Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder featuring brief, dystonic or choreoathetotic attacks, typically triggered by sudden movements. Symptoms usually start in mid-childhood, although in several pedigrees infantile convulsions have been reported as the presenting sign. Previous linkage studies have identified two PKD loci on 16 p12.1-q21. We report here the clinical features of a Spanish kindred with autosomal dominant PKD, in which haplotype data are compatible with linkage to the pericentromeric region of chromosome 16 and exclude linkage to the locus for Paroxysmal Non Kinesigenic Dyskinesia (PNKD) on chromosome 2 q35. In this family, the conservative candidate region for the disease lies between markers D16S3145 and GATA140E03 on 16 p12.1-q21 and partially overlaps with both the Paroxysmal Kinesigenic Dyskinesia - Infantile Convulsions (PKD-IC) critical interval and the Episodic Kinesigenic Dyskinesia 2 (EKD2) locus. Unusual findings in our pedigree were early infantile onset of the dyskinesias in one patient and generalized seizures as adults in two, adding to previous observations of phenotypic overlap between epileptic and non-epileptic paroxysmal disorders. Further clinical and genetic studies are needed to elucidate whether PKD and PKD-IC are allelic disorders with age-dependent phenotypic expression.
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PMID:Paroxysmal kinesigenic dyskinesia and generalized seizures: clinical and genetic analysis in a Spanish pedigree. 1257 82

Chorea-acanthocytosis is a rare autosomal recessive disorder. Its characteristics are orofacial dyskinesia, hyporeflexia, seizures, aberrant behavior, atrophy of the caudate and putamen, and acanthocytes in the blood with a normal level of lipoproteins. We describe three families with chorea-acanthocytosis. The inheritance pattern was recessive and the average age at onset was 27 years (range, 18-35 years). The presenting symptoms were seizures, aberrant behaviour, chorea, tics, and/or abnormal gait. Phase-contrast and electron microscopy examinations of blood showed 10 to 40% acanthocytes. The lipid profile was normal except that, in one family, no prebetalipoprotein bands corresponding to the fraction of very low-density lipoprotein were seen in high-resolution lipoprotein electrophoresis. Magnetic resonance imaging of the brain showed marked atrophy in the caudate and putamen; 18-fluorodeoxyglucose positron emission tomography scan showed hypometabolism in the striatum. In all three families, the disease was linked to a 6-cM region of chromosome 9q21 flanked by the recombinant markers GATA 89a11 and D9S1843. This finding strongly suggests the involvement of a single locus for this syndrome. Three different homozygous mutations of this gene have been identified. Although the clinical presentation was variable, the genetic studies on these three Saudi Arabian families with chorea-acanthocytosis provide strong evidence for a genetic locus for chorea-acanthocytosis at chromosome 9q21.
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PMID:Chorea-acanthocytosis: clinical and genetic findings in three families from the Arabian peninsula. 1267 46

Infantile convulsions and paroxysmal choreoathetosis is a rare autosomal-dominant disorder characterized by variable presentation of benign infantile seizures and paroxysmal dyskinesia. The disease gene was mapped to chromosome 16p12-q12. We report a consanguineous Turkish family with three individuals affected by infantile convulsions and paroxysmal choreoathetosis. Two siblings whose parents were first cousins had benign infantile convulsions and paroxysmal choreoathetosis. Whereas their father presented only paroxysmal choreoathetosis. The siblings displayed an earlier age of onset and increased frequency of the paroxysmal symptoms than their father. We genotyped the pedigree with polymorphic microsatellite markers, spanning the pericentromeric region of chromosome 16. Construction of the haplotypes demonstrated the segregation of the disease with the infantile convulsions and paroxysmal choreoathetosis locus. The disease was inherited as an autosomal-dominant trait with incomplete penetrance. The affected father was heterozygous for the disease haplotype. However, the two affected siblings manifested homozygosity for the disease haplotype. By haplotype analysis, we confirmed the assignment of the locus for infantile convulsions and paroxysmal choreoathetosis to chromosome 16p12-q12 in this family, and our results also demonstrate that homozygotes for infantile convulsions and paroxysmal choreoathetosis may have a more severe form of the disease than heterozygotes.
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PMID:Infantile convulsions and paroxysmal choreoathetosis in a consanguineous family. 1516 38

