Analysis of novel ARG1 mutations causing hyperargininemia and correlation with arginase I activity in erythrocytes

Carvalho, Daniel R.; Brand, Guilherme D.; Brum, Jaime Moritz; Takata, Reinaldo Issao; Speck‐Martins, Carlos E.; Pratesi, Riccardo

doi:10.1016/j.gene.2012.08.003

Cited by 23 publications

(22 citation statements)

References 36 publications

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“…Many different pathogenic mutations have been described (Uchino et al 1995;Vockley et al 1994Vockley et al , 1996Hertecant et al 2009;Carvalho et al 2012a;Wu et al 2013;Cohen et al 2012;Baranello et al 2014; Scaglia and Lee 2006), including a complex re-arrangement (Mohseni et al 2014) and whole-gene deletion (Korman et al 2004). Hyperargininemia is most commonly caused by heterogeneous missense mutations in the occurring in highly conserved regions of the ARG1 gene (Vockley et al 1996) that disrupt the active sites required for the catalytic reaction or interfere with the assembly of the protein trimer (Ash et al 1998).…”

Section: Geneticsmentioning

confidence: 99%

Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature

et al. 2015

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Hyperargininemia is caused by deficiency of arginase 1, which catalyzes the hydrolysis of L-arginine to urea as the final enzyme in the urea cycle. In contrast to other urea cycle defects, arginase 1 deficiency usually does not cause catastrophic neonatal hyperammonemia but rather presents with progressive neurological symptoms including seizures and spastic paraplegia in the first years of life and hepatic pathology, such as neonatal cholestasis, acute liver failure, or liver fibrosis. Some patients have developed hepatocellular carcinoma. A usually mild or moderate hyperammonemia may occur at any age. The pathogenesis of arginase I deficiency is yet not fully understood. However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. This article provides an update on the first patients ever described, gives an overview of the distinct clinical characteristics, biochemical as well as genetical background and discusses treatment options.

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Section: Geneticsmentioning

confidence: 99%

Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature

et al. 2015

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“…In the liver, ARG1 hydrolyzes arginine into ornithine, which re-enters the urea cycle as urea and then is excreted as waste. Multiple heterogeneous missense and nonsense mutations and deletions, resulting in an inability to detoxify ammonia and an elevation in arginine, have been described in diverse human populations [1-8]. Variability in penetrance is seen: affected children can present neonatally with severe hyperammonemia [4,9], but ARG1 deficiency usually presents in late infancy.…”

Section: 1 Introductionmentioning

confidence: 99%

Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse

Kasten

Bhargava

et al. 2013

Molecular Genetics and Metabolism

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Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia, which lead to neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation; uncommonly, patients suffer early death from this disorder. In a murine targeted knockout model, onset of the phenotypic abnormality is heralded by weight loss at around day 15, and death occurs typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. This discrepancy between the more attenuated juvenile-onset human disease and the lethal neonatal murine model has remained suboptimal for studying and developing therapy for the more common presentation of argianse deficiency. These investigations aimed to address this issue by creating an adult conditional knockout mouse to determine whether later onset of arginase deficiency also resulted in lethality. Animal survival and ammonia levels, body weight, circulating amino acids, and tissue arginase levels were examined as outcome parameters after widespread Cre-recombinase activation in a conditional knockout model of arginase 1 deficiency. One hundred percent of adult female and 70 percent of adult male mice died an average of 21.0 and 21.6 days, respectively, after the initiation of tamoxifen administration. Animals demonstrated elevated circulating ammonia and arginine at the onset of phenotypic abnormalities. In addition, brain and liver amino acids demonstrated abnormalities. These studies demonstrate that (a) the absence of arginase in adult animals results in a disease profile (leading to death) similar to that of the targeted knockout and (b) the phenotypic abnormalities seen in the juvenile-onset model are not exclusive to the age of the animal but instead to the biochemistry of the disorder. This adult model will be useful for developing gene- and cell-based therapies for this disorder that will not limited by by the small animal size of neonatal therapy and for developing a better understanding of the characteristics of hyperargininemia.

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“…Onset is usually in late infancy, and may be insidious, leading to misdiagnosis with CP . Additional clinical features are epilepsy and intellectual disability . A careful history elucidating the presence of slowly progressive symptoms, or an acute presentation with encephalopathy and vomiting associated with hyperammonemia, if one occurs, help to distinguish this disorder from CP.…”

Section: Selected Disorders With Prominent Spasticitymentioning

confidence: 99%

“…32 Additional clinical features are epilepsy and intellectual disability. 33,34 A careful history elucidating the presence of slowly progressive symptoms, or an acute presentation with encephalopathy and vomiting associated with hyperammonemia, if one occurs, help to distinguish this disorder from CP. The diagnosis is suggested by raised arginine concentrations on plasma amino acid analysis, and now typically confirmed with molecular genetic analysis.…”

Section: Arginase Deficiencymentioning

confidence: 99%

Genetic mimics of cerebral palsy

et al. 2019

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The term “cerebral palsy mimic” is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have specific disease‐modifying treatment. In this article, we discuss clinical features that should alert the clinician to the possibility of a cerebral palsy mimic, provide a practical framework for selecting and interpreting neuroimaging, biochemical, and genetic investigations, and highlight selected conditions that may present with predominant spasticity, dystonia/chorea, and ataxia. Making a precise diagnosis of a genetic disorder has important implications for treatment, and for advising the family regarding prognosis and genetic counseling. © 2019 International Parkinson and Movement Disorder Society

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Analysis of novel ARG1 mutations causing hyperargininemia and correlation with arginase I activity in erythrocytes

Cited by 23 publications

References 36 publications

Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature

Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature

Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse

Genetic mimics of cerebral palsy

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