Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A simple fluorescent spot screening test has been developed for the identification of individuals with arginase deficiency (hyperargininemia). The assay is based on the coversion of arginine to ornithine and urea by arginase present in 1/8 inch disc of dried blood on filter paper. The enzyme activity is visually estimated by the oxidation of NAD-H to NAD+ in a coupled kinetic reaction. In the absence of the enzyme, there is no oxidation of the NAD-H and consequently no loss of fluorescence. The screening assay has been used to identify successfully both heterozygous and homozygous arginase-deficient crabeater macaques (M. fascicularis) as well as three patients with hyperargininemia. This test can be used to screen large numbers of patients with mental retardation or seizure disorders rapidly to determine the frequency of this disorder more precisely.
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PMID:A simple screening test for arginase deficiency (hyperargininemia). 84 87

The effects of arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid and argininic acid (guanidino compounds that were found to be increased in hyperargininemia) were evaluated on responses to gamma-aminoburtyric acid (GABA) and glycine (Gly) on mouse neurons in primary dissociated cell culture. GABA and Gly were applied iontophoretically and intracellular microelectrode recording techniques were used. The guanidino compounds rapidly and reversibly inhibited both GABA and Gly responses. The guanidino compounds inhibited GABA responses in a concentration-dependent manner and inhibited Gly responses at a concentration of 10 mM. Argininic acid was the most potent in reducing inhibitory amino acid responses, followed in decreasing potency by alpha-keto-delta-guanidinovaleric acid, homoarginine and arginine. The guanidino compounds were equally potent in decreasing Gly and GABA responses. Co-application of CGS 9896, a benzodiazepine receptor antagonist, did not antagonize the guanidino compound-induced inhibition of GABA responses. These findings suggest that the guanidino compounds inhibited responses to the inhibitory neurotransmitters GABA and Gly by blocking the chloride channel. This effect might underlie the in vivo epileptogenicity of some of the guanidino compounds and might contribute to the pathogenesis of seizures in hyperargininemia.
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PMID:Guanidino compounds that are increased in hyperargininemia inhibit GABA and glycine responses on mouse neurons in cell culture. 171 85

Congenital hyperargininaemia is a rare condition transmitted as an autosomal dominant trait. Following a one-year free interval, repeated vomiting, psychomotor regression and spastic paraparesis with talipes equinus progressively develop. The diagnosis, confirmed by arginine assays in blood and urine, is probably often missed. We report a case of homozygous arginase deficiency belatedly diagnosed at the age of 18 years, when treatment with sodium valproate (VPA) was instituted. This female patient presented with psychomotor regression since the age of 15 months and with paraparesis since she was 3 years' old. These symptoms rapidly became worse. At the age of 18 years, when she was bed-ridden, she was hospitalized for subintrant tonic seizures. EEG showed generalized, continuous spike-wave discharges at the rate of 3.5 c/s. Treatment with VPA was instituted. Five days later, she went into a state of stupor. Blood ammonia level was elevated at 362 mumol/l. VPA was discontinued, and this was followed by a regression of disturbances of consciousness and by a decrease in arterial ammoniaemia, although the ammonia levels remained high, fluctuating between 40 and 100 mumol/l. Several months after VPA treatment was interrupted, the patient had a second episode of stupor, and her ammoniaemia was 500 mumol/l. Serum amino acid chromatography showed hyperargininaemia at 501 mumol/l (N = 30-150 mumol/l). The diagnosis of arginase deficiency was confirmed by the rise of arginine in red cells, cerebrospinal fluid and urine and, above all, by the finding of a deeply depressed arginase activity in erythrocytes. In all cases of intolerance to VPA, arterial ammoniaemia should be measured after withdrawal of VPA, some time after the acute episode.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Late diagnosis of congenital argininemia during administration of sodium valproate]. 229 Oct 40

A 5-year-old boy with severe mental retardation and spastic quadriplegia accompanied by tonic seizures and hyperammonemia was diagnosed as having argininemia due to an arginase deficiency in his erythrocytes. His motor and mental abilities began to deteriorate at the age of 3 years. Thereafter, he lost his ability to stand alone, to sit and even to crawl by himself. After he was diagnosed as argininemia , a protein restricted diet was given as therapy, which was accompanied with a supplement of essential amino acids. However, his clinical condition had not improved very much. The erythrocytes in a normal person was found to have the ability to decrease the patient's elevated plasma arginine level to normal when they are mixed in vitro. First we tried replacing his red cells by a blood transfusion. Then we replaced them with the aid of an IBM 2997 blood cell separator. Following this his clinical and biochemical condition improved, and as a result so did his sitting and crawling abilities. It appears that the replacement of red blood cells improves not only the clinical and biochemical conditions, but the general condition of the patient as well.
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PMID:A successful trial of enzyme replacement therapy in a case of argininemia. 672 10

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

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

Hyperargininemia is an autosomal recessive metabolic disorder caused by a deficiency of enzyme arginase I. It is a rare pan-ethnic disease with a clinical presentation distinct from that of other urea cycle disorders, and hyperammonemic encephalopathy is not usually observed. Hyperargininemia is one of the few treatable causes of pediatric spastic paraparesis, and can be confused with cerebral palsy. We retrospectively evaluated the clinical onset, neurologic manifestations, progression of abnormalities, electroencephalographic abnormalities, and laboratory findings of 16 Brazilian patients with hyperargininemia. Relevant data about the clinical spectrum and natural history of hyperargininemia are detailed. Progressive spastic diplegia constituted the key clinical abnormality in this group, but variability in clinical presentation and progression were evident in our series. Seizures in hyperargininemia may be more common than reported in previous studies. Features distinguishing hyperargininemia from cerebral palsy and hereditary spastic paraplegia are emphasized in this large series of patients.
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PMID:Clinical features and neurologic progression of hyperargininemia. 2263 32

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

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 arginase 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% 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 be limited by the small animal size of neonatal therapy and for developing a better understanding of the characteristics of hyperargininemia.
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PMID:Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse. 2392 45


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