Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a possible preventive measure for brain dysfunction in Menkes disease, prenatal treatment by maternal administration of zinc, vitamin E and copper was examined in brindled mutant mice. During pregnancy and lactation, female heterozygous mice received 20 ppm zinc or 0.004% alpha-tocopherol acetate (vitamin E) throughout and 6 ppm copper from gestational day 13 in the drinking fluid, ad libitum. The maternal administration of zinc and vitamin E, as antioxidants, or copper resulted in decreased fetal and neonatal death of offspring, especially those of hemizygous males, as compared with the administration of water only. When offspring did not grow, maternal abnormal movements, which comprised rotatory movements of high speed with tremor and ataxia, were frequently observed. In the heterozygotes with abnormal movements, the level of lipid peroxidation in cerebrum and the concentration of copper in kidney were much higher than those in the heterozygotes with normal movement. Morphologically, in cerebellum of the heterozygotes with abnormal movements, the loss of Purkinje cells, abundance of lipofuscin granules and abnormal mitochondria or degenerative bodies of high electron density were frequently observed, as compared with heterozygotes with normal movement. These findings suggest that the development of hemizygous male mice may be influenced by both copper and oxygen radical metabolism.
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PMID:Abnormal movements in brindled mutant mouse heterozygotes: as related to the development of their offspring--biochemical and morphological studies. 216 11

Hepatolenticular degeneration (Wilson's disease) is a hereditary disease in which metabolic disorder of copper leads to its accumulation in the liver, brain, cornea and kidneys with consequent pathologic changes in those organs. Hereditary mechanism of the disease is autosomal recessive with prevalence of 30-100 per 1,000,000 inhabitants. Etiology of this disease is not yet explained. There are two hypotheses. The first one is that it is the disorder of ceruloplasmine metabolism caused by insufficient synthesis of normal ceruloplasmine, or synthesis of functionally abnormal ceruloplasmine. The second one is: the block of copper biliar excretion which is the consequence of the liver lysosomes functional defect. Pathogenetic mechanism of disease is firstly long-term accumulation of copper in the liver, and later, when the liver depo is full, its releasing in circulation and accumulation in the brain, cornea, kidneys and bones, which causes adequate pathologic changes. Toxic activity of copper is the consequence of its activity on enzymes, particularly on those with -SH group. There are two basic clinical forms of the disease: liver disease or neurologic disease. Before puberty the liver damage is more frequent, while in adolescents and young adults neurologic form of the disease is usual. The liver disease is nonspecific and characterized by symptoms of cirrhosis and chronic aggressive hepatitis. The only specificity is hemolytic anemia which, in combination with previous symptoms, is important for diagnosis of the disease. Neurologic symptoms are the most frequent consequence of pathologic changes in the basal ganglia. In our patients the most frequent symptoms were tremor (63%); dysarthria, choreoathetosis and rigor (38%); ataxia and mental disorders (31%); dysphagia and dystonia (12%), diplopia, hypersalivation, nystagmus and Babinski's sign (6%). Among pathologic changes in other tissues and organs the most important is the finding of Kayser-Fleischer ring in the cornea as a result of copper accumulation. Its importance for precise diagnosis is great. The diagnosis of the disease is based on anamnesis, clinical examination, specific and nonspecific laboratory tests. The therapy of choice is penicillamine. If we use it early, the result will be good remission in the majority of patients. Late diagnosis or delay in treatment cause death which is the result of bleeding from esophageal varices or basal ganglia disease. Immunologic damages caused by penicillamine demand interruption of therapy and substitution by three-ethyl-tetra-amine (TETA). We also use zinc salts and tetratiomolibdate in therapy of this disease. Pathogenesis, clinical picture and therapy of the disease are based on our own results.
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PMID:[Hepatolenticular degeneration]. 226 49

Manganese, zinc and copper are essential for normal prenatal and neonatal development. Manganese deficiency causes skeletal abnormalities, congenital ataxia due to abnormal inner ear development, and abnormal brain function. Depression of mucopolysaccharide synthesis and manganese superoxide dismutase activity may be fundamental to ultrastructural and other defects. In copper deficiency, neurological and skeletal abnormalities are due to impairment of phospholipid synthesis and collagen crosslinking, and possibly to low activity of copper metalloenzymes. The fundamental defect leading to the extremely teratogenic effects of zinc deficiency is related to depressed synthesis of DNA. In the neonatal period, poor survival and growth and depressed function of the immune system are salient features. Developmental patterns of trace element concentrations in various tissues suggest that important changes in metabolic regulation of trace elements may occur during the neonatal period. This hypothesis is being investigated by studies of molecular localization of trace elements in certain neonatal tissues, in conjunction with similar observations in milk.
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PMID:The roles of trace elements in foetal and neonatal development. 611 92

