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)

The prion protein gene, Prnp, encodes PrP(Sc), the major structural component of prions, infectious pathogens causing a number of disorders including scrapie and bovine spongiform encephalopathy (or BSE). Missense mutations in the human Prnp gene cause inherited prion diseases such as familial Creutzfeldt-Jakob disease. In uninfected animals Prnp encodes a glycophosphatidylinositol (GPI)-anchored protein denoted PrP(C) and in prion infections PrP(C) is converted to PrP(Sc) by templated refolding. Though Prnp is conserved in mammalian species, attempts to verify interactions of putative PrP binding proteins by genetic means have proven frustrating and the ZrchI and Npu lines of Prnp gene-ablated mice (Prnp(0/0) mice) lacking PrP(C) remain healthy throughout development. This indicates that PrP(C) serves a function that is not apparent in a laboratory setting or that other molecules have overlapping functions. Current possibilities involve shuttling or sequestration of synaptic Cu(II) via binding to N-terminal octapeptide residues and/or signal transduction involving the fyn kinase. A new point of entry into the issue of prion protein function has emerged from identification of a paralogue, Prnd, with 24% coding sequence identity to Prnp. Prnd lies downstream of Prnp and encodes the doppel (Dpl) protein. Like PrP(C), Dpl is presented on the cell surface via a GPI anchor and has three alpha-helices: however, it lacks the conformationally plastic and octapeptide repeat domains present in its well-known relative. Interestingly, Dpl is overexpressed in the Ngsk and Rcm0 lines of Prnp(0/0) mice via intergenic splicing events. These lines of Prnp(0/0) mice exhibit ataxia and apoptosis of cerebellar cells, indicating that ectopic synthesis of Dpl protein is toxic to central nervous system neurons: this inference has now been confirmed by the construction of transgenic mice expressing Dpl under the direct control of the PrP promoter. Remarkably, Dpl-programmed ataxia is rescued by wild-type Prnp transgenes. The interaction between the Prnp and Prnd genes in mouse cerebellar neurons may have a physical correlate in competition between Dpl and PrP(C) within a common biochemical pathway that when mis-regulated leads to apoptosis.
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PMID:The prion gene complex encoding PrP(C) and Doppel: insights from mutational analysis. 1157 47

The prion protein gene Prnp encodes PrPSc, the major structural component of prions, infectious pathogens causing a number of disorders including scrapie and bovine spongiform encephalopathy (BSE). Missense mutations in the human Prnp gene, PRNP, cause inherited prion diseases such as familial Creutzfeldt-Jakob Disease. In uninfected animals, Prnp encodes a GPI-anchored protein denoted PrPC, and in prion infections, PrPC is converted to PrPSc by templated refolding. Although Prnp is conserved in mammalian species, attempts to verify interactions of putative PrP-binding proteins by genetic means have proven frustrating in that two independent lines of Prnp gene ablated mice (Prnp0/0 mice: ZrchI and Npu) lacking PrPC remain healthy throughout development. This indicates that PrPC serves a function that is not apparent in a laboratory setting or that other molecules have overlapping functions. Shuttling or sequestration of synaptic Cu(II) via binding to N-terminal octapeptide residues and (or) signal transduction involving the fyn kinase are possibilities currently under consideration. A new point of entry into the issue of prion protein function has emerged from identification of a paralog, Prnd, with 25% coding sequence identity to Prnp. Prnd lies downstream of Prnp and encodes the Dpl protein. Like PrPC, Dpl is presented on the cell surface via a GPI anchor and has three alpha-helices: however, it lacks the conformationally plastic and octapeptide repeat domains present in its well-known relative. Interestingly, Dpl is overexpressed in two other lines of Prnp0/0 mice (Ngsk and Rcm0) via intergenic splicing events. These lines of Prnp0/0 mice exhibit ataxia and apoptosis of cerebellar cells, indicating that ectopic synthesis of Dpl protein is toxic to CNS neurons: this inference has now been confirmed by the construction of transgenic mice expressing Dpl under the direct control of the PrP promoter. Remarkably, Dpl-programmed ataxia is rescued by wt Prnp transgenes. The interaction between the Prnp and Prnd genes in mouse cerebellar neurons may have a physical correlate in competition between Dpl and PrPC within a common biochemical pathway that, when misregulated, leads to apoptosis.
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PMID:Biology of the prion gene complex. 1171 3

