Header

UZH-Logo

Maintenance Infos

Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects


Baruteau, Julien; Diez-Fernandez, Carmen; Lerner, Shaul; Ranucci, Giusy; Gissen, Paul; Dionisi-Vici, Carlo; Nagamani, Sandesh; Erez, Ayelet; Häberle, Johannes (2019). Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects. Journal of Inherited Metabolic Disease, 42(6):1147-1161.

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.

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.

Statistics

Citations

Dimensions.ai Metrics
5 citations in Web of Science®
4 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

12 downloads since deposited on 07 Feb 2020
12 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:November 2019
Deposited On:07 Feb 2020 11:27
Last Modified:07 Feb 2020 11:27
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0141-8955
OA Status:Green
Publisher DOI:https://doi.org/10.1002/jimd.12047
PubMed ID:30723942

Download

Green Open Access

Download PDF  'Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects'.
Preview
Content: Accepted Version
Filetype: PDF
Size: 181kB
View at publisher