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)

Acrylamide, a widely used and chemically active substance, has caused delayed distal neuropathy in man and in experimental animals. Male rats administered 50 mg/kg/day acrylamide for 5 days demonstrated ataxia in preliminary rotorod experiments. Additional groups of rats were dosed with 5, 15 or 50 mg/kg/day acrylamide for 5 days, then sacrificed on day 6 at various time intervals after iv injections of tritiated tyrosine (Tyr) or tryptophan (Trp). Brain levels of Tyr, Trp, norepinephrine (NE), dopamine (DA), serotonin (5-HT), and respective metabolites, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MOPEG-sulfate), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were assayed fluorometrically. Turnover rates of NE, DA and 5-HT were estimated by evaluating the rates of specific activity changes in neurotransmitters and precursor amino acids over time. A slight reduction of whole brain NE content was observed in rats administered 50 mg/kg/day acrylamide. Other neurotransmitter levels were not affected by acrylamide levels administered, nor were turnover rates affected. Levels of MOPEG-sulfate and DOPAC were unchanged at any dose tested. Increased levels of 5-HIAA were observed in rats receiving 15 and 50 mg/kg/day acrylamide. Results suggest that acrylamide neurotoxicity does not entail widespread damage to the neurons associated with these biogenic amines; however, the acid metabolite efflux from brain was significantly inhibited.
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PMID:Evaluation of acrylamide treatment on levels of major brain biogenic amines, their turnover rates, and metabolites. 688 32

The serotonin syndrome has increasingly been recognised in patients who have received combined serotonergic drugs. This syndrome is characterised by a constellation of symptoms (confusion, fever, shivering, diaphoresis, ataxia, hyperelflexia, myoclonus or diarrhoea) in the setting of the recent addition of a serotonergic agent. The most common drug combinations causing the serotonin syndrome are monoamine oxidase inhibitors (MAOIs) and serotonin selective reuptake inhibitors (SSRIs), MAOIs and tricyclic antidepressants, MAOIs and tryptophan, and MAOIs and pethidine (meperidine). This syndrome is caused by excess serotonin (5-hydroxytryptamine; 5-HT) availability in the CNS at the 5-HT1A-receptor. There may also be some interaction with dopamine and 5-HT2-receptors. This syndrome probably has a low incidence, even among patients taking these drug combinations, and there is likely to be some other as yet unidentified inciting factor causing some patients to develop a full serotonin syndrome. Because fatalities and severe complications have accompanied the serotonin syndrome, the previously described drug combinations should be used cautiously or not at all. The serotonin syndrome is usually mild and, if managed with drug withdrawal and supportive therapy, generally improves within hours. Patients who develop hyperthermia should be treated aggressively with external cooling and paralysis. Methysergide and cyproheptadine appear to be useful adjuncts in treating the serotonin syndrome.
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PMID:The serotonin syndrome. Implicated drugs, pathophysiology and management. 757 68

Two half-brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1 alpha and E1 beta subunits of the complex. Northern blot analysis for the E1 alpha subunit showed normal results. In the 2 sons, complementary DNA sequence analysis revealed a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1 alpha subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1 alpha gene revealed that the mother was a heterozygotes. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X-inactivation patterns in different organs of female heterozygotes.
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PMID:Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity. 802 67

There have been several reports describing that immunoadsorption therapy improves the neurologic involvement in Fisher's syndrome (FS). However, few studies have assessed the usefulness of immunoadsorption therapy in view of the removal ability of anti-GQ(1b) antibody, which may function the development of FS. We examined the ability of immunoadsorbents for the anti-GQ(1b) antibody in a patient with FS. A 28-year-old woman developed diplopia and giddiness following a cough, fever and diarrhea. On admission (day 22), neurologic examination showed bilateral moderate oculomotor paralysis and bilateral complete abducens paralysis. She had areflexia, numbness of middle and ring fingers on the left and mild ataxic gait. Her serum had IgG anti-GQ(1b) and anti-GD(1b) antibodies. We examined the absorption of anti-ganglioside antibodies onto a polyvinyl alcohol gel (PVA), a phenylalanine-linked PVA (PH-350) and a tryptophan-linked PVA (TR-350) by the batchwise adsorption method. TR-350 absorbed the autoantibodies, but the removal ability of autoantibody by PVA and PH-350 was not proved. The FS patient was treated with TR-350 (days 29, 34 and 43) and PH-350 (day 39). Anti-GQ(1b) and anti-GD(1b) antibodies were significantly removed by the TR-350, in accordance with the results of the in vivo study. There was little loss of albumin as compared with the immunoglobulins and complements. The numbness and ataxia disappeared on day 44. The diplopia disappeared on day 106. TR-350 would be better than PH-350 in the treatment of FS by immunoadsorption therapy.
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PMID:[Immunoadsorption therapy on Fisher's syndrome--removal ability of anti-ganglioside antibodies by tryptophan-linked immunoadsorbent]. 866 31

