Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027066 (myoclonus)
 4,275 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One strategy for deciphering inherited neurological disease is to examine the expression of individual genes controlling the assembly and physiology of specific cell groups within the developing mammalian central nervous system (CNS). This neurogenetic approach, using defined single-locus mutations arising on coisogeneic mouse strains, has recently been used to analyse a major class of neuronal membrane diseases involving abnormal excitability, the epilepsies, and to identify examples of hereditary variation in signalling properties at central synapses. An interesting mutation, the Tottering (tg) gene, causes a delayed onset, recessive neurological disorder in the mouse featuring a stereotyped triad of ataxia, intermittent myoclonus and cortical spike-wave discharges accompanied by behavioural absence seizures which resemble petit mal epilepsy. Axon branches of the locus coeruleus, a noradrenergic brain-stem nucleus, hyperinnervate specific target regions of the tg brain. The number of parent coerulean perikarya is unaffected, indicating a true proliferation of the terminal axonal arbor. With the exception of this unusually precise error of axonal growth, no other cytopathology has been identified in the tg brain. Here I present evidence that selective lesions of the central noradrenergic axons early in development limit the expression of the disease.
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PMID:A single gene error of noradrenergic axon growth synchronizes central neurones. 646 26

We review the neurochemical and behavioral profile of the selective gamma-aminobutyric acid (GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy. TGB is a potent, and specific GABA uptake inhibitor. TGB lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous GABA. In vivo microdialysis shows that TGB also increases extracellular GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent anticonvulsant agent against methyl-6,7-dimethyoxy-4-ethyl-B-carboline-3-carboxylate (DMCM)-induced clonic convulsions (mice), subcutaneous pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious, against subcutaneous PTZ-induced clonic convulsions, and photically induced myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against bicuculline (BIC)-induced convulsions in rats. The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic-tonic epilepsy (GTCS), photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.
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PMID:A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. 755 76

The mutant mice tottering, leaner and the compound heterozygous tottering/leaner exhibit varying degrees of several abnormal neurological phenotypes including petit mal-like epilepsy, ataxia and an intermittent myoclonus-like movement disorder. Aberrant expression of tyrosine hydroxylase in cerebellar Purkinje cells of tottering, leaner and tottering/leaner mice has been observed previously [Austin M. C. et al. (1992) Molec. Brain Res. 15, 227-240; Hess E. J. and Wilson M. C. (1991) Neuron 6, 123-132]. In the present study, the distribution of tyrosine hydroxylase expression was compared with that of Zebrin II in Purkinje cells of adult homozygous tottering and compound heterozygous tottering/leaner mutant mice using single and double immunocytochemistry and double immunofluorescence. The pattern of Zebrin II expression in the cerebella of the mutant mice was identical to that described for normal mice [Hawkes R. et al. (1985) Brain Res. 333, 359-365; Hawkes R. and Leclerc N. (1987) J. comp. Neurol. 256, 29-41]. In addition, sections through tottering and tottering/leaner cerebella demonstrated an exact correspondence between the bands of tyrosine hydroxylase immunoreactivity and bands of Zebrin II immunoreactivity. Similarly, the compartments of the Purkinje cell layer which were negative for Zebrin II staining were also negative for tyrosine hydroxylase immunoreactivity. This study provides evidence that the cerebellar Purkinje cells of tottering and tottering/leaner mice were able to express a normal gene product, Zebrin II, in a normal spatial pattern and the same Purkinje cells can also express an aberrant gene product, tyrosine hydroxylase. This abnormal gene expression may indicate that at least some Purkinje cells in these mutant mice are not functioning normally. This possibility, taken together with the morphological changes observed in many mutant Purkinje cell axons, suggests that Purkinje cell function could be altered in tottering and tottering/leaner mice, thereby contributing to the neurological abnormalities exhibited by these mice. It is also possible that alteration in function of mutant Purkinje cells could correlate with the rostrocaudal zonation pattern described in this study.
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PMID:Co-localization of tyrosine hydroxylase and zebrin II immunoreactivities in Purkinje cells of the mutant mice, tottering and tottering/leaner. 905

