Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the effects of the addition of nifedipine, a calcium channel antagonist, to the antiepileptic therapy of 20 patients with severe medically refractory epilepsy. Six patients developed side effects and in two the drug had to be discontinued because of these. The commonest side effects were headaches, dizziness and lethargy. Two patients experienced deterioration in seizure control and only 2 patients showed improved seizure control. One of these patients subsequently developed tolerance at 5 months. In 16 patients there was no change.
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PMID:Nifedipine as an add-on drug in the management of refractory epilepsy. 235 58

A 3-year-old Chinese girl with alternating hemiplegia syndrome failed to respond to anticonvulsants, antimigrainous drugs, and calcium channel blockers. She made a complete remission with a 4-week course of steroid, and relapsed after steroid withdrawal. Electroencephalogram and brain mapping during the hemiplegic attack showed unilateral high-voltage sharp slow-wave discharges in the temporo-occipital region contralateral to the hemiplegic side and diffuse high-voltage slowing during attacks of quadriplegia or other clinical manifestation such as dullness, lethargy, or yawning. Brain perfusion single photon emission computed tomographic (SPECT) scan study during the attack showed decreased uptake in the temporoparietal region contralateral to the hemiplegic side and in the ipsilateral basal ganglia, whereas the perfusion was normal between attacks. Electroencephalogram background activity was improved while the child was in clinical remission with steroid treatment. Computed tomographic and magnetic resonance imaging scans of the brain were normal. Carotid angiogram failed to show any structural or dynamic changes of the carotid arteries. The possible mechanism underlying alternating hemiplegia syndrome might be transient and reversible cerebral ischemia with high-voltage slow-wave discharges shown in the electroencephalogram and decreased perfusion in SPECT scan.
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PMID:Alternating hemiplegia syndrome: electroencephalogram, brain mapping, and brain perfusion SPECT scan study in a Chinese girl. 840 62

Analysis of the molecular defects in mouse mutants can identify candidate genes for human neurological disorders. During the past 2 years, mutations in sodium channels, calcium channels and potassium channels have been identified by positional cloning of the spontaneous mouse mutants motor endplate disease, tottering, lethargic and weaver. The phenotypes of four allelic mutations identified in the sodium channel gene Scn8a range from ataxia and muscle weakness through severe dystonia and progressive paralysis, indicating that human mutations in this gene could be associated with a variety of clinical syndromes. Mutations of the calcium channel subunits beta 4 in the lethargic mouse and alpha 1A in the tottering mouse have specific effects on cerebellar function. Targeted mutation of ligand-gated ion channels has also been used to generate new models of neurological disease. We will review these recent achievements and their implications for human neurological disease. The mouse studies indicate that mutations in ion channel genes are likely to be responsible for a broad spectrum of clinical phenotypes in human neurological disorders.
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PMID:Ion channel mutations in mouse models of inherited neurological disease. 956 26

Voltage-gated calcium channels (VDCC) are essential to neuronal maturation and differentiation. It is believed that important signaling information is encoded by VDCC-mediated calcium influx that has both spatial and temporal components. VDCC are multimeric complexes comprised of a pore-forming alpha1 subunit and auxiliary beta and alpha2/delta subunits. Changes in the fractional contribution of distinct calcium conductances to the total calcium current have been noted in developing and differentiating neurons. These changes are anticipated to reflect the differential expression and localization of the pore-forming alpha1 subunits. However, as in vitro studies have established that beta regulates the channel properties and targeting of alpha1, attention has been directed toward the developmental expression and assembly of beta isoforms. Recently, changes in the beta component of the omega-conotoxin GVIA (CTX)-sensitive N-type VDCC have indicated differential assembly of alpha1B with beta in postnatal rat brain. In addition, unique properties of beta4 have been noted with respect to its temporal pattern of expression and incorporation into N-type VDCC complexes. Therefore, the expression and assembly of specific alpha1/beta complexes may reflect an elaborate cellular strategy for regulating VDCC diversity. The importance of these developmental findings is bolstered by a recent study which identified mutations in the beta4 as the molecular defect in the mutant epileptic mouse (lethargic; lh/lh). As beta4 is normally expressed in both forebrain and cerebellum, one may consider the impact of the loss of beta4 upon VDCC assembly and activity. The importance of the beta1b and beta4 isoforms to calcium channel maturation and assembly is discussed.
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PMID:Differential expression and association of calcium channel subunits in development and disease. 975 36

