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)

We report a patient with small cell lung cancer associated with Lambert-Eaton myasthenic syndrome (LEMS) and subacute cerebellar degeneration (SCD). The patient was a 71-year-old man suffering from weakness of the limbs and a gait disturbance who developed limb ataxia and dysarthria one month after admission. Electrophysiologic studies confirmed the diagnosis of Lambert-Eaton myasthenic syndrome. Chest X-rays 2 months after admission revealed an abnormal shadow, and small cell lung cancer was diagnosed on the basis of biopsy specimens. Anti-voltage-gated calcium channel antibody was positive. Anti-Yo and -Hu antibodies were negative. The patient was treated by plasmapheresis and chemotherapy, which resulted in a transient improvement in the LEMS symptoms but not in the SCD. Fifteen cases of LEMS associated with SCD have been reported in the Japanese literature, and all were accompanied by small cell lung cancer. We discuss the frequency of association with LEMS and SCD and the effects of plasmapheresis and chemotherapy in both diseases.
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PMID:[Report of a case of small cell lung cancer associated with Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration--with a review of the Japanese literature]. 819 44

Some of the most common diseases in humans occur intermittently in people who are otherwise healthy and active. Such disorders include migraine headache, epilepsy, and cardiac arrhythmias. Because electrical signals are critical to the function of neurons, muscle cells, and heart cells, proteins that regulate electrical signaling in these cells are logical sites where abnormalities might lead to disease. All of these diseases have prominent genetic components. Difficulty in understanding these diseases arises from the complexity of the clinical phenotypes as well as from the genetic heterogeneity that is almost certain to exist. Therefore, early work in may laboratory was aimed at understanding the pathogenesis of rare disorders that are similar in their episodic nature. These disorders of muscle (the periodic paralyses), lead to attacks of weakness that occur intermittently in otherwise normal people. We, and others, have shown that hyperkalemic periodic paralysis (hyperKPP) and paramyotonia congenita (PC) result from mutations in a gene encoding a skeletal muscle sodium channel. We have also shown that hypokalemic periodic paralysis (hypoKPP) is caused by mutations in a gene encoding a voltage-gated calcium channel. The characterization of these diseases as channelopathies has served as a paradigm for other episodic disorders. One example is periodic ataxia, which results from mutations in voltage-gated potassium calcium channels. Long QT syndrome, an episodic cardiac dysrhythmia syndrome, is known to result from mutations in either voltage-gated sodium or potassium channels. We have recently mapped genes that cause a familial paroxysmal dyskinesia (non-kinesiogenic paroxysmal dystonia/choreoathetosis) in humans and a reflex epilepsy in mice. The similarities among all these disorders, including their episodic nature, precipitating factors, and therapeutic responses, are striking. Understanding gained from work in these rare monogenic episodic disorders is not only allowing characterization of the molecular and physiologic basis of these diseases, but may ultimately shed light on our understanding of the pathophysiology of more common and genetically complex disorders of the central nervous system.
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PMID:Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. 919 7

Channels involved in the influx and intracellular mobilization of calcium have been implicated as targets of diverse genetic and immune-mediated neurological diseases. These include the L-type voltage-gated calcium channel of skeletal muscle (hypokalemic periodic paralysis), the neuronal P/Q-type voltage-gated calcium channel (familial hemiplegic migraine, episodic ataxia type 2, spinocerebellar ataxia 6, and Lambert-Eaton myasthenic syndrome), and the skeletal muscle ryanodine receptor (malignant hyperthermia and central core disease). The discovery of these and other calcium channelopathies should help to clarify how different mutations affect channel function and how altered channel function produces disease, and may lead to new treatments for these conditions.
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PMID:Calcium channels in neurological disease. 930 47

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the alpha1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.
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PMID:Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. 940 87

