging novel therapies. We propose recommendations for monitoring of ASA patients. Ongoing research aims to better understand the underlying pathogenic mechanisms of the systemic disease to design novel therapies.
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Argininosuccinic aciduria: from a monogenic to a complex disorder
Genetics in Medicine, 2013Co-Authors: Ayelet ErezAbstract:In the early 1930s, phenylketonuria was among the first metabolic diseases to be defined. In the following years, multiple attempts to correlate genotype and phenotype in several inherited metabolic diseases, including phenylketonuria, were encountered with difficulties. It is becoming evident that the phenotype of metabolic disorders is often more multifaceted than expected from the disruption of a specific enzyme function caused by a single-gene disorder. Undoubtedly, revealing the factors contributing to the discrepancy between the loss of a single enzymatic function and the wide spectrum of clinical consequences would allow clinicians to optimize treatment for their patients. This article discusses several possible contributors to the unique, complex phenotypes observed in inherited metabolic disorders, using Argininosuccinic aciduria as a disease model. Genet Med 2013:15(4):251–257
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A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in Argininosuccinic aciduria
Molecular Genetics and Metabolism, 2012Co-Authors: Sandesh C S Nagamani, Oleg A. Shchelochkov, Mary A. Mullins, Susan Carter, Brendan C. Lanpher, Soledad Kleppe, Ayelet Erez, E. O'brian Smith, Juan C. MariniAbstract:Abstract Objective To compare the effects of combinatorial therapy with low-dose arginine and a nitrogen scavenging agent (sodium phenylbutyrate) vs. monotherapy with high-dose arginine on liver function tests in patients with Argininosuccinic aciduria (ASA). Study design Twelve patients with ASA were enrolled in a double-blind, placebo-controlled, cross-over study design. Subjects were randomized to receive either a low-dose of arginine therapy (100 mg·kg − 1 ·d − 1 ) combined with sodium phenylbutyrate (500 mg·kg − 1 ·d − 1 ) (LDA arm) or a high-dose of arginine alone (500 mg·kg − 1 ·d − 1 ) (HDA arm) for one week. At the end of one week of therapy, liver function tests were assessed and metabolite fluxes were measured using a multi-tracer stable isotope protocol. Results Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and measures of synthetic functions of the liver were the primary outcomes. Subjects had significantly increased levels of argininosuccinate ( P P Conclusions Administering higher doses of arginine in subjects with ASA results in increases in AST and ALT levels, especially in the subset of patients with elevated baseline aminotransferases. Hence, low-dose arginine sufficient to normalize arginine levels in plasma combined with nitrogen scavenging therapy should be considered as a therapeutic option for treatment of ASA in patients with elevations of hepatic aminotransferases.
Brian F. Meyer – One of the best experts on this subject based on the ideXlab platform.
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SHORT REPORT Open Access Novel mutations underlying Argininosuccinic aciduria in Saudi Arabia
, 2013Co-Authors: Faiqa Imtiaz, Moeen Al-sayed, Danyah Trabzuni, Bashair R Al-mubarak, Osama Alsmadi, Mohamed S. Rashed, Brian F. MeyerAbstract:Background: Argininosuccinic aciduria (ASAuria) is an autosomal recessive disorder of the urea cycle relatively common in Saudi Arabia as a consequence of extensive consanguinity. It is the most common urea cycle disorder identified in the Saudi population, which therefore prioritizes the need to delineate the underlying molecular defects leading to disease. Findings: We utilized Whole Genome Amplification (WGA), PCR and direct sequencing to identify mutations underlying ASAuria cases diagnosed by our institution. A missense mutation that accounts for 50 % of Saudi ASAuria patients was recently reported by our laboratory. In this study we report a further six novel mutations (and one previously reported) found in Saudi patients with ASAuria. The novel four missense, one nonsense and one splice-site mutation were confirmed by their absence in>300 chromosomes from the normal population. Pathogenicity of the novel splice-site mutation was also confirmed using reverse transcriptase-PCR analysis. Cross species amino acid conservation at the substituted residues described were observed in some but not all instances. Conclusions: Together, the eight mutations described by our laboratory, encompass>90 % of ASAuria patients in Saudi Arabia and add to about 45 other ASAuria mutations reported worldwide
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Novel mutations underlying Argininosuccinic aciduria in Saudi Arabia.
BMC Research Notes, 2010Co-Authors: Faiqa Imtiaz, Moeen Al-sayed, Danyah Trabzuni, Bashair R Al-mubarak, Osama Alsmadi, Mohamed S. Rashed, Brian F. MeyerAbstract:Background
Argininosuccinic aciduria (ASAuria) is an autosomal recessive disorder of the urea cycle relatively common in Saudi Arabia as a consequence of extensive consanguinity. It is the most common urea cycle disorder identified in the Saudi population, which therefore prioritizes the need to delineate the underlying molecular defects leading to disease. -
Identification of a common novel mutation in Saudi patients with Argininosuccinic aciduria
Journal of Inherited Metabolic Disease, 2005Co-Authors: Moeen Al-sayed, Faiqa Imtiaz, Osama Alsmadi, Mohamed S. Rashed, S. Alahmed, H. Khalil, Brian F. MeyerAbstract:We have identified a common novel mutation (Q354X) in the argininosuccinate lyase ( ASL ) gene in Saudi patients with Argininosuccinic aciduria (ASAuria; McKusick 207900). The two index patients were siblings, had a neonatal onset of the disease and were diagnosed based on the clinical presentation and confirmed by analysis of their dried blood spots (DBS) by tandem mass spectrometry (MS/MS). The ASL gene was then analysed by direct sequencing. A further 28 patients with a confirmed diagnosis of ASAuria based on MS/MS of their DBS were tested by sequencing for the presence of the Q354X mutation. This mutation was found in 14 out of the 28 patients (50%) tested. Our work indicates that the Q354X allele is common, may account for 50% of the abnormal ASL genes in the Saudi population, and is likely to be associated with the neonatal form of the disease. We recommend that all patients diagnosed with ASAuria in Saudi Arabia or of Arab origin be tested for this mutation and for Q116X, which has been described previously. In addition, further analysis is needed to identify other underlying disease mutations for ASAuria in the Saudi population.