We studied clinical features of 131 patients with juvenile myoclonic epilepsy (JME). The prevalence was 7.7% among the epileptic patients registered. The mean age at onset was 13.37+/-4.93 years and the diagnosis was established at a mean age of 19.53+/-7.85 years. Absence seizures were reported by 27 (20.6%) patients, myoclonic jerks by 131 (100%) and generalized tonic-clonic seizures (GTCS) by 111 (84.7%). The triad of absence seizures, myoclonic jerks and GTCS was noted in 23 (17.5%) patients, 88 (67.2%) had myoclonic jerks and GTCS, 4 (3%) had absence seizures and myoclonic jerks and 16 (12.2%) had only myoclonic jerks. Early onset absences were seen in 21 (16%) patients and the onset was late in 6 (4.6%). Absences antedated other types of seizures in all the patients. Myoclonic jerks were predominantly unilateral or had unilateral onset in 22 (16.8%). In 17 (13%) patients GTCS antedated myoclonic jerks. Myoclonic jerks had characteristic circadian distribution in 112 (85.5%) patients. On awakening GTCS occurred in 87 (78.4%) patients and in 4 (3.6%) patients they were purely nocturnal. Sleep deprivation was the most important precipitating factor (54.2%). Initial electroencephalogram (EEG) showed classical generalized spike or multiple-spike slow-wave paroxysms in 81% of records. Focal EEG abnormalities were noted in 20.6% of records. The most common focal abnormality was voltage asymmetry. A family history of epilepsy was noted in 31 (23.6%) probands. Diagnosis of JME was made in all the cases in the clinic. The factors responsible for delay in diagnosis of the 36 patients seen by neurologists included failure to ask or interpret the history which was otherwise suggestive of myoclonic jerks in all 36 (100%) cases, the type of seizure for which the patients sought medical attention, and misinterpretation of EEGs in 28 patients. Diagnosis of partial epilepsy was made in seven patients. The factors responsible for such diagnoses were, unilateral jerks in one patient, unilateral jerks and absence seizures in three patients and focal EEG abnormalities in three patients.
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PMID:Clinical observations of juvenile myoclonic epilepsy in 131 patients: a study in South India. 954 25

Homozygous tottering (tg/tg) and compound heterozygous tottering/leaner (tg/tg(la)) mutant mice exhibit juvenile onset of three abnormal neurological phenotypes: (i) petit mal-like epilepsy; (ii) ataxia; and (iii) an intermittent myoclonus-like movement disorder. Homozygous leaner mice (tg(la)/tg(la)) exhibit early onset of ataxia (postnatal days 10-12), and also exhibit the myoclonus-like movement disorder and evidence of absence seizure activity; the myoclonus-like disorder is most evident in the first month of life, then diminishes in severity and frequency. The ultrastructure of the cerebellar molecular layer was examined in adult (six to eight months) and juvenile (20-25 days) mice of all three mutant genotypes. In mice of all three genotypes and both ages, Purkinje cell dendritic spines were observed to make multiple contacts with individual parallel fiber varicosities in all sections analysed. These multiple synaptic units were observed in both anterior and posterior vermis and hemispheres of the cerebellum, and ranged from two to nine spines/parallel fiber varicosity. Occasionally, one of the postsynaptic spines belonged to an ectopic spine emerging from the proximal region of a Purkinje cell dendrite. This increase in the multiple synaptic index of some parallel fiber varicosities was observed in juvenile tottering mice before the onset of the symptoms of the neurological disorders. This is highly suggestive that the onset of the neurological phenotype is not a primary cause of multiple Purkinje cell dendritic spines synapsing with single parallel fiber varicosities in these mice, but on the contrary, that it could be the cause of the ataxic symptoms.
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PMID:An ultrastructural study of granule cell/Purkinje cell synapses in tottering (tg/tg), leaner (tg(la)/tg(la)) and compound heterozygous tottering/leaner (tg/tg(la)) mice. 1021 73

Recently it has been discovered that defects in neuronal ion channels can result in seizure disorders. The tottering mouse is a genetic animal model carrying a mutation in the alpha1A calcium channel subunit that causes these mice to exhibit generalized petit mal-like epilepsy, cerebellar ataxia, and an intermittent movement disorder that has some characteristics similar to myoclonus or myoclonic epilepsy. We postulate that abnormal cerebellar Purkinje cell output to the deep cerebellar nuclei results in the intermittent movement disorder observed in these mice. The frequency and duration of seizure activity were measured in tottering mice before and 2 weeks after surgical or chemical lesioning of the cerebellum. Surgical lesions in the anterior cerebellar vermis of tottering mice produced significant reductions in seizure duration and frequency. Surgical lesioning of the posterior cerebellar vermis had no significant effect. Chemical lesions of the same cerebellar regions, using a locally applied neurotoxin, NMD-L-A, appear to produce effects similar to the surgical lesions. These data indicate that anterior vermal cerebellar output is important for production of the seizures associated with the intermittent movement disorder observed in tottering mice.
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PMID:Investigation of the role of the cerebellum in the myoclonic-like movement disorder exhibited by tottering mice. 1075 73