A 33-year-old male patient began to develop schizophrenia-like symptoms and slowly progressive cerebellar ataxia. He was 170 cm tall and he had mild frontal baldness. Psychiatrically he was aconative, only willing to do nothing all day long after admission. He had neither hallucinations nor delusions, and his mental acuity was normal. Neurological examination revealed positive cerebellar signs including clumsiness in F-N-T and K-H-T and dysdiadochokinesis. He could neither stand up nor walk because of ataxia. The brain MRI showed severe cerebellar atrophy with normal basal ganglia. His EEG and the value of NCV were within normal range, whereas electroretinography showed a notable abnormality, pointing to the extremely small b-wave, resulting in a negative shape of the ERG. Although he was eating sufficiently, the level of serum iron and ferritin remained constantly low. The serum copper level was within normal range, whereas the serum ceruloplasmin level was mildly decreased. A hepatic biopsy indicated no accumulation of copper or iron. This case suggests the importance of the investigation of the serum iron and ceruloplasmin levels in patients who have cerebellar degeneration with psychosis.
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PMID:[A case of cerebellar degeneration with schizophrenia-like psychosis, severe iron deficiency, hypoceruloplasminemia and abnormal electroretinography: a new syndrome?]. 1188 36

We present the first reported study of Ruta graveolens toxicity in 7-8-month-old Nubian goats. Oral administration of 5 g/kg bw per day of R. graveolens leaves caused tremor, dyspnoea, frequent urination, incoordination of movement, ataxia and recumbency, with death after 1-7 days. In goats receiving oral doses of 1 g/kg bw per day of the leaves, the course of toxicity was prolonged and the animals had pallor of the visible mucous membranes and loss in condition; one died on day 17, the others being slaughtered on days 41 and 46. The clinical effects were correlated with pathological changes in various organs, alterations in serum aspartate transaminase, creatine kinase, total protein, cholesterol, urea and other serum constituents, haematological values and the concentrations in the tissues of copper, iron, zinc, manganese, calcium and phosphorus.
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PMID:Preliminary observations on experimental Ruta graveolens toxicosis in Nubian goats. 1216 28

Ceruloplasmin, a multi-copper ferroxidase that affects the distribution of tissue iron, has antioxidant effects through the oxidation of ferrous iron to ferric iron. Aceruloplasminemia is an inherited disorder of iron metabolism due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurological disease, which include ataxia, involuntary movements, and dementia. These symptoms reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Twenty-one mutations in the ceruloplasmin gene have been reported in 24 families worldwide. In Japan, the incidence was estimated to be approximately one per 2,000,000 in the case of non-consanguineous marriages. Excess iron functions as a potent catalyst of biologic oxidation. Previously we showed that an increased iron concentration is associated with increased levels of lipid peroxidation in the serum, cerebrospinal fluid, and erythrocyte membranes. The levels of malondialdehyde and 4-hydroxynonenals, indicators of lipid peroxidation, were also elevated in the basal ganglia and cerebral cortex. Positron emission tomography showed diminished brain metabolism of glucose and oxygen. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to approximate 45% and 42%, respectively, for complexes I and IV. These findings suggest that iron-mediated free radicals causes neuronal cell damage through lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains.
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PMID:Aceruloplasminemia, an inherited disorder of iron metabolism. 1257 80

Creutzfeldt-Jakob disease (CJD) is a presenile dementia characterized by rapidly progressive mental deterioration, myoclonic jerking, and other less common neurological signs. Few autoctonous cases have been described in Brazil. A 54-year-old white woman, was admitted in our service with a month history of progressive, bilateral cortical blindness. After admission, she developed right partial motor seizures( right facial, upper and lower limbs), she became progressively aphasic( mixed aphasia). Seizures were controlled with phenytoin, but she developed choreoathetotic movements on her right dimidium, with partial control after introduction of chlorpromazine 25 mg q/d. She could no longer stand up or walk due to severe ataxia. The first EEG (October, 2001) showed left hemisphere severe seizure activity (status epilepticus partialis). She was delivered home with enteral nutrition, phenytoin, chlorpromazine and mepacrine 100 mg qd. The following laboratorial tests were negative or normal: blood series, platelets, ESR, kidney and liver function, copper, ceruloplasmin, VDRL, HIV, HTLV-1, lactate, and cerebral DSA (performed in other service).A spinal tap with normal opening pressure was perform and CSF examination was normal. CSF 14-3-3 protein was positive, CSF specific neuronal enolase 7.5 ng/ml(normal). Genetic study of PRNP gene did not disclosed any known mutation. A MRI (October, 2001) showed areas of hyperintense signal (T2 and FLAIR) without Gd-enhancement on T1, in the left temporal lobe and in both occipital lobes; basal ganglia have a normal appearance. DWI imaging showed bright areas at the same sites. An EEG (March, 2002) disclosed a periodical sharp triphasic waves pattern, suggestive of CJD. A second MRI (April, 2002) showed mild generalized atrophy, no ventricular dilatation, and the hyperintense sites disappeared. She remained clinically stable and under use of chlorpromazine and mepacrine until she died due to pulmonary complications on April, 2003.
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PMID:[Creutzfeldt-Jakob disease, Heidenhain variant: case report with MRI (DWI) findings]. 1523 44

Six cows died 5 d after the owner put them in an old battery factory. The clinical symptoms were ataxia, blindness, rapid and difficult breathing, increased heart rate, tremors and coma. Necropsy was performed on 1 cow and pieces of metals were observed in the rumen. Serosal vessels of the rumen were hyperemic and slight fluid accumulation was observed in the abdominal cavity. Oedema was seen at the cerebrum. Severe necrosis and lipid accumulations were seen in the liver. All visceral organs were hyperemic. Zinc in the liver, kidney and lungs were 232, 103.5 and 97.3 ppm, respectively. Copper was 123.6 ppm in the liver 23.2 ppm in kidney and 11.8 ppm in lungs. The cadmium levels were normal, these were 66.7 ppm lead in liver, 80.5 ppm lead in kidneys and 35.8 ppm lead in lungs.
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PMID:Acute lead intoxication in cattle housed in an old battery factory. 1548 47

In a herd of German Improved Fawn breed of goat in the year 2000 neonatal kid losses due to congenital copper deficiencies were observed. To clarify the problems and to prevent losses in the next breeding season serum copper levels of 10 dams and four control Boer goats were investigated at four time points during one year. Additionally ten kids of the following year were sampled and the serum copper levels were studied. Immediatly after parturition and 8 weeks later the dams showed low serum copper levels (10.4 +/- 11.1 micromol/l, 5.7 +/- 2.9 micromol/l resp.). At the end of the pasture season an increase of serum copper could be measured (19.3 +/- 16.0 micromol/l). To prevent enzootic ataxia due to congenital copper deficiency, the dams were treated with copper oxide wire particles in the next late gestation. At this time point serum copper concentrations started to decrease (18.5 +/- 8.4 micromol/l). The re-examination 3 month later demonstrated an increase of the serum mean copper concentrations up to 23.4 micromol/l in the dams and to 16.2 micromol/l in the kids. The serum copper levels were significantly higher compared to the levels the year before. Big variation of the serum copper levels in the control Boer goats occurred during the year, but no clinical symptoms of copper deficiency could be observed. The copper levels in the grass and soil samples were 6.8 mg/kg and 0.2 mg/kg dry substance, respectively. A secondary copper deficiency based on cadmium could be excluded through the low levels of soil samples. The contents of sulphur and molybdenum were not determined. The results indicate that the German Improved Fawn breed of goats suffered from a primary copper deficiency due to the inefficient mineral supplementation. The administration of Copinox in the last third of the gestation leads to a continious raising of the copper concentrations in the serum and is suited to prevent ataxia due to congential copper deficiency in neonatal kids.
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PMID:[Use of copper oxide wire particles (Copinox) for the prevention of congenital copper deficiency in a herd of German Improved Fawn breed of goat]. 1556 37

A diagnosis of secondary copper deficiency was established on a deer farm with a peat soil type, on the basis of confirmed enzootic ataxia in hinds, liver and serum copper concentrations and pasture and soil element analyses. Seventy-four weaner stags were selected for a trial to investigate a growth response to copper supplementation. Thirty-seven red and red x wapiti type stags were treated with 4g copper oxide wire particles at four months of age (April). A further 8g copper oxide wire was given in June. Thirty-seven untreated animals acted as controls. Bodyweights were measured on five occasions, from April 24 to November 26. Serum copper analyses were undertaken on ten deer prior to commencement of the trial, and on seven treated and eight control deer in June, July and October. Serum copper concentrations ranged from 2.0 to 19.3 micromol/l prior to the trial. In June, July and October serum copper ranged from 0.1-6.7, 0.6-5.0, and 1.3-6.3 micromol/l respectively, in control deer. In treated deer concentrations ranged from 7.2-14.7, 5.2-10.8, and 6.9-13.7 micromol/l in June, July and October respectively. The difference between mean copper concentration at each post-treatment sampling date was highly significant, (P<0.001). At the conclusion of the trial (November 26) the treated deer averaged 3.1kg heavier than controls, but this difference was not statistically significant. In view of these results and the variation in growth response trials in other species, further investigation of the effects of copper on the growth of young deer is warranted.
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PMID:Bodyweight and serum copper concentrations of farmed red deer stags following oral copper oxide wire administration. 1603 33

A red deer herd of 150 mixed-age hinds, 48 stags and 102 weaners was identified as severely copper deficient during an observational study of 15 deer farms in the lower North Island of New Zealand during 1992 and 1993. Severe lameness was observed in nine weaners in 1992 (8.8% prevalence) and 15 in 1993 (12% prevalence). Typical abnormalities included swollen hocks and carpal joints and outward rotation of hind legs with hocks touching. At postmortem examination, there were epiphyseal fractures of the femoral head, severe degenerative arthropathy of the coxo-femoral joints and erosions of cartilage in many other limb joints. Osteochondrosis was confirmed histologically. Concurrently, three adult hinds and one adult stag developed into-ordination typical of enzootic ataxia which was confirmed histologically. Blood and liver copper concentrations in untreated affected weaner deer ranged from undetectable to 16.0 micromol/l (mean 7.6 micromol/l) and 25 to 53 micromol/kg (mean 39 micromol/kg), respectively. Mean blood copper concentrations in unaffected weaners in March 1992 and 1993 were 5.3 micromol/l and 4.4 micromol/l, respectively. The mean blood copper concentration in seven hinds in September 1992, prior to onset of clinical signs of enzootic ataxia, was 1.5 micromol/l (range 1.0-2.4 micromol/l). At other times of the year, mean blood copper concentrations ranged up to 12.5 micromol/l in adults and 8.9 micromol/l in weaners before treatment began in 1993. Pasture analyses showed copper contents of 6-11 ppm in 11 samples collected during 1992 and 1993. Sulphur ranged from 0.18 to 0.37%, molybdenum from 0.51 to 3.56 ppm and iron from 130 to 2886 ppm. These measurements supported a diagnosis of secondary copper deficiency. Supplementation with oral oxidised copper wire particles was undertaken from December 1992, resulting in an improvement in blood copper concentrations in some classes of deer. No further clinical abnormalities have been observed.
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PMID:Osteochondrosis, skeletal abnormalities and enzootic ataxia associated with copper deficiency in a farmed red deer (Cervus elaphus) herd. 1603 12


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