During a 6-year period, 23 Navajo adolescents were hospitalized 47 times for presumed lead intoxication secondary to gasoline sniffing. Most patients were male (87%) and sniffed gasoline as a social activity, more frequently in spring and summer. Sixty-five percent of the patients first presented with toxic encephalopathy. Of total episodes, 31% involved asymptomatic lead overload; 31% involved tremor, ataxia, and other neurologic signs; and 38% involved encephalopathy with disorientation and hallucinations. Free erythrocyte protoporphyrin levels were not consistently high, although blood lead levels were all elevated. One death occurred. Approximately 11% of 537 Navajo adolescents said they inhaled gasoline for enjoyment at least occasionally. Among 147 junior high school students, blood lead levels averaged 18 +/- 6 micrograms/dL with no values greater than 40 micrograms/dL. Three of these students had elevated zinc protoporphyrin levels and all three were anemic. No correlation was found between levels of blood lead or zinc protoporphyrin and whether or not the youth reported sniffing gasoline. However, sniffing gasoline was associated with poor school performance and delinquent behavior. Although apparently many Navajo adolescents experiment with gasoline inhalation, only a few engage in this activity frequently enough to develop either asymptomatic or symptomatic lead overload.
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PMID:Gasoline sniffing and lead toxicity in Navajo adolescents. 684 58

Systemic administration of N-methyl-D-aspartate (NMDA) receptor antagonists induces a well defined behaviour in rodents characterized by, for example increased locomotion and ataxia. It is not clear in what brain region(s) NMDA antagonists induce this behaviour. We have studied the possible involvement of olfactory pathways by making adult mice anosmic via intranasal injection of zinc sulphate, a procedure that is known to destroy the olfactory epithelium. The NMDA antagonist MK-801 was given intraperitoneally (0.1-1.0 mg/kg) and the animals were scored for locomotion and ataxia 60-90 min later. Before MK-801 administration, olfactory-lesioned mice did not differ from non-lesioned controls with regard to locomotion or ataxia. MK-801 caused locomotor activation (> or = 0.2 mg/kg) and ataxia (> or = 0.5 mg/kg) in both groups. In general, olfactory-lesioned animals showed more locomotion and less ataxia after MK-801 administration than non-lesioned animals. Lesioned animals displayed 2.0- (P < 0.05) and 3.7-fold (P < 0.05) more extensive locomotor activation than non-lesioned animals after 0.5 and 1.0 mg/kg of MK-801, respectively. No difference in the degree of ataxia was seen between the two groups at 0.5 mg/kg, whereas non-lesioned animals showed a 2.1-fold higher degree of ataxia after 1.0 mg/kg of MK-801, indicating that the enhanced MK-801-induced locomotor activation in olfactory-lesioned mice was not simply due to less ataxia. These results suggest that olfactory input is involved in NMDA antagonist-induced behaviour.
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PMID:The effect of anosmia on MK-801-induced behaviour in mice. 764 17

Liver transplantation (LTX) is an approved method to treat patients with end-stage liver cirrhosis and acute liver failure due to Wilson's disease. Initially, there was some consideration about the indication for LTX in the case of Wilson's disease with severe neurological impairment but normal liver function. From 1988 until 1995, 13 out of 700 LTX (1.9%) were performed for Wilson's disease. Indications for LTX were (I) intractable neurological impairment with normal liver function (n = 4; including one patient with Child A cirrhosis), (II) fulminant hepatic failure (n = 3), and (III) end-stage liver cirrhosis (n = 6) (Child B, n = 1; Child C, n = 5). There were 8 females and 5 males with a mean age of 27 yr (range 15-34 yr). All patients of group I required continuous nursing care before LTX, in spite of pretreatment with d-penicillamine and zinc. The most frequent symptoms in these patients were dysphagia (n = 4), dysarthria (n = 4), tremor (n = 4), sialorrhea (n = 3), ataxia (n = 3), dystonia (n = 3) and handwriting difficulties (n = 3). All patients of group II presented with hemolytic anemia. The survival rate was 100%, and all patients were doing well after a mean follow-up period of 32.8 months (range 8-68 months). The postoperative course was without severe infectious and other complications. All patients of group I revealed the first signs of improvement for all types of neurological symptoms 4-6 wk after LTX. One patient has been without any symptoms from 18 months until 5.5 yr after LTX. Two patients with short-term follow-up also had noticeable improvement of neurological impairment, but residual symptoms are still present. One patient showed only slight improvement. We conclude that Wilson's disease may be a good indication for LTX for both neurological manifestation with stable liver function and hepatic manifestation with cirrhosis or acute liver failure.
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PMID:Liver transplantation: treatment of choice for hepatic and neurological manifestation of Wilson's disease. 919 46

