Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arginase deficiency is an urea cycle disorder that generally presents with mental retardation and spasticity, yet uncommonly with episodes of hyperammonemia. A female adolescent with arginase deficiency developed hyperammonemic episodes temporally related to her menstrual cycle, which ceased upon adequate treatment with depot medroxy progesterone acetate. A similar case was previously reported. A catamenial trigger should be considered in adolescent female arginase-deficient patients with episodes of hyperammonemia.
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PMID:A patient with arginase deficiency and episodic hyperammonemia successfully treated with menses cessation. 1696

In humans, arginase I (AI)-deficiency results in hyperargininemia, a metabolic disorder with symptoms of progressive neurological and intellectual impairment, spasticity, persistent growth retardation, and episodic hyperammonemia. A deficiency of arginase II (AII) has never been detected and the clinical disorder, if any, associated with its deficiency has not been defined. Since the spasticity and paucity of hyperammonemic crises seen in human AI-deficient patients are not features of the other urea cycle disorders, the likelihood of ammonia as the main neuropathogenic agent becomes extremely low, and the modest elevations of arginine seen in the brains of our mouse model of hyperargininemia make it an unlikely candidate as well. Specific guanidino compounds, direct or indirect metabolites of arginine, are elevated in the blood of patients with uremia. Other guanidino compounds are also increased in plasma and cerebrospinal fluid of hyperargininemic patients making them plausible as neurotoxins in these disorders. We analyzed several guanidino compounds in our arginase single and double knockout animals and found that alpha-keto-delta-guanidinovaleric acid, alpha-N-acetylarginine, and argininic acid were increased in the brain tissue from the AI knockout and double knockout animals. Several compounds were also increased in the plasma, liver, and kidneys. This is the first time that several of the guanidino compounds have been shown to be elevated in the brain tissue of an arginase-deficient mammal, and it further supports their possible role as the neuropathogenic agents responsible for the complications seen in arginase deficiency.
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PMID:Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia. 1799 38

The platinum compound cisplatin is one of the most potent chemotherapy agents available to treat various malignancies. Nephrotoxicity is a common complication of cisplatin chemotherapy, which involves increased oxidative and nitrosative stress, limiting its clinical use. In this study, we have investigated the effects of a nonpsychoactive cannabinoid cannabidiol, which was reported to exert antioxidant effects and has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in patients in a mouse model of cisplatin-induced nephropathy. Cisplatin induced increased expression of superoxide-generating enzymes RENOX (NOX4) and NOX1, enhanced reactive oxygen species generation, inducible nitric-oxide synthase expression, nitrotyrosine formation, apoptosis (caspase-3/7 activity, DNA fragmentation, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining), poly(ADP-ribose) polymerase activity, and inflammation (tumor necrosis factor-alpha and interleukin-1beta) in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum blood urea nitrogen and creatinine levels) 72 h after the administration of the drug. Treatment of mice with cannabidiol markedly attenuated the cisplatin-induced oxidative/nitrosative stress, inflammation, and cell death in the kidney, and it improved renal function. Thus, our results suggest that cannabidiol may represent a promising new protective strategy against cisplatin-induced nephrotoxicity.
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PMID:Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. 1907 81

Individuals with a proximal urea cycle disorder, such as carbamoyl phosphate synthetase deficiency 1 or ornithine transcarbamylase deficiency, may present with encephalopathy resulting from hyperammonemia. The clinical presentation of arginase deficiency is considerably different, characterized by progressive spasticity involving the lower extremities and usually dementia. Diagnosis may be delayed, and patients are often thought to have cerebral palsy. The true etiology of brain injury in arginase deficiency is unknown, but is not thought to be due to hyperammonemia and brain swelling, the mechanism of injury recognized in ornithine transcarbamylase deficiency. Elevated arginine could augment nitric oxide synthesis, leading to oxidative damage. The hypothesis for the present study was that specific brain vulnerability in arginase deficiency would involve microstructural alterations in corticospinal tracts and that this finding, as measured by diffusion tensor imaging, would differ from age-matched control subjects and those with ornithine transcarbamylase deficiency. Diffusion tensor imaging data were compared for a 17-year-old male patient with arginase deficiency, age-matched normal control subjects, and age-matched individuals with ornithine transcarbamylase deficiency. Significant differences were found in suspected areas of interest, specifically in the corticospinal tracts. This finding confirms the hypothesis that the mechanism of injury in arginase deficiency, although still unknown, is unlikely to be similar to that causing ornithine transcarbamylase deficiency.
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PMID:Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. 2000 62