We report here a 9-year-old boy presenting with absence and complex partial seizures. Absence seizures occurred several times a day, with sudden arrest of speech and gesture, alteration of consciousness, myoclonus of unilateral or bilateral angles of the mouth, occasional simple automatism and brisk recovery of consciousness. Complex partial seizures occurred once to three times a month with loss of consciousness, salivation, deviation of the head and eyes toward the left, elevation of upper limbs and tonic convulsion of the left upper and lower limbs. Interictal EEG showed right frontal pole-dominant high-voltage slow waves or spike-and-waves. Ictal simultaneous video-EEG recordings of absence seizures revealed a frontal dominant 3-3.5 Hz spike-wave burst lasting several seconds. A partial seizure never preceded the absence seizure. Transverse topographical analysis revealed that the first spike component of the spike-wave burst of absence seizure always showed phase reversal on the right anterior temporal electrode. The following ones, however, showed phase reversal on the left anterior temporal electrode. Ictal EEG of the complex partial seizure could not be detected because it rarely occurred. There was no abnormal finding on brain MRI. Interictal single photon emission tomography (SPECT) indicated hypoperfusion of the dorsal and medial cortex of the right middle frontal lobe. Interictal positron emission tomography (PET) also indicated hypometabolic areas in the dorsal and medial cortex of the right frontal lobe, together with those in the right temporal and parietal cortex. EEG evolution and neuroimaging studies suggested that the epileptic focus of the absence seizure might have originated at the dorsal cortex of the right middle frontal lobe and immediately spread to the medial cortex. Both the seizures were well controlled by the combination of phenytoin and high dose sodium valproate.
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PMID:[A case with frontal lobe epilepsy presenting with absence seizures as cardinal manifestation: ictal EEG findings]. 1180 12

Classification of epilepsy has been refined to a degree that begins to allow identification of syndromes that are benign, if not in clinical pattern, at least with regard to ultimate outcome. Infants, children, adolescents, and even adults, on occasion, develop seizures that challenge judgment regarding selection of drugs and duration of treatment. Childhood absence epilepsy tends to follow a benign course, with abatement of need for treatment in many patients. However, in approximately 40% of patients with onset of this syndrome, there is evolution to juvenile myoclonic epilepsy (JME), a form of seizure disorder that requires life-long treatment. One syndrome that is clearly almost always benign is benign epilepsy with centrotemporal spikes (BECTS). This clinical problem is defined by complaints, observations of behavior, and by a specific electroencephalographic pattern. Some patients are not treated; many undergo brief administration of medication. Infantile convulsive seizures that may be partial or with myoclonus tend to be familial and require treatment for 1 or 2 years. Time is required to make a decision about treatment because observation over time is required to be sure patients are developing normally, a hallmark of these syndromes. Familial groupings of partial seizures in adolescents appear to follow a benign course, as do those in many elderly patients with seizures after cerebral infarction. Treatment decisions require clinical judgment and observations over time. Drug selection is governed more by experience of individual clinicians, because benign syndromes occur infrequently and prospective studies are seldom performed.
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PMID:Treatment of benign epilepsy syndromes throughout life. 1190 28

Levetiracetam is a novel antiepileptic drug (AED) with proven efficacy against partial seizures, but there is limited information about its effectiveness against generalized seizures. In animal models, levetiracetam protects against seizures in audiogenic susceptible rodents, and it is effective in the Genetic Absence Epilepsy Rat from Strasbourg, a model of absence seizures. In these models, levetiracetam has a therapeutic index that is higher than those of other AEDs. A number of small open-label studies suggest that levetiracetam reduces seizure frequency in patients with generalized seizures, including primarily generalized seizures and myoclonic seizures. Case reports provide additional information regarding the potential efficacy of levetiracetam