The ability of N,N,N',N'-tetrakis (2-pyridylmethyl)-ethyenediamine (TPEN) to protect against botulinum neurotoxin (BoNT) A and B was examined in vivo in mice. To determine the protective efficacy of TPEN, mice were injected i.p. with TPEN as a single bolus or as multiple injections 30 min before and 0, 2, 4 and 6 hr following i.v. challenges with BoNT-A or -B. TPEN treatment did not alter the 24 hr lethality of BoNT but did produce a significant delay in the time to death. For a moderate dose of serotype A (20 LD50), five divided doses of TPEN prolonged the time to death from 7.8 +/- 0.4 hr to 9.9 +/- 0.5 hr. For serotype B, examined under comparable conditions, the prolongation of the time to death was from 6.1 +/- 0.2 hr to 9.4 +/- 0.6 hr. The range of TPEN doses that could be examined in vivo was limited by its acute toxicity. Although low doses of TPEN (< or = 10 mg/kg) were well tolerated, higher doses (> or = 30 mg/kg) led to ataxia, loss of coordination, convulsions and death in 20.3 min or less. In clonal NG108-15 cells, TPEN was found to produce cytotoxicity as revealed by increases in the secretion of the marker enzyme lactate dehydrogenase (LDH), and enhanced reactivity with the vital dye trypan blue. From LDH concentration-response data determined 24 hr after addition of TPEN, the threshold concentration for observing cytotoxicity was 10 microM and the IC50 was 19.8 microM. At the highest TPEN concentration tested (100 microM), cytotoxicity was detected 8 hr after TPEN addition and increased in severity over a 3 day period. The cytotoxicity in NG108-15 cells appears to be distinct from the rapid-onset toxicity observed in whole animals. These results suggest that TPEN may be of potential benefit in delaying the lethal actions of BoNT-A and -B, but its use is limited by its initial and delayed toxicity. Since the therapeutic and toxic actions of TPEN are both related to zinc chelation, the use of TPEN would need to be restricted to low doses as part of a combination therapy.
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PMID:Protection by the heavy metal chelator N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) against the lethal action of botulinum neurotoxin A and B. 924 7

Muscle spindles are skeletal muscle sensory organs that provide axial and limb position information (proprioception) to the central nervous system. Spindles consist of encapsulated muscle fibers (intrafusal fibers) that are innervated by specialized motor and sensory axons. Although the molecular mechanisms involved in spindle ontogeny are poorly understood, the innervation of a subset of developing myotubes (type I) by peripheral sensory afferents (group Ia) is a critical event for inducing intrafusal fiber differentiation and subsequent spindle formation. The Egr family of zinc-finger transcription factors, whose members include Egr1 (NGFI-A), Egr2 (Krox-20), Egr3 and Egr4 (NGFI-C), are thought to regulate critical genetic programs involved in cellular growth and differentiation (refs 4-8, and W.G.T. et al., manuscript submitted). Mice deficient in Egr3 were generated by gene targeting and had gait ataxia, increased frequency of perinatal mortality, scoliosis, resting tremors and ptosis. Although extrafusal skeletal muscle fibers appeared normal, Egr3-deficient animals lacked muscle spindles, a finding that is consistent with their profound gait ataxia. Egr3 was highly expressed in developing muscle spindles, but not in Ia afferent neurons or their terminals during developmental periods that coincided with the induction of spindle morphogenesis by sensory afferent axons. These results indicate that type I myotubes are dependent upon Egr3-mediated transcription for proper spindle development.
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PMID:Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3. 973 39

The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.
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PMID:The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. 1158

Two brothers with X-linked ataxia (XLA) were found to have hypochromic red cells and increased erythrocyte protoporphyrin despite normal iron stores. The mother was unaffected by ataxia and had normal iron stores but showed evidence of some red cell hypochromia with heavy basophilic stippling that stained positive for iron. Bone marrow biopsy confirmed the presence of ring sideroblasts in one of the brothers. The absence of mutations in the ALAS2 gene and the predominance of zinc over free protoporphyrin led to a search using a combination of DNA and cDNA analysis for the presence of mutations in the ABC7 gene. ABC7 encodes a mitochondrial half-type ATP Binding Cassette transporter involved in iron homeostasis. The published cDNA sequence was used to search databases for the genomic sequence of which 12 exons spanning 23.4 kb were mapped leaving the most 5' nucleotides unaccounted for. The identified exons and their exon-intron boundaries were amplified from DNA while the most 5' sequence including the initiation codon was amplified from cDNA of peripheral blood cells. Direct sequencing revealed hemizygosity in the brothers and heterozygosity in the mother for a G-->C transversion at position 1299 of the published cDNA. This predicts a V411L substitution at the beginning of the last of six putative transmembrane regions of the protein. Restriction enzyme digestion confirmed the presence of this mutation in the three family members but could not detect it in 200 normal alleles. An uncle affected by ataxia also carried this mutation. This study supports the recently hypothesized involvement of the ABC7 gene in XLSA/A and highlights a protein structure region of importance to this syndrome.
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PMID:X-linked cerebellar ataxia and sideroblastic anaemia associated with a missense mutation in the ABC7 gene predicting V411L. 1184 25


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