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 male infant with ornithine transcarbamylase (OTC) deficiency is described who was relatively symptom free for 4 months, gradually developed severe spasticity due to cerebral atrophy, and died at 13 months of age. Liver OTC activity was 1.5% of the normal mean. The mutant OTC showed an increased apparent Km for ornithine and an increased pH optimum. These kinetic findings fail to explain the atypical clinical course. The clinical picture of patients with genetic OTC deficiency who present during acute exacerbations together with the elevation of serum glutamic oxaloacetic transaminase and microvesicular fat accumulation in liver, as seen in this case, may suggest Reye's syndrome; however, electronmicroscopic examination of this patient suggested that the normal appearance of mitochondria helps to distinguish the two.
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PMID:Atypical clinical course of ornithine transcarbamylase deficiency due to a new mutant (comparison with Reye's disease). 42 91

A 13-year-old girl with Fahr disease (infantile form) was reported. Her parents were consanguineous. Her elder sister had mental retardation and spasticity of the lower limbs, and died at 23 years of age. The patient suffered from infantile spasms at 3 month. She was bed-ridden, nonverbal, microcephalic and blind. Cranial CT revealed massive calcifications in the basal ganglia, periventricular white matter, dentate nucleus and cerebellar white matter. EEG showed a suppression-burst pattern. At 13 years, she died of pneumonia and hyperammonemia. Microscopic examination of brain showed perivascular non-arteriosclerotic ferro-calcinosis. The periventricular granules are 1-4 mu or 12 mu in diameter. This pathological change was observed only in the central nervous system above midbrain. No calcifications were found in the pituitary and the vessels of pia mater. Also a reduced ornithine transcarbamylase activity was found in the liver, which was probably not related with cerebral calcifications. Infantile form of Fahr disease is rare and may be heterogeneous in etiology. However, clinical manifestations and pathological findings were similar to those in previous reports of Fahr disease in childhood. It is one of the disorders causing infantile spasms.
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PMID:[An autopsy case of Fahr disease (infantile form)]. 152 May 12

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

Sporadic spastic paraplegia (SSP) and hereditary spastic paraplegia (HSP) belong to a clinical and genetically heterogeneous group of disorders characterized by progressive spasticity and weakness in the lower extremities. The symptoms are associated with pyramidal tract dysfunction and degeneration of the corticospinal tracts. Parkinsonism is uncommon in SSP/HSP patients. However, both disorders are associated with damage to the nigrostriatal dopaminergic system. In the present study, the clinical features of patients with SSP/HSP were investigated, and nigrostriatal dopaminergic binding potential was assessed using dopamine transporter (DAT) single-photon emission computer tomography (SPECT). Nine patients with spastic paraplegia participated in the present study. The subjects underwent DAT SPECT using the agent [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato (3-)-N2,N20,S2,S20]oxo-[IR-(exo-exo)])-[(99)mTc]technetium ([(99)mTc]TRODAT-1). The [(99)mTc]TRODAT-1 SPECT images of five patients appeared normal, whereas the images of four patients revealed reduced striatal ligand uptake. Among the four patients with reduced uptake, two had parkinsonism, and one exhibited periodic limb movements and restless leg syndrome. Our DAT SPECT imaging study shows that reduced DAT density may be observed in patients with parkinsonism. The results of the present study offer an explanation for the spectrum of spastic paraplegia symptoms and the progression of the disorder.
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PMID:Striatal dopaminergic functioning in patients with sporadic and hereditary spastic paraplegias with parkinsonism. 2426 32