Mutations in P/Q-type calcium channels generate common phenotypes in mice and humans, which are characterized by ataxia, paroxysmal dyskinesia, and absence seizures. Subsequent functional changes of T-type calcium channels in thalamus are observed in P/Q-type calcium channel mutant mice and these changes play important roles in generation of absence seizures. However, the changes in T-type calcium channel function and/or expression in the cerebellum, which may be related to movement disorders, are still unknown. The leaner mouse exhibits severe ataxia, paroxysmal dyskinesia, and absence epilepsy due to a P/Q-type calcium channel mutation. We investigated changes in T-type calcium channel expression in the leaner mouse thalamus and cerebellum using quantitative real-time polymerase chain reaction (qRT-PCR) and quantitative in situ hybridization histochemistry (ISHH). qRT-PCR analysis showed no change in T-type calcium channel alpha 1G subunit (Cav3.1) expression in the leaner thalamus, but a significant decrease in alpha 1G expression in the whole leaner mouse cerebellum. Interestingly, quantitative ISHH revealed differential changes in alpha 1G expression in the leaner cerebellum, where the granule cell layer showed decreased alpha 1G expression while Purkinje cells showed increased alpha 1G expression. To confirm these observations, the granule cell layer and the Purkinje cell layer were laser capture microdissected separately, then analyzed with qRT-PCR. Similar to the observation obtained by ISHH, the leaner granule cell layer showed decreased alpha 1G expression and the leaner Purkinje cell layer showed increased alpha 1G expression. These results suggest that differential expression of T-type calcium channels in the leaner cerebellum may be involved in the observed movement disorders.
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PMID:Differential expression of T-type calcium channels in P/Q-type calcium channel mutant mice with ataxia and absence epilepsy. 1551 88

Leaner mice carry a homozygous, autosomal recessive mutation in the mouse CACNA1A gene encoding the Alpha1A subunit of P/Q-type calcium channels, which results in an out-of-frame splicing event in the carboxy terminus of the Alpha1A protein. Leaner mice exhibit severe ataxia, paroxysmal dyskinesia and absence seizures. Functional studies have revealed a marked decrease in calcium currents through leaner P/Q-type channels and altered neuronal calcium ion homeostasis in cerebellar Purkinje cells. Histopathological studies of leaner mice have revealed extensive postnatal cerebellar Purkinje and granule cell loss. We examined the temporospatial pattern of cerebellar granule cell death in the leaner mouse between postnatal days (P) 10 and 40. Our observations clearly indicate that leaner cerebellar granule cells die via an apoptotic process and that the peak time of neuronal death is P20. We did not observe a significant increase in microglial and astrocytic responses at P20, suggesting that glial responses are not a cause of neuronal cell death. We propose that the leaner cerebellar granule cell represents an in vivo animal model for low intracellular [Ca2+]-induced apoptosis. Since intracellular [Ca2+] is critical in the control of gene expression, it is quite likely that reduced intracellular [Ca2+] could activate a lethal cascade of altered gene expression leading to the apoptotic granule cell death in the leaner cerebellum.
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PMID:Postnatal apoptosis in cerebellar granule cells of homozygous leaner (tg1a/tg1a) mice. 1554 10

The frequency, phenomenology, and risk factors of hallucinations and delusions were investigated in 64 consecutive inpatients with Parkinson's disease. Fifty patients were admitted to our hospital with symptoms related to Parkinson's disease: psychiatric problems 27 (psychosis 22; anxiety 2; depression 2; mania 1): motor symptoms, 20 (wearing-off 5; akinesia 4; freezing 4; postural instability 4; dyskinesia 2; tremor 2; dystonia 1), and sensory symptoms, 3. Fourteen patients were admitted with other medical problems (pneumonia 4; cerebral infarction 3; bone fracture 3; lumbago 2; seizure 1; cat bite 1). Totally 49 patients had psychiatric problems. Psychosis was present in 43 patients, dementia in 10, depression in 8, mania in 1, anxiety in 10, agitation in 6, stereotypy in 2, and hypersexuality in 2. Of the 43 patients with psychoses, 40 presented with visual hallucinations, 18 with auditory hallucinations, and 23 with delusions. To determine what the clinical correlates with the severity of psychosis were, we divided the patients into 3 groups: the severe group, 22 patients admitted because of psychotic symptoms; the mild group, 21 patients admitted because of problems other than psychosis but presenting psychotic symptoms; and the control group, 21 patients who had no psychotic symptoms. Incidences of auditory hallucinations and delusions were higher in the severe group as compared to the mild group. Patients in the severe group had higher Hoehn-Yahr stages, lower Mini-Mental State Examination scores, decreased H/M ratios of cardiac 123I-MIBG uptake, and lower frequencies of background activity on electroencephalograms. There were no differences in age at admission, age at onset of Parkinson's disease, duration of illness, amounts of levodopa and dopamine agonists received, Hamilton's depression rating scores, and brain MR findings, including atrophy and ischemic changes. Emergence of psychotic symptoms in parkinsonian patients appears to be clearly associated with impaired cognitive function. Therefore, it may be associated with the disease process itself. Terms such as dopaminomimetic or levodopa-induced psychosis may not be appropriate when describing psychosis in Parkinson's disease.
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PMID:[Psychoses in patients with Parkinson's disease; their frequency, phenomenology, and clinical correlates]. 1571 92

Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.
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PMID:A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena. 1602 63

An 86-year-old woman was admitted to our hospital for orobuccolingual dyskinesia. She did not take any medication. Her relatives had no similar symptoms nor consanguineous marriage. Although orobuccolingual dyskinesia was improved by administration of haloperidol for a while, orobuccolingual dyskinesia with biting of tongue and lips, chorea and muscular atrophy in the legs, seizures and dementia appeared half a year after the onset. The decrease of cMAP suggested axonopathy in the extremities by a nerve conduction study. The serum level of CK was normal. The EEG showed generally slow wave activities. A head MRI showed mild atrophy of the bilateral caudate nuclei and frontal lobes with scattered old lacunars in the deep white matter. She was diagnosed as having chorea-acanthocytosis (ChAc) because acanthocytes (10-20%) appeared in the peripheral blood. The normal lipoprotein levels and Kell antigen expression excluded the possibilities of Bassen-Kornzweig syndrome and McLeod syndrome. In all reported cases of ChAc, she was the oldest onset patient. ChAc is warranted in a patient presenting with orobuccolingual dyskinesia with biting, in spite of elderly onset.
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PMID:[A case of chorea-acanthocytosis onset with at age 86]. 1618 Jul 11

Ion channelopathies are a diverse array of human disorders caused by mutations in ion channel genes. This review focuses on the pathogenic mechanisms of channelopathies affecting skeletal muscle and brain arising from mutations of voltage-gated ion channels and fast ligand-gated ion channels expressed at the surface membrane. Derangements in channel function alter the electrical excitability of the cell and thereby increase susceptibility to transient symptomatic attacks including myasthenia, periodic paralysis, myotonic stiffness, seizures, headache, dyskinesia, or episodic ataxia. Although these disorders are rare, they stand out as exemplary cases for which disease pathogenesis can be traced from a point mutation to altered protein function, to altered cellular activity, and to clinical phenotype. The study of these disorders has provided insights on channel structure-function relations, the physiological roles of ion channels, and rational approaches toward therapeutic intervention for many disorders of cellular excitability.
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PMID:Pathomechanisms in channelopathies of skeletal muscle and brain. 1677 91

AMPA receptors are fast ligand-gated members of glutamate receptors in neuronal and many types of non-neuronal cells. The heterotetramer complexes are assembled from four subunits (GluR1-4) in region-, development- and function-selective patterns. Each subunit contains three extracellular domains (a large amino terminal domain, an agonist-binding domain and a transducer domain), and three transmembrane segments with a loop (pore forming domain), as well as the intracellular carboxy terminal tail (traffic and conductance regulatory domain). The binding of the agonist (excitatory amino acids and their derivatives) initiates conformational realignments, which transmit to the transducer domain and membrane spanning segments to gate the channel permeable to Na+, K+ and more or less to Ca2+. Several 2,3-benzodiazepines act as non-competitive antagonists of the AMPA receptor (termed also negative allosteric modulators), which are thought to bind to the transducer domains and inhibit channel gating. Analysing their effects in vitro, it has been possible to recognize a structure-activity relationship, and to describe the critical parts of the molecules involved in their action at AMPA receptors. Blockade of AMPA receptors can protect the brain from apoptotic and necrotic cell death by preventing neuronal excitotoxicity during pathophysiological activation of glutamatergic neurons. Animal experiments provided evidence for the potential usefulness of non-competitive AMPA antagonists in the treatment of human ischemic and neurodegenerative disorders including stroke, multiple sclerosis, Parkinson's disease, periventricular leukomalacia and motoneuron disease. 2,3-benzodiazepine AMPA antagonists can protect against seizures, decrease levodopa-induced dyskinesia in animal models of Parkinson's disease demonstrating their utility for the treatment of a variety of CNS disorders.
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PMID:2,3-benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects. 1770 50


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