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Argininosuccinic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The diagnostic metabolic characteristic is argininosuccinic aciduria. Hyperammonemia may be massive in the neonatal form. In patients with variant forms of the disease, it is usually episodic and less dramatically elevated. Plasma concentrations of glutamine and alanine are mostly elevated while plasma citrulline is slightly increased as is urinary orotic acid. Plasma arginine may be low. Argininosuccinic acid is specific and best found in the urine. This compound is so efficiently excreted that it may be missed in the blood, as it can also overlie the peak for leucine or isoleucine.. High levels are found in the cerebrospinal fluid. In the urine, argininosuccinic acid is excreted in gram quantities. Values for argininosuccinic acid and its anhydride in the urine ranged from 1163 to 6060 mmol/mol creatinine [19]. However, it may sometimes be missed on routine assays even of the urine for amino acids because the compound is unstable, the peaks occur in a place unfamiliar to the operator, or they may overlap those of other amino acids. The best way to assay for argininosuccinic acid is to boil the urine; this quantitatively converts the compound to its anhydrides, which are then readily seen on the amino acid analyzer [27].
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In argininosuccinic aciduria, the defect is in the enzyme argininosuccinase localized in the liver, brain, and blood cells where only traces of argininosuccinase activity have been demonstrated. Large amounts of argininosuccinic acid accumulates in body fluids as a consequence of this lesion. The highest quantity is found in the cerebrospinal fluid and higher than in plasma. Massive amounts are excreted in the urine daily, comparable to the glomerular filtration rate. Beside the general neurological symptoms, this disease is characterized by ataxia, hepatomegaly, and brittle hair. An interesting observation indicates that thyroid hormones may be capable of inducing additional quantities of the deficient enzyme.
Amino acid disorders and urea cycle disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
This disorder is one of a group of conditions, known as the urea cycle disorders, in which the body’s ability to manage dietary protein is impaired. In argininosuccinic aciduria there is a deficiency or absence of the enzyme argininosuccinate lyase (ASL), which is an important part of the urea cycle. This leads to an accumulation of the amino acid argininosuccinic acid (hence the name), and may lead to a build-up of ammonia (and its related product glutamine) in the body, giving rise to the symptoms of the disorder.
Metabolomics markers in Neurology: current knowledge and future perspectives for therapeutic targeting
Published in Expert Review of Neurotherapeutics, 2020
Roberta Bonomo, Guido Cavaletti, Debra J. Skene
Considering the growing evidence of impaired circadian rhythms in Huntington’s disease (HD) animal models, Morton and colleagues investigated alterations in melatonin and cortisol levels in pre-symptomatic transgenic HD sheep [165]. The authors found normal concentrations of serotonin and cortisol, whereas levels of plasma melatonin were significantly elevated, thus suggesting a compensatory neuroprotective response of melatonin in the first stages of the disorder. A number of studies have reported raised levels of citrulline in both pre-clinical and clinical models of HD, suggesting a dysfunction in the urea and NO cycles [166–168]. The possible dysregulation of CCAAT-enhancer-binding proteins (C/EBP) due to mutant huntingtin has been proposed as a causative mechanism of argininosuccinic acid synthetase and argininosuccinase acid lyase suppression [166].
Metabolomics reveals the effects of hydroxysafflor yellow A on neurogenesis and axon regeneration after experimental traumatic brain injury
Published in Pharmaceutical Biology, 2023
En Hu, Teng Li, Zhilin Li, Hong Su, Qiuju Yan, Lei Wang, Haigang Li, Wei Zhang, Tao Tang, Yang Wang
‘Arginine and proline metabolism’ pathway is related to axon regeneration (Zhang et al. 2022). In addition, citrulline and argininosuccinic acid in the ‘arginine biosynthesis’ pathways strongly correlate to neurogenesis in depression (Taniguchi et al. 2021). Mechanically, the enhanced arginine metabolism supplies essential raw materials for axon regeneration and leads to insulin growth factor-1 (IGF-1) upregulation that eases neurogenesis (Taniguchi et al. 2021; Zhang et al. 2022). L-phenylalanine is a critical metabolite in the ‘phenylalanine, tyrosine and tryptophan biosynthesis pathway. In our study, it was markedly increased after TBI in the cortex and the hippocampus. HSYA further elevated l-phenylalanine intensity in the cortex but reduced it in the hippocampus. The discrepancy probably resulted from different morphological and metabolic patterns between the cortex and hippocampus (Hall et al. 2005; Osier et al. 2015; Zheng et al. 2020). Excessive phenylalanine inhibits neurite outgrowth (Hartwig et al. 2006) and induces oxidative stress (Fernandes et al. 2010). Therefore, the overexpressed phenylalanine found in our study may hamper post-TBI neurogenesis and axon regeneration. HSYA normalized the phenylalanine level in the hippocampus, which may create a permissive environment for neural restoration. The presumption is supported by a previous study in ischemic stroke, suggesting that HSYA elicits a neuroprotective effect by downregulating phenylalanine (Chen et al. 2019). However, phenylalanine reduces the viability of astrocytes (Preissler et al. 2016). In the subacute stage of TBI, astrocyte over-proliferates and forms scars around the wound, which obstacles axon elongation and neuron migration (Chen et al. 2019; Michinaga and Koyama Y 2021). Thus, the HSYA-augmented phenylalanine in the cortex may also facilitate neural rehabilitation by reducing astroglia scar formation.
Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis
Published in Expert Opinion on Orphan Drugs, 2018
Evelina Maines, Giovanni Piccoli, Antonia Pascarella, Francesca Colucci, Alberto B. Burlina
Increased level of Cit may be suggestive for ASSD, ASLD and citrin-D. In ASLD, argininosuccinic acid (ASA) will also be present. An increased Arg is suggestive for ARG1D [82], while a low Cit concentration can be detected in patients with CPS1D, NAGSD and OTCD.