Since 1990, many mutations, in genes encoding ion channels have been discovered to cause disorders characterized by hyper- or hypoexcitability of skeletal muscle or the central nervous system (CNS): i) mutations in the muscle chloride channel gene lead to a loss or change of function of the channels and cause an abnormally low total chloride conductance resulting in hyperexcitability of the muscle fiber membrane in the dominant and recessive form of myotonia congenita; ii) numerous dominant point mutations in the gene encoding the muscle sodium channel alpha-subunit cause incomplete sodium channel inactivation. Dependent on the inactivation parameter altered and the degree of the gain of function induced by a given mutation, the muscle episodically becomes hyper- or hypoexcitable (i.e. stiff or weak), particularly in response to elevated serum potassium (potassium-aggravated myotonia, hyperkalemic periodic paralysis) or cold environment (paramyotonia congenita); iii) dominant point mutations in the gene coding for the muscle L-type calcium channel alpha(1)-subunit can cause episodes of muscle inexcitability (i.e. weakness), particularly in response to lowered serum potassium (hypokalemic periodic paralysis); despite the recently discovered etiology of the disease, the pathogenesis of the weakness is still unknown; iv) dominant mutations in a voltage-gated potassium channel expressed in the CNS cause episodic ataxia type 1 presumably by antagonizing repolarization of the cell membrane; v) dominant mutations in a neuronal calcium channel alpha-subunit may cause either episodic ataxia type II or familial hemiplegic migraine by a so far unknown pathomechanism; vi) the first mutation in an ion channel associated with an inherited form of epilepsy, nocturnal frontal lobe epilepsy, was found in the alpha(4)-subunit of a neuronal nicotinic acetylcholine receptor.
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PMID:[Ion channel diseases in neurology]. 948 Feb 90

The mouse neurological mutant lethargic (lh) is characterized by ataxia, focal myoclonus, and absence epilepsy due to a loss-of-function mutation in the beta4 subunit of the voltage-gated calcium channel. To evaluate the role of this channel subunit in human neurological disease, we determined the chromosomal location and intron/exon structure of the human CACNB4 gene. The 1560-bp open reading frame of the CACNB4 cDNA predicts a 58-kDa protein with an amino acid sequence that is 99% identical to the rat protein. The 13 coding exons of CACNB4 span >55 kb of genomic DNA. Human cerebellar RNA contains one major CACNB4 transcript that is 9 kb in length. Expression of CACNB4 was detected in cerebellum, kidney, testis, retina, lymphoblasts, and circulating lymphocytes. Retinal transcripts were localized by in situ hybridization to ganglion cells and the inner nuclear layer. Analysis of the GeneBridge 4 radiation hybrid mapping panel localized CACNB4 to position 791 cR on human chromosome 2, in a conserved linkage group on human 2q22-q31 and mouse chromosome 2. We localized CACNB4 to the 1.3-Mb YAC clone 952F10 in Whitehead contig WC861, along with the polymorphic markers D2S2236 and D2S2299. The chromosomal linkage of three of the four beta subunit genes to homeobox gene clusters associates the evolutionary origin of the beta gene family with the events that generated the four HOX clusters early in vertebrate evolution.
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PMID:Calcium channel beta 4 (CACNB4): human ortholog of the mouse epilepsy gene lethargic. 962 18

Tottering mice inherit a recessive mutation of the calcium channel alpha1A subunit that causes ataxia, polyspike discharges, and intermittent dystonic episodes. The calcium channel alpha1A subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the tottering mouse phenotype, calcium channel blockers were tested for their ability to block the motor episodes. Pharmacologic agents that specifically block L-type voltage-dependent calcium channels, but not P/Q-type calcium channels, prevented the inducible dystonia of tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented restraint-induced tottering mouse motor episodes. Conversely, the L-type calcium channel agonist Bay K8644 induced stereotypic tottering mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated that L-type calcium channel alpha1C subunit mRNA expression was up-regulated in the Purkinje cells of tottering mice. Radioligand binding with [3H]nitrendipine also revealed a significant increase in the density of L-type calcium channels in tottering mouse cerebellum. These data suggest that although a P/Q-type calcium channel mutation is the primary defect in tottering mice, L-type calcium channels may contribute to the generation of the intermittent dystonia observed in these mice. The susceptibility of L-type calcium channels to voltage-dependent facilitation may promote this abnormal motor phenotype.
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PMID:L-type calcium channels contribute to the tottering mouse dystonic episodes. 988 94

