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)

Several studies have reported an association between HTLV-II and a neurological condition which has come to be called HTLV-II-associated myelopathy and is similar, in some cases, to HTLV-I-associated myelopathy. To further explore the establishment of an etiological link between this virus and neurological disease, we determined the HTLV status of three individuals, one of which presented with symptoms of progressive ataxia. Since the patient with neurological disease and her husband were HTLV-II positive, we had the potential to study one of few cases of an HTLV-II-associated neurological disorder, and the first case in Canada. However, although the individual with the neurological disease was HTLV-II positive, we discovered that her brother, who displays the same clinical symptoms, was not positive for either HTLV-II or HTLV-I. Thus, disease association with HTLV-II became unsupportable. We present here, nevertheless, the first sequence and phylogenetic analysis of an HTLV-II isolate in Canada. This study suggests that cases of HTLV-II and neurological disease must be carefully investigated before any etiological conclusions can be made.
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PMID:An apparent case of human T-cell lymphotropic virus type II (HTLV-II)-associated neurological disease: a clinical, molecular, and phylogenetic characterisation. 1054 29

We report the outcome of two prenatal analyses for the T to G mutation at nucleotide 8993 in the mitochondrial DNA. This mutation is associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) and the neurodegenerative condition, Leigh syndrome. One prospective mother was the sister of a severely affected individual, and had previously had an unaffected child and a stillborn child. The second prospective mother had two unaffected children and two affected children. The mutation was not detected in the chorionic villus sample from one fetus nor in the amniocytes from the other fetus. Both pregnancies were continued, and the resulting children were healthy at two years and five years of age. Prenatal diagnosis of this mitochondrial DNA mutation is an option likely to be acceptable to some families to prevent the birth of a child at high risk for neurological disease.
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PMID:Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA. 1059 Apr 37

We examined the involvement of multiple monoaminergic receptors in the induction of spontaneous tail-flicks (STFs) by the open channel blocker at N-methyl-D-aspartate (NMDA) receptors, dizocilpine, and the NMDA recognition site antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). At doses eliciting a maximal STF response, dizocilpine and CPP elevated levels of norepinephrine, but not dopamine or serotonin, in dialysates of nucleus accumbens, their known locus of action in eliciting STFs. Chemically diverse alpha(2)-adrenergic receptor (AR) antagonists atipamezole, L745,743, RX821,002, idazoxan, and desfluparoxan abolished induction of STFs by dizocilpine, whereas the preferential alpha(1)-AR antagonists prazosin, WB4101, and ARC239 were weakly active: relative potencies in blocking STFs correlated significantly with affinity at alpha(2)-ARs. The D(1)/D(5) receptor antagonists SCH23390, SCH39166, and NNC756 potently abolished STFs, whereas the D(2) antagonist L741,626, the D(3) antagonists GR218,231 and S14297, and the D(4) antagonists S18126 and L745,870 were inactive. D(1) and alpha(2)-AR antagonists also blocked induction of STFs by CPP. Blockade of dizocilpine-induced STFs was specific inasmuch as idazoxan and SCH 23390 did not modify induction of ataxia by dizocilpine. Antagonists at multiple 5-hydroxytryptamine receptors failed to modify induction of STFs. Finally, dizocilpine-induced STFs were blocked by clozapine and 11 other antipsychotics, the potency of which correlated significantly with affinity at alpha(2)-ARs. In conclusion, STFs evoked by interruption of transmission at NMDA receptors are dependent on D(1) receptors and alpha(2)-ARs for their expression. Antagonism of the alpha(2)-ARs is involved in their blockade by antipsychotics. This model should facilitate exploration of interrelationships between glutamatergic and monoaminergic mechanisms involved in psychiatric and neurologic disorders.
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PMID:Induction of spontaneous tail-flicks in rats by blockade of transmission at N-methyl-D-aspartate receptors: roles of multiple monoaminergic receptors in relation to the actions of antipsychotic agents. 1064 Mar 5

Thanks largely to cloning the genes for several neurodegenerative diseases over the past decade and the existence of mouse mutants, the molecular basis of neurodegeneration is finally beginning to yield some of its secrets. We discuss what has been learned about the pathogenesis of "triplet repeat" diseases through mouse models for spinocerebellar ataxia types 1 and 3 and Huntington disease, including the roles of nuclear aggregates and protein cleavage. We also discuss the neurologic phenotypes that arise from mutations in neurotransmitter receptors (lurcher mice) and ion channels (weaver, leaner, and tottering mice), drawing parallels between ischemic cell death and the neurodegeneration that occurs in the lurcher mouse. Finally, we discuss common mechanisms of cell death and lessons learned from these mouse models that might have broader relevance to other neurologic disorders.
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PMID:Insights from mouse models into the molecular basis of neurodegeneration. 1084 11

We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA)Lys mutation. The phenotype of one child in the family was consistent with autism. During his second year of life, he lost previously acquired language skills and developed marked hyperactivity with toe-walking, abnormal reciprocal social interaction, stereotyped mannerisms, restricted interests, self-injurious behavior, and seizures. Brain magnetic resonance imaging (MRI) and repeated serum lactate studies were normal. His older sister developed signs of Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive regression. Her laboratory studies revealed increased MRI T2-weighted signal in the putamen and posterior medulla, elevated lactate in serum and cerebrospinal fluid, and absence of cytochrome c oxidase staining in muscle histochemistry. Molecular analysis in her revealed the G8363A mutation of the mitochondrial transfer RNA(Lys) gene in blood (82% mutant mitochondrial DNA) and muscle (86%). The proportions of mutant mitochondrial DNA from her brother with autism were lower (blood 60%, muscle 61%). It is likely that the origin of his autism phenotype is the pathogenic G8363A mitochondrial DNA mutation. This observation suggests that certain mitochondrial point mutations could be the basis for autism in some individuals.
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PMID:Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation. 1086 77

We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis. Genetic analysis demonstrated a CAG expansion in the SCA1 locus in five members, while all subjects with microcytosis revealed a C-T substitution at codon 39 of the beta-globin gene. A pure cerebellar syndrome with prominent gait ataxia characterized the first stages of the neurological disease. The fully developed disease included additional clinical findings such as dysarthria and dysphagia, and instrumental signs of axonal involvement of the peripheral nerves. Ophthalmoplegia was not observed. The coexistence of hereditary spinocerebellar degeneration and erythropathies or hemoglobinopathies has been previously described. We discuss the possible linkages between these two pathologies.
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PMID:Clinical and genetic study of a family with spinocerebellar ataxia type 1 (SCA1) and beta-thalassemia. 1093 28

Poliovirus replicon vectors transiently express foreign proteins selectively in motor neurons of the anterior horn of the spinal cord. Here we intraspinally inoculated mice transgenic for the poliovirus receptor (PVR) with replicons encoding murine tumor necrosis factor alpha (mTNF-alpha). We detected high-level expression of mTNF-alpha in the spinal cords of these animals at 8-12 h post inoculation; this returned to background by 72 h. The mice exhibited ataxia and tail atony, whereas animals given a replicon encoding green fluorescent protein (GFP) exhibited no neurological symptoms. Histology of spinal cords from mice given the replicon encoding mTNF-alpha revealed neuronal chromatolysis, reactive astrogliosis, decreased expression of myelin basic protein, and demyelination. These animals recovered with only slight residual damage. This study shows that replicon vectors have potential for targeted delivery of therapeutic proteins to the central nervous system and provide a new approach for treatment of spinal cord trauma and neurological disease.
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PMID:Cytokine production in motor neurons by poliovirus replicon vector gene delivery. 1097 8

Genetic defects affecting the mitochondrial respiratory chain are an important cause of neurological disease. Previously, we identified a family with complex II deficiency and late-onset neurodegenerative disease with progressive optic atrophy, ataxia, and myopathy. The affected family members are now shown to carry a C-to-T transition in one allele of the nuclear gene encoding the flavoprotein subunit of complex II. Mutation of the equivalent base in Escherichia coli generates an inactive enzyme unable to bind flavin adenine dinucleotide covalently. Compatible with these findings, our patients have an approximate 50% decrease in complex II and succinate dehydrogenase activity. These results suggest that genetic defects of nuclear-encoded subunits of the mitochondrial respiratory chain can result in late-onset neurodegenerative disease.
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PMID:Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. 1097 39

Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.
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PMID:Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. 1102 57

Familial episodic ataxias are unusual hereditary disorders of early onset characterized by recurrent episodes of ataxia. Most patients recover fully between attacks, but some may develop progressive ataxia with cerebellar atrophy. There are two subtypes of episodic ataxia: type 1 (EA1), with interictal myokymia, and type 2 (EA2), with interictal nystagmus. Stress and fatigue can trigger ataxic spells, which can be responsive to acetazolamide. These clinical features are reminiscent of other channelopathies or paroxysmal neurologic disorders with progressive features caused by ion channel mutations. Familial episodic ataxias indeed are channelopathies. EA1 is caused by mutations in a potassium channel-encoding gene, whereas EA2 is caused by mutations in a calcium channel-encoding gene, which is also the disease-causing gene in spinocerebellar ataxia type 6 and several kindreds with familial hemiplegic migraine. Treatment with acetazolamide can be effective in decreasing the frequency of attacks and is generally well tolerated. Understanding the mechanism of action of acetazolamide and the functional consequences of these mutations will help one to develop a rational pharmacologic treatment for these disorders, which may share similar mechanisms with benign recurrent vertigo and more common forms of migraine.
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PMID:Familial Episodic Ataxias and Related Ion Channel Disorders. 1109 68


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