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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.
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Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer
Nature Publishing Group, 2018Co-Authors: Jc Baruteau, Dany P. Perocheau, Joanna Hanley, Rajvinder Karda, Natalie Suff, Maëlle Lorvellec, Eridan Rocha-ferreira, Juan Antinao Diaz, Ahad A. RahimAbstract:Patients with mutations in the ASL gene present with Argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice
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A gene therapy approach for Argininosuccinic aciduria
2017Co-Authors: Jc BaruteauAbstract:Argininosuccinate lyase (ASL) is central to two metabolic pathways: i) the liver-based urea cycle, which detoxifies ammonia, ii) the citrulline-nitric oxide cycle, which synthesises nitric oxide from L-arginine. Patients deficient in argininosuccinate lyase present with Argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with a severe neurological phenotype. Compared to other urea cycle disorders, Argininosuccinic aciduria presents a low frequency of hyperammonaemic crises but a high frequency of cognitive impairment. This paradox questions the causative role of hyperammonaemia in the neuropathology. An observational UK-wide study was designed to study the natural history. Data about clinical status, neuroimaging and hASL genotyping were collected from 56 patients. Six had molecular analysis performed in this work. A homogeneous neurological phenotype was observed in most patients. hASL sequencing was available in 19 patients and 20 mutations (1) were found. A genotype-phenotype correlation showed that the prognosis was more likely related to genotype rather than severity of hyperammonaemia. The hypomorph mouse model AslNeo/Neo mimicking the human disease was used to study the neuropathology in Argininosuccinic aciduria and showed a neuronal disease with oxidative/nitrosative stress. To define the role of hyperammonaemia in this finding, a gene therapy approach using an adeno-associated viral vector (AAV) encoding the murine Asl gene was delivered in AslNeo/Neo mice. The long-term correction of both pathways was observed: i) the urea cycle after a single systemic injection in adult mice; ii) the citrulline-nitric oxide cycle in the brain after a single systemic injection at birth. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This demonstrated the key-role of a neuronal disease independent from hyperammonaemia in Argininosuccinic aciduria. This work provides new insight in the neuropathology of Argininosuccinic aciduria and a proof of concept of successful AAV-mediated gene therapy.
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, Mary A. Mullins, Susan Carter, Brendan C. Lanpher, Soledad Kleppe, E. O'brian Smith, Oleg A. Shchelochkov, Ayelet Erez, 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.
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Optimizing therapy for Argininosuccinic aciduria.
Molecular Genetics and Metabolism, 2012Co-Authors: Sandesh C S Nagamani, Brendan Lee, Ayelet ErezAbstract:Argininosuccinic aciduria (ASA) is a urea cycle disorder with a complex phenotype. In spite of a lower risk for recurrent hyperammonemic episodes as compared to the proximal disorders of ureagenesis, subjects with ASA are at risk for long-term complications including, poor neurocognitive outcome, hepatic disease and systemic hypertension. These complications can occur in spite of current standard therapy that includes dietary modifications and arginine supplementation suggesting that the presently available therapy is suboptimal. In this article, we discuss the natural history of ASA and the recent mechanistic insights from animal studies that have shown the requirement of argininosuccinate lyase, the enzyme deficient in ASA, for systemic nitric oxide production. These findings may have therapeutic implications and may help optimize therapy in ASA.
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argininosuccinate lyase deficiency Argininosuccinic aciduria and beyond
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2011Co-Authors: Ayelet Erez, Sandesh C S NagamaniAbstract:The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate Lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, i.e. the breakdown of Argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of Argininosuccinic acid in tissues, and excretion of Argininosuccinic acid in urine leading to the condition Argininosuccinic aciduria, ASA. ASA is an autosomal recessive disorder and is the second most common urea cycle disorder. In addition to the accumulation of Argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine which is in common with all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell’s needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of Argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed.
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.
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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.
Sandesh C S Nagamani - 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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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, Mary A. Mullins, Susan Carter, Brendan C. Lanpher, Soledad Kleppe, E. O'brian Smith, Oleg A. Shchelochkov, Ayelet Erez, 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.
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Optimizing therapy for Argininosuccinic aciduria.
Molecular Genetics and Metabolism, 2012Co-Authors: Sandesh C S Nagamani, Brendan Lee, Ayelet ErezAbstract:Argininosuccinic aciduria (ASA) is a urea cycle disorder with a complex phenotype. In spite of a lower risk for recurrent hyperammonemic episodes as compared to the proximal disorders of ureagenesis, subjects with ASA are at risk for long-term complications including, poor neurocognitive outcome, hepatic disease and systemic hypertension. These complications can occur in spite of current standard therapy that includes dietary modifications and arginine supplementation suggesting that the presently available therapy is suboptimal. In this article, we discuss the natural history of ASA and the recent mechanistic insights from animal studies that have shown the requirement of argininosuccinate lyase, the enzyme deficient in ASA, for systemic nitric oxide production. These findings may have therapeutic implications and may help optimize therapy in ASA.
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argininosuccinate lyase deficiency Argininosuccinic aciduria and beyond
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2011Co-Authors: Ayelet Erez, Sandesh C S NagamaniAbstract:The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate Lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, i.e. the breakdown of Argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of Argininosuccinic acid in tissues, and excretion of Argininosuccinic acid in urine leading to the condition Argininosuccinic aciduria, ASA. ASA is an autosomal recessive disorder and is the second most common urea cycle disorder. In addition to the accumulation of Argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine which is in common with all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell’s needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of Argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed.
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Argininosuccinate Lyase Deficiency – Argininosuccinic aciduria and Beyond
American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2011Co-Authors: Ayelet Erez, Sandesh C S Nagamani, Brendan LeeAbstract:The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, that is, the breakdown of Argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of Argininosuccinic acid in tissues, and excretion of Argininosuccinic acid in urine leading to the condition Argininosuccinic aciduria (ASA). ASA is an autosomal recessive disorder and is the second most common UCD. In addition to the accumulation of Argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine, a feature common to all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine, and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell's needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy, and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of Argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed.
Clare E Beesley - One of the best experts on this subject based on the ideXlab platform.
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Expanding the phenotype in Argininosuccinic aciduria: need for new therapies
Journal of Inherited Metabolic Disease, 2017Co-Authors: Jc Baruteau, Elisabeth Jameson, Andrew A M Morris, Anupam Chakrapani, Saikat Santra, Suresh Vijay, Huriye Kocadag, Clare E Beesley, Stephanie Grunewald, Elaine MurphyAbstract:Objectives This UK-wide study defines the natural history of Argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs. Methods Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping. Results Fifty-six patients were defined as early-onset ( n = 23) if symptomatic
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expanding the phenotype in Argininosuccinic aciduria need for new therapies
Journal of Inherited Metabolic Disease, 2017Co-Authors: Jc Baruteau, Elisabeth Jameson, Andrew A M Morris, Anupam Chakrapani, Saikat Santra, Suresh Vijay, Huriye Kocadag, Clare E BeesleyAbstract:Objectives This UK-wide study defines the natural history of Argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.