The mutated gene in the lethargic (Cacnb4lh) mouse model of absence seizures encodes the beta4 subunit of voltage-gated calcium channels (VGCCs), leading to decreased mRNA expression of a beta4 subunit that is truncated and cannot bind to alpha1 subunits of VGCCs. In this study we accomplished two goals. First, we studied the functional consequence of altered VGCCs by examining the effects of a selective P/Q-type channel antagonist on KCl-induced (45)Ca(2)(+) uptake in brain synaptosomes from Cacnb4lh homozygotes and non-epileptic controls (designated by +/+). We found that depolarization-induced (45)Ca(2)(+) uptake was significantly reduced in the brains of Cacnb4lh homozygotes, and that the reduced uptake was completely accounted for by reduced function of P/Q-type calcium channel. Second, we examined VGCC subunit composition to determine if other subunits were altered in addition to the mutation affecting beta4 subunits in Cacnb4lh homozygotes; when alterations were found, we determined if they were regional or global. We used in situ hybridization histochemistry (ISHH) to analyze the neuro-anatomic distribution of beta4, beta1b, beta2, beta3, alpha1A, alpha1B, alpha1C, alpha1E, and alpha1G subunit mRNAs in brain sections from matched Cacnb4lh homozygotes and +/+ controls. Our results indicated that expression of beta4 subunit mRNA is globally reduced throughout the brains of Cacnb4lh homozygotes, in contrast to a small but significant global increase in the expression of beta3 subunit mRNA. There were no significant differences in expression of the other VGCC subunit mRNAs examined. Together, these findings indicate that a host of changes in VGCC subunit composition accompany reduced function of P/Q-type channels in homozygous lethargic mice.
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PMID:Decreased (45)Ca(2)(+) uptake in P/Q-type calcium channels in homozygous lethargic (Cacnb4lh) mice is associated with increased beta3 and decreased beta4 calcium channel subunit mRNA expression. 1040 81

The mouse is a well-established model for human genetic disorders. An increasing number of single-gene human diseases are being elucidated through the use of mouse models. Recently genes for three of the six well-characterised single locus models for human spike-wave epilepsy have been isolated and published. The tottering mouse has been shown to be due to mutations in the gene encoding the high voltage-activated alpha1A calcium channel subunit. The lethargic mouse has been shown to be due to mutations in the gene encoding another calcium channel subunit, beta4. The slow-wave epilepsy mouse phenotype is the result of loss of function of the ubiquitous sodium hydrogen exchanger NHEI. These genes and the pathways they are involved in are now candidates for human spike-wave epilepsy. The six mouse models and those genes underlying the spike-wave phenotype are discussed in conjunction with how these mutations were discovered and how they may give rise to the seizure phenotypes. Several nonepilepsy human neurologic disorders have been shown to be allelic with the tottering mouse. The question this raises as to the validity of these models for human spike-wave epilepsy is considered. Finally, the effect these discoveries will have on the understanding and treatment of human spike-wave epilepsy are discussed.
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PMID:Mouse models of spike-wave epilepsy. 1044 46

