Baruteau, J;
Diez-Fernandez, C;
Lerner, S;
Ranucci, G;
Gissen, P;
Dionisi-Vici, C;
Nagamani, S;
... Häberle, J; + view all
(2019)
Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects.
Journal of Inherited Metabolic Disease
, 42
(6)
pp. 1147-1161.
10.1002/jimd.12047.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/jimd.12047 |
| Publisher version: | https://doi.org/10.1002/jimd.12047 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | arginine, argininosuccinate lyase, argininosuccinic aciduria, creatine, nitric oxide, nitrosative stress, oxidative stress, urea cycle |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10075553 |
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