The pathogenesis of human cerebral malaria (CM) remains unresolved. In the most widely used murine model of CM, the presence of T lymphocytes and/or interferon (IFN)-gamma is a prerequisite. IFN-gamma is the key inducer of indoleamine 2,3-dioxygenase (IDO), which is the catalyst of the first, and rate-limiting, step in the metabolism of tryptophan (Trp) along the kynurenine (Kyn) pathway. Quinolinic acid (QA), a product of this pathway, is a neuro-excitotoxin, like glutamic acid (Glu) and aspartic acid (Asp). Kynurenic acid (KA), also produced from the Kyn pathway, antagonizes the neuro-excitotoxic effects of QA, Glu, and Asp. We therefore examined the possible roles of IDO, metabolites of the Kyn pathway, Glu, and Asp in the pathogenesis of fatal murine CM. Plasmodium berghei ANKA infection was studied on days 6 and 7 post-inoculation (p.i.), at which time the mice exhibited cerebral symptoms such as convulsions, ataxia, coma, and a positive Wooly/White sign and died within 24 hours. A model for noncerebral malaria (NCM), P. berghei K173 infection, was also studied on days 6 and 7 and 13 to 17 p.i. to examine whether any changes were a general response to malaria infection. Biochemical analyses were done by high-pressure liquid chromatography and gas chromatography/mass spectrometry/mass spectrometry (GC/MS/MS). IDO activity was low or absent in the brains of uninfected mice and NCM mice (days 6 and 7 p.i.) and was induced strongly in the brains of fatal murine CM mice (days 6 and 7 p.i.) and NCM animals (days 13 to 17 p.i.). This induction was inhibited greatly by administration of dexamethasone, a treatment that also prevented CM symptoms and death. Furthermore, IDO induction was absent in IFN-gamma gene knockout mice, which were also resistant to CM. Brain concentrations of Kyn, 3-hydroxykynurenine, and the neuro-excitotoxin QA were significantly increased in both CM mice on days 6 and 7 p.i. and NCM mice on days 13 to 17 p.i., whereas an increase in the ratio of brain QA to KA occurred only in the CM mice at the time they were exhibiting cerebral symptoms. Brain concentrations of Glu and Asp were significantly decreased in CM and NCM mice (days 13 to 17 p.i.). The results imply that neuro-excitation induced by QA may contribute to the convulsions and neuro-excitatory signs observed in CM.
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PMID:Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria. 946 88

Immunoadsorption plasmapheresis (IAP) using a tryptophan linked gel column has been shown to effectively remove serum IgG anti-GQ1b antibody which may contribute to the pathogenesis of Miller Fisher syndrome. Two patients are reported on with Miller Fisher syndrome, who developed bilateral facial palsy during IAP using a tryptophan column, while ophthalmoplegia, ataxia, and, areflexia were improving. In these patients, the titre of anti-GQ1b antibodies was reduced. The IAP using a tryptophan column has a beneficial effect on Miller Fisher syndrome but may not inhibit the development of facial palsy. The mechanism of such a dissociated effect of IAP on Miller Fisher syndrome is discussed.
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PMID:Development of facial palsy during immunoadsorption plasmapheresis in Miller Fisher syndrome: a clinical report of two cases. 952 60

