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)

A 5 9/12-year-old Mexican female with argininemia presented at 4 years of age with severe growth retardation, microcephaly, mental retardation, loss of ability to walk, spasticity and epileptiform electroencephalogram. At follow-up, blood ammonia was elevated only twice out of 30 determinations. Blood arginine was 544 to 1,074 mumol/l (normal 61 to 173); cerebrospinal fluid arginine was 88 mumol/l (normal 6 to 29); and urinary arginine, citruline and argininosuccinic acid were consistently elevated. Arginase activities in tissues from the propositus were 0.01 mU/mg hemoglobin in erythrocytes (normal 29.8 to 96.1); 9 mU/mg protein in liver (normal 1,522 to 5,491); and 5 mU/mg protein in stratum corneum (normal 2,856 to 7,556). The demonstration of arginase deficiency in liver and stratum corneum suggests a generalized deficiency and helps to explain the elevation of blood arginine. Therapeutic trials of orally administered lysine to enhance dibasic amino acid competition and of enzyme replacement using erythrocyte transfusion did not result in significantly decreased blood arginine or clinical improvement.
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PMID:Arginase deficiency in multiple tissues in argininemia. 62 88

The clinical features of argininemia in two cousins included hyperactivity, spasticity, ataxia, retardation, and repeated attacks of hyperammonemia. Study of a large kindred suggests that arginase-deficiency is transmitted as a Mendelian recessive. Treatment with an essential amino acid mixture with the total nitrogen intake limited to the requirement, controlled the hyperammonemia, reduced the plasma arginine level, and permitted a marked clinical improvement. There has been a significant increase in intelligence levels; the previously retarded children are now approaching the normal range of function.
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PMID:Argininemia. 83 67

A 7 1/2-year-old boy had progressive psychomotor retardation, behavior disturbance, and spasticity, and had growth arrest from age three. Plasma arginine on a self-selected protein-poor diet was increased (4.05 mg/dl; nl 0.4 to 2.6), whereas urinary amino acid excretion was normal. Red blood cell arginase was less than 1% of normal in the patient and was half normal in both parents, in two normal siblings, and in his paternal grandfather. Three hours after a meal providing 2 gm protein/kg body weight, the plasma arginine value rose to 13.2 mg/dl, dibasic aminoaciduria was seen clearly for the only time, but blood ammonia concentration remained normal. We conclude that arginase deficiency in the red blood cells and probably in the liver is inherited in an autosomal recessive manner and is responsible for the clinical syndrome in this patient.
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PMID:Hyperargininemia. 83 68

In a patient with hyperargininemia, oral administration of sodium benzoate or phenylacetic acid together with an essential amino acid mixture was used to prevent hyperammonemia and to decrease plasma and CSF concentrations of arginine. Sodium benzoate reduced the plasma ammonia levels, which was confirmed by the increase of urinary excretion of hippuric acid. Phenylacetic acid also controlled hyperammonemia, and EEG findings also improved. By these treatments, plasma and CSF concentrations of arginine showed a slight decrease, but were far above the normal range. There was no clinical improvement, and spasticity of the lower and upper extremities was progressive with mental deterioration.
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PMID:Hyperargininemia: clinical course and treatment with sodium benzoate and phenylacetic acid. 667 Jul 11

Deficiency of liver arginase (AI) is characterized clinically by hyperargininemia, progressive mental impairment, growth retardation, spasticity, and periodic episodes of hyperammonemia. The rarest of the inborn errors of urea cycle enzymes, it has been considered the least life-threatening, by virtue of the typical absence of catastrophic neonatal hyperammonemia and its compatibility with a longer life span. This has been attributed to the persistence of some ureagenesis in these patients through the activity of a second isozyme of arginase (AII) located predominantly in the kidney. We have treated a number of arginase-deficient patients into young adulthood. While they are severely retarded and wheelchair-bound, their general medical care has been quite tractable. Recently, however, two of the oldest (M.U., age 20, and M.O., age 22) underwent rapid deterioration, ending in hyperammonemic coma and death, precipitated by relatively minor viral respiratory illnesses inducing a catabolic state with increased endogenous nitrogen load. In both cases, postmortem examination revealed severe global cerebral edema and aspiration pneumonia. Enzyme assays confirmed the absence of AI activity in the livers of both patients. In contrast, AII activity (identified by its different cation cofactor requirements and lack of precipitation with anti-AI antibody) was markedly elevated in kidney tissues, 20-fold in M.O. and 34-fold in M.U. Terminal plasma arginine (1500 mumols/l) and ammonia (1693 mmol/l) levels of M.U. were substantially higher than those of M.O. (348 mumols/l and 259 mumols/l, respectively). By Northern blot analysis, AI mRNA was detected in M.O.'s liver but not in M.U.'s; similarly, anti-AI crossreacting material was observed by Western blot in M.O. only. These findings indicate that, despite their more long-lived course, patients with arginase deficiency remain vulnerable to the same catastrophic events of hyperammonemia that patients with other urea cycle disorders typically suffer in infancy. Further, unlike those other disorders, an attempt is made to compensate for the primary enzyme deficiency by induction of another isozyme in a different tissue. Such substrate-stimulated induction of an enzyme may be unique in a medical genetics setting and raises novel options for eventual gene therapy of this disorder.
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PMID:Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme. 845 80