Nineteen genes encoding alpha1, beta, gamma, or alpha2delta voltage-dependent calcium channel subunits have been identified to date. Recent studies have found that three of these genes are mutated in mice with generalised cortical spike-wave discharges (models of human absence epilepsy), emphasising the importance of calcium channels in regulating the expression of this inherited seizure phenotype. The tottering (tg) locus encodes the calcium channel alpha1 subunit gene Cacna1a, lethargic (lh) encodes the beta subunit gene Cacnb4, and stargazer (stg) encodes the gamma subunit gene Cacng2. These calcium channel mutants should provide important insights into the basic mechanisms of neuronal synchronisation, and the genes may be considered candidates for involvement in similar human disorders. The mutant models offer an important opportunity to elucidate the molecular, developmental, and physiological mechanisms underlying one subtype of absence epilepsy. Since calcium channels are involved in numerous cellular functions, including proliferation and differentiation, membrane excitability, neurite outgrowth and synaptogenesis, signal transduction, and gene expression, their role in generating the absence epilepsy phenotype may be complex. A comparative analysis of channel function and neural excitability patterns in tottering, lethargic, and stargazer brain should be useful in identifying the common elements of calcium channel involvement in these absence models.
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PMID:Single gene defects in mice: the role of voltage-dependent calcium channels in absence models. 1051 59

Inactivation of the beta4 subunit of the calcium channel in the mouse neurological mutant lethargic results in a complex neurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel beta4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in small pedigrees with familial epilepsy and ataxia. The premature-termination mutation R482X was identified in a patient with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alpha1 subunit. The missense mutation C104F was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. These coding mutations were not detected in 255 unaffected control individuals (510 chromosomes), and they may be considered candidate disease mutations. The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected alpha1 subunit. Further studies will be required to evaluate the in vivo consequences of these mutations. We also describe eight noncoding single-nucleotide substitutions, two of which are present at polymorphic frequency, and a previously unrecognized first intron of CACNB4 that interrupts exon 1 at codon 21.
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PMID:Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. 1076 41

1. In order to exclude a significant effect of the calcium channel antagonist amlodipine on cardiopulmonary performance in normal subjects, we performed a double-blind cross-over study of amlodipine (10 mg daily for 2 weeks) on oxygen uptake and catecholamine responses during exercise in eight volunteers. 2. Despite a therapeutic plasma concentration of amlodipine (22.8+/-9 ng/mL), there was no change in resting heart rate or blood pressure. Amlodipine did not cause significant change in oxygen uptake at the anaerobic threshold or at maximum exercise and there was also no change in heart rate or catecholamine responses. 3. Although there was an awareness of peripheral vasodilation and reports of lethargy during the active treatment period, the volunteers had no objective evidence of a decrease in cardiopulmonary performance. We suggest that use of amlodipine as a vasodilator in the perioperative period would not add to the myocardial depressant effects of general anaesthesia in patients with normal cardiac function.
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PMID:Effect of amlodipine on cardiopulmonary performance in volunteers. 1115 33

Several inherited human neurological disorders can be caused by mutations in genes encoding Ca2+ channel subunits. This review deals with known human and mouse calcium channelopathies of the central nervous system (CNS). The human diseases comprise: 1) a recessive retinal disorder, X-linked congenital stationary night blindness, associated with mutations in the CACNA1F gene, encoding alpha(1)1.4 subunits of L-type channels; and 2) a group of rare allelic autosomal dominant human neurological disorders including familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6, all associated with mutations in the CACNA1A gene, encoding alpha(1)2.1 subunits of P/Q-type calcium channels. Mutations at the mouse orthologue of the CACNA1A gene cause a group of recessive neurological disorders, including the tottering, leaner, and rocker phenotypes with ataxia and absence epilepsy, and the rolling Nagoya phenotype with ataxia without seizures. Two other spontaneous mouse mutants with ataxia and absence epilepsy, lethargic and stargazer, have mutations in genes encoding a calcium channel auxiliary beta subunit and a putative calcium channel auxiliary gamma subunit. For each channelopathy, the review describes disease phenotype, channel genotype, and known functional consequences of the pathological mutations; in some cases, it also describes working hypothesis and/or speculations addressing the challenging question of how the alterations in channel function lead to selective cellular dysfunction and disease.
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PMID:Calcium channels and channelopathies of the central nervous system. 1189 Apr 56


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