期刊
JOURNAL OF INHERITED METABOLIC DISEASE
卷 42, 期 6, 页码 1147-1161出版社
WILEY
DOI: 10.1002/jimd.12047
关键词
arginine; argininosuccinate lyase; argininosuccinic aciduria; creatine; nitric oxide; nitrosative stress; oxidative stress; urea cycle
资金
- Adelis Foundation
- Dukler Fund for Cancer Research
- Estate of Fannie Sherr
- European Research Council [ERC614204]
- Henry S. and Anne S. Reich Research Fund
- Israel Science Foundation [ISF-1343/13, 1952/13]
- Medical Research Council [MR/N019075/1]
- NIHR Great Ormond Street Hospital Biomedical Research Centre
- Paul Sparr Foundation
- Saul and Theresa Esman Foundation
- Spendenstiftung Bank Vontobel
- Swiss National Science Foundation [320030_176088]
- Swiss National Science Foundation (SNF) [320030_176088] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MR/S019111/1, MR/N019075/1] Funding Source: UKRI
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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