Autosomal dominant, autosomal recessive and X-linked recessive varieties of spastic paraplegia have been recognized. Recently, Japanese patients with complicated form of autosomal recessive hereditary spastic paraplegia (HSP) associated with hypoplasia of the corpus callosum have been reported by Iwabuchi et al. We describe a patient with complicated HSP (Iwabuchi type) and cataracta. A 38-year-old man (his parents were a second cousin) was born uneventfully. His motor development was normal. Motor and mental dysfunctions were noticed during the lower classes of an elementary school. He could ride a bicycle at 18 years old but gradually developed galt disturbance and confined to wheelchair since 35 years. He was admitted to our hospital on February 25, 1994. A neurological examination showed mental retardation, dementia, cataracta, cerebellar ataxia, rigidity, spasticity, severe atrophy of the distal muscles of his extremities, paraparesis, hyperreflexia, positive Hoffmann reflexes and Babinski signs, pes cavus and hammer toes. Brain MRI showed thinning of corpus callosum. Clinical and laboratory findings did not support a diagnosis of metabolic disorders showing spastic paraparesis including adrenomyeloneuropathy, Globoid leukodystrophy, metachromatic leukodystrophy, cerebrotendinous xanthomatosis, Arginase deficiency. We considered that our patient was complicated form of HSP (Iwabuchi et al). However, cataract has not been found in Iwabuchi type of HSP. We discussed here other reports showing cataracta with spastic paraparesis.
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PMID:[A case of complicated form of hereditary spastic paraplegia associated with hypoplasia of the corpus callosum and cataracta]. 877 6

As a toxic metabolic byproduct in mammals, excess ammonia is converted into urea by a series of five enzymatic reactions in the liver that constitute the urea cycle. A portion of this cycle takes place in the mitochondria, while the remainder is cytosolic. Liver arginase (L-arginine ureahydrolase, A1) is the fifth enzyme of the cycle, catalyzing the hydrolysis of arginine to ornithine and urea within the cytosol. Patients deficient in this enzyme exhibit hyperargininemia with episodic hyperammonemia and long-term effects of mental retardation and spasticity. However, the hyperammonemic effects are not so catastrophic in arginase deficiency as compared to other urea cycle defects. Earlier studies have suggested that this is due to the mitigating effect of a second isozyme of arginase (AII) expressed predominantly in the kidney and localized within the mitochondria. In order to explore the curious dual evolution of these two isozymes, and the ways in which the intriguing, aspects of AII physiology might be exploited for gene replacement therapy of AI deficiency, the cloned cDNA for human AI was inserted into an expression vector downstream from the mitochondrial targeting leader sequence for the mitochondrial enzyme ornithine transcarbamylase and transfected into a variety of recipient cell types. AI expression in the target cells was confirmed by northern blot analysis, and competition and immunoprecipitation studies showed successful translocation of the exogenous AI enzyme into the transfected cell mitochondria. Stability studies demonstrated that the translocated enzyme had a longer half-life than either native cytosolic AI or mitochondrial AII. Incubation of the transfected cells with increasing amounts of arginine produced enhanced levels of mitochondrial AI activity, a substrate-induced effect that we have previously seen with native AII but never AI. Along with exploring the basic biological questions of regulation and subcellular localization in this unique dual-enzyme system, these results suggest that the mitochondrial matrix space may be a preferred site for delivery of enzymes in gene replacement therapy.
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PMID:Delivery of cytosolic liver arginase into the mitochondrial matrix space: a possible novel site for gene replacement therapy. 913 Oct 18

Two forms of arginase, both catalyzing the hydrolysis of arginine to ornithine and urea, are found in animals ranging from amphibians to mammals. In humans, inherited deficiency of hepatic or type I arginase results in hyperargininemia, a syndrome characterized by periodic episodes of hyperammonemia, spasticity, and neurological deterioration. In these patients, a second extrahepatic or type II arginase activity is significantly increased, an induction that may partially compensate for the lack of AI activity and apparently mitigates some of the clinical effects of the condition. Cloning and characterization of the human AII cDNA was recently accomplished. The cloning, sequencing, and partial characterization of the mouse and rat AII cDNAs are reported herein. The DNA sequences predicted polypeptides of 354 amino acids, including a N-terminal mitochondrial import signal. Sequence homology to the human type II arginase, arginase activity data, and immunoprecipitation with an anti-AII antibody confirm the identity of these cloned genes as rodent extrahepatic type II arginases.
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PMID:Cloning and characterization of the mouse and rat type II arginase genes. 960 38

Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional AI gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice--understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.
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PMID:Mouse model for human arginase deficiency. 1205 59

Arginase deficiency is a rare, autosomal recessive, disorder of the urea cycle characterized by mild hyperammonaemia, hyperargininaemia, dibasic aminoaciduria and orotic aciduria, associated with progressive spastic tetraplegia, seizures, psychomotor retardation, and growth failure. We report a family who presented with their daughter at 4 years 11 months of age with an acute encephalopathy. Initial laboratory results revealed hyperammonaemia (160 micromol/L; normal 0-34), hyperargininaemia (512 micromol/L; normal 23-86) and orotic aciduria. A diagnosis of arginase deficiency was confirmed by enzyme assay, and treatment with a modified protein-restricted diet along with sodium benzoate therapy was initiated. Over time, intellectual development has been normal, but the child developed spasticity in her lower extremities. Subsequently, the mother presented at 6 weeks of pregnancy seeking prenatal diagnosis. Prenatal testing for arginase deficiency has only been reported in one other case. Arginase is not expressed in cultured amniotic fluid cells or chorionic villus samples. Testing for arginase activity assay in red blood cells, isolated by cordocentesis, was performed and predicted an unaffected fetus. The result was confirmed by postnatal enzyme analysis of red cells from the newborn. On the basis of our experience, prenatal diagnosis of arginase deficiency by cord red blood cell arginase activity assay appears possible.
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PMID:Prenatal diagnosis for arginase deficiency: a case study. 1460 7


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