The paucity of hyperammonemic crises together with spasticity, only seen in human arginase I deficient patients and not in patients with other urea cycle disorders, forces a search for candidates other than ammonia to associate with the pathophysiology and symptomatology. Therefore, we determined arginine together with some catabolites of arginine in blood and cerebrospinal fluid of these patients as well as in extremely rare post-mortem brain material of two patients with argininemia. The levels of alpha-keto-delta-guanidinovaleric acid, argininic acid and alpha-N-acetylarginine correlate with the arginine levels in blood and cerebrospinal fluid of patients with imposed or spontaneous protein restriction. The levels in blood are higher than the upper limit of normal in all studied patients. In addition to the highly increased levels of these same compounds in blood of a child with argininemia, the increase of guanidinoacetic acid, 24h before death, is remarkable. However, the manifest increases of these studied catabolites of arginine are not seen in post-mortem brain material of the same pediatric patient. Otherwise a clear increase of guanidinoacetic acid in post-mortem brain material of an adult patient was shown. A similar, comparable increase of homoarginine in both studied post-mortem brain materials is observed. Therefore the study of the pathobiochemistry of arginine in argininemia must be completed in the future by the determination of the end catabolites of the nitric oxide and agmatine biosynthesis pathways in the knockouts as well as in the patients to evaluate their role, together with the here studied catabolites, as candidates for association with pathophysiology and symptomatology.
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PMID:Guanidino compound levels in blood, cerebrospinal fluid, and post-mortem brain material of patients with argininemia. 2017 99

Enzyme defects of the urea cycle typically present with significant hyperammonemia and its associated toxicity, in the first few months of life. However, arginase I (ARG1) deficiency, a rare autosomal recessive disorder, has classically been the exception. ARG1 deficiency usually presents later in life with spasticity, seizures, failure to thrive and developmental regression. Neonatal and early infantile presentation of ARG1 deficiency with severe hyperammonemia remains rare and only six such cases have been described. We report a severely affected infant with ARG1 deficiency who presented at 6 weeks of age with lethargy, poor feeding and severe encephalopathy caused by hyperammonemia. The clinical and biochemical features of the proband and six other previously reported cases with neonatal or infantile-onset presentation of ARG1 deficiency with hyperammonemia are reviewed. In addition, the clinical spectrum of seven previously unpublished patients with later onset ARG1 deficiency, who also experienced recurrent hyperammonemia, is presented. Several biochemical abnormalities have been postulated to play a role in the pathogenesis of the neurological changes in ARG1 deficiency including hyperargininemia, elevated guanidino compounds and elevated glutamine levels, as well as the hyperammonemia. The index case demonstrated many of these. The cases reviewed here suggest a genotype/phenotype correlation and advocate for the addition of arginine as a primary target in newborn screening programs.
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PMID:Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported? 2180 29

Arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia. Human patients suffer from neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation. In a murine model, onset of the phenotypic abnormality is heralded by weight loss beginning around day 15 with death occurring typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. The goal of this study was to address the development of a gene therapy approach for arginase deficiency beginning in the neonatal period. Lifespan extension, body weight, circulating amino acids and ammonia levels were examined as outcome parameters after gene therapy with an adeno-associated viral vector expressing arginase was administered to mice on the second day of life (DOL). One-hundred percent of untreated arginase-deficient mice died by DOL 24, whereas 89% of the adeno-associated virus (AAV)-treated arginase deficient mice have survived for >8 months. While animals at 8 months demonstrate elevated glutamine levels, ammonia is less than three times that of controls and arginine levels are normal. These studies are the first to demonstrate that AAV-based therapy for arginase deficiency is effective and supports the development of gene therapy for this and the other urea cycle disorders.
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PMID:Long-term survival of the juvenile lethal arginase-deficient mouse with AAV gene therapy. 2276 May 43

Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia. Patients suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation and seizures, and is associated with intellectual disability. In mice, onset is heralded by weight loss beginning around day 15; gait instability follows progressing to inability to stand and development of tail tremor with seizure-like activity and death. Here we report that hyperargininemic mice treated neonatally with an adeno-associated virus (AAV)-expressing arginase and followed long-term lack any presentation consistent with brain dysfunction. Behavioral and histopathological evaluation demonstrated that treated mice are indistinguishable from littermates, and that putative compounds associated with neurotoxicity are diminished. In addition, treatment results in near complete resolution of metabolic abnormalities early in life; however, there is the development of some derangement later with decline in transgene expression. Ammonium challenging revealed that treated mice are affected by exogenous loading much greater than littermates. These results demonstrate that AAV-based therapy for hyperargininemia is effective and prevents development of neurological abnormalities and cognitive dysfunction in a mouse model of hyperargininemia; however, nitrogen challenging reveals that these mice remain impaired in the handling of waste nitrogen.
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PMID:AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse. 2338 1

The Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter, ORNT1 (SLC25A15). In general, the majority of patients with HHH syndrome come to medical attention during infancy or early school years with symptoms such as learning disabilities, changes in cognitive development, spasticity, or liver dysfunction. In this report, we describe a 35-year-old male of Indian descent who was diagnosed with HHH syndrome after he presented to the emergency room with gastroenteritis, disorientation, and slurred speech. Molecular analysis revealed that this patient was heterozygous for two ORNT1 mutations, p.[Gly220Arg(+)Arg275X] (c.[658G>A(+)823C>T]) that had been previously reported in homozygous probands who presented during the first year of life. Cellular studies revealed that the ORNT1 p.Gly220Arg mutation was nonfunctional but targeted to the mitochondria. Given that this patient was a successful college graduate on a vegetarian diet without a prior history of learning or neurological impairment, additional factors such as gene redundancy, environmental, and epigenetic factors may have contributed to the delay in onset of presentation and lack of any previous symptoms. To the best of our knowledge, this is the first reported case of an adult-onset HHH syndrome presentation without a prior history of neurological or cognitive deficiency.
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PMID:Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications. 2343 Aug 80

Hyperargininemia is a rare autosomal recessive disorder of the last step of the urea cycle characterized by a deficiency in liver arginase1. Clinically, it differs from other urea cycle defects by a progressive paraparesis of the lower limbs (spasticity and contractures) with hyperreflexia, neurodevelopmental delay and regression in early childhood. Growth is affected as well. Hyperammonemia is episodic, if present at all. The disease is caused by mutations in the ARG1 gene; there are approximately 20 different known ARG1 mutations with considerable genetic heterogeneity. We describe two Arab siblings with a late diagnosis of hyperargininemia and present the genetic findings in their family. As ARG1 sequencing was unrevealing despite suggestive clinical and laboratory findings, molecular cDNA analysis was performed. The ARG1 expression pattern identified a 125-bp out-of-frame insertion between exons 3 and 4, leading to the addition of 41 amino acids and a premature termination codon TGA at the sixth codon downstream. The insertion originated at intron 3 and was attributable to a novel c.305 + 1323 t > c intronic base change that enabled an enhancement phenomenon. This is the first reported exon-splicing-enhancer mutation in patients with hyperargininemia. The clinical course and genetic findings emphasize the possibility that hyperargininemia causes neurological deterioration in children and the importance of analyzing the expression pattern of the candidate gene when sequencing at the DNA level is unrevealing.
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PMID:Hyperargininemia: a family with a novel mutation in an unexpected site. 2343 Sep 21


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