Ataxia is defined as a disturbance which, quite independent of any motor weakness, alters direction and extent of voluntary movement and impairs the sustained voluntary of reflex muscle contraction necessary for maintaining postiue and equilibrium [1]. Since pathophysiological basis of cerebeller ataxia is still not completely clear, the current therapeutic attempts are mainly symptom-oriented [3]. One possible approach could be a modification of potentially involved neurotransmitter systems of the cerebellum, where particularly interesting is the serotonergic system. However, attempts with levorotatory form of tryptophan (5-HT precursors) proved to be ineffective [4, 5]. Since receptors in the cerebellum are mainly of 5-HTIA subtype, the use of specific agonists might be a more reasonable therapy [6]. The study initially involved 11 patients, but only 9 completed the protocol due to unfavorable side effects. Our open label prospective study lasted for 15 weeks. The patients were tested before the beginning of the treatment (initial visit), at 7th (first visit) and 11th week (second visit) of continuous therapy, and eventually at 15th week (final visit). The daily dose was 40 mg at the first and 60 mg at the second visit. We used the evaluation scale gurposed for cerebellar functions testing (speech, gait, coordination and ocular movements). Significant improvement of cerebellar ataxia in patients under buspiron therapy has been noted. We analyzed the results obtained from our 9 patients (4 females and 5 males), of which 6 patients suffered from cerebellar degeneration, one from multiple sclerosis, one from Ramsey-Hunt syndrome, and one from pontine myelinolysis. At the initial visit the patient score was 18.9 (SD = 7.3), subsequently, at the iirst visit the score was 15.4 (SD = 8), while the second visit yielded the score of 12.9 (SD = 8.2), and finally, after a two-weeks lasting wash-out period, it was 17.7 (SD = 7.1) (Table 1). It was found that patients exhibiting mild ataxia showed a better improvement in comparison to the patients who had marked cerebellar symptoms at the beginning of the treatment (Table 2). In conclusion, our prospective study shows that buspiron treatment improves cerebellar symptoms.
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PMID:[Buspirone in the treatment of cerebellar ataxia]. 1064

The authors describe two patients in a Japanese family with autosomal recessive spastic ataxia of Charlevoix-Saguenay. They presented early onset spastic ataxia, sensorimotor neuropathy, nystagmus, slurred speech, and hypermyelinated retinal nerve fibers. The authors identified a homozygous missense mutation (T7492C) in the SACS gene, which resulted in the substitution of arginine for tryptophan at amino acid residue 2498 (W2498R).
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PMID:Identification of a SACS gene missense mutation in ARSACS. 1471 87

The tocopherol transfer protein (TTP) is a member of the CRAL-TRIO family of lipid binding proteins that facilitates vitamin E transfer between membrane vesicles in vitro. In cultured hepatocytes, TTP enhances the secretion of tocopherol to the media; presumably, tocopherol transfer is at the basis of this biological activity. The mechanism underlying ligand transfer by TTP is presently unknown, and available tools for monitoring this activity suffer from complicated assay procedure and poor sensitivity. We report the characterization of a fluorescent vitamin E analogue, (R)-2,5,7,8-tetramethylchroman-2-[9-(7-nitrobenz[1,2,5]oxadiazol-4-ylamino)nonyl]chroman-6-ol (NBD-TOH), as a sensitive and convenient probe for the ligand binding and transfer activities of TTP. Upon binding to TTP, NBD-TOH fluorescence is blue shifted, and its intensity is greatly enhanced. We used these properties to accurately determine the affinity of NBD-TOH to TTP. The analogue binds to TTP reversibly and with high affinity (K(d) = 8.5 +/- 6 nM). We determined the affinity of NBD-TOH to a TTP protein in which lysine 59 is replaced with a tryptophan. When occurring in humans, this heritable mutation causes the ataxia with vitamin E deficiency (AVED) disorder. We find that the affinity of NBD-TOH to this mutant TTP is greatly diminished (K(d) = 71 +/- 19 nM). NBD-TOH functioned as a sensitive fluorophore in fluorescent resonance energy transfer (FRET) experiments. Using the fluorescent lipids TRITC-DHPE or Marina Blue-DHPE as a donor or an acceptor for NBD-TOH fluorescence, we obtained high-resolution kinetic data for tocopherol movement out of lipid bilayers, a key step in the TTP-facilitated ligand transfer reaction.
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PMID:Utility of a fluorescent vitamin E analogue as a probe for tocopherol transfer protein activity. 1643 Feb 3

A 10-year-old boy developed corticosteroid-responsive relapsing neurologic signs, including nystagmus and ataxia. MRI revealed multifocal T2 white matter hyperintensities; several were gadolinium-enhancing. CSF contained oligoclonal bands. Although the patient met criteria for multiple sclerosis (MS), the proteolipid protein-1 gene (PLP1) contained a mutation in exon 3B (c.409C>T), predicting a tryptophan-for-arginine substitution. This case raises questions about the role of inflammation in PLP1-related disorders and, conversely, PLP1 mutations in MS.
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PMID:Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. 1743 21


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