Different aspects of expanded polyglutamine tracts and of their pathogenetic role are taken into consideration here. (i) The (CAG)n length of wild-type alleles of the Huntington disease gene was analysed in instability-prone tumour tissue from colon cancer patients to test whether the process leading to the elongation of alleles towards the expansion range involves single-unit stepwise mutations or larger jumps. The analysis showed that length changes of a single unit had a relatively low frequency. (ii) The observation of an expanded spinocerebellar ataxia (SCA)1 allele with an unusual pattern of multiple CAT interruptions showed that cryptic sequence variations are critical not only for sequence length stability but also for the expression of the disease phenotype. (iii) Small expansions of the (CAG)n sequence at the CACNA1A gene have been reported as causing SCA6. The analysis of families with SCA6 and episodic ataxia type 2 showed that these phenotypes are, in fact, expressions of the same disorder caused either by point mutations or by small (CAG)n expansions. A gain of function has been hypothesized for all proteins containing an expanded polyglutamine stretch, including the alpha 1A subunit of the voltage-gated calcium channel type P/Q coded by the CACNA1A gene. Because point mutations at the same gene with similar phenotypic consequences are highly unlikely to have this effect, an alternative common pathogenetic mechanism for all these mutations, including small expansions, can be hypothesized.
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PMID:CAG repeat instability, cryptic sequence variation and pathogeneticity: evidence from different loci. 1043 11

The ectopic expression of neuronal P/Q-type voltage-gated calcium channels in small cell lung carcinoma (SCLC) is thought to induce antisynaptic autoimmunity in the paraneoplastic Lambert-Eaton myasthenic syndrome. The gene CACNL1A4, encoding the principal (alpha1A) subunit of this calcium channel, is mutated in several inherited neurological disorders. One of these disorders (spinocerebellar ataxia, type 6, or SCA-6) involves the expansion of a trinucleotide (CAG) repeat unit. We hypothesized that a somatic CAG repeat instability of this gene in neoplastic cells might generate a non-self epitope capable of initiating autoimmunity to P/Q-type calcium channels. We therefore analyzed the CACNL1A4 gene in SCLC lines established from metastases derived from seven individual patients (four associated with Lambert-Eaton myasthenic syndrome, one associated with myasthenia gravis, and two not associated with neurological autoimmunity). We compared their CAG repeat numbers (determined by polymerase chain reaction (PCR) amplification followed by separation of products on a 6% polyacrylamide/8M urea gel) to published norms and to DNA from a patient with SCA-6. The number of CAG repeats in SCLC DNA fell within a normal range whether or not the neoplasm was complicated by neurological autoimmunity. Therefore, it is unlikely that somatically unstable CAG repeat units in the gene encoding the P/Q-type voltage-gated calcium channel account for this tumor protein's immunogenicity in the Lambert-Eaton myasthenic syndrome.
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PMID:Immunogenicity of P/Q-type calcium channel in small cell lung cancer: investigation of alpha1 subunit polyglutamine expansion. 1067 74

Steroid, amine and peptide hormones affect the peripheral vestibular system. Vasopressin hypersensitivity of the endolymphatic sac may be implicated in the pathogenesis of Meniere's disease. Specific vasopressin antagonists will help define the role of vasopressin in Meniere's disease. The modulation of central vestibular pathways by neuroactive steroids may involve effects on gamma-aminobutyric acid-ergic and glutaminergic pathways. The vestibular nuclei also express enzymes that are important in the synthesis of steroids and the modulation of their activity. Steroids mediate both facilitatory and deleterious effects of stress on vestibular compensation. The quality and quantity of stressor that determines the pattern of hormonal output, may be important. Clinical observation suggests that episodic ataxia type 2, a P/Q calcium channelopathy, may be phenotypically modulated by endocrine fluctuations. Steroid hormones may affect the episodic ataxia type 2 phenotype by modulation of voltage-gated calcium channel activity via second messenger systems and ion channel subunit expression. Despite evidence to support the link, the role of the endocrine system in vestibular function and disease is as yet virtually unexplored.
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PMID:The endocrine system, vertigo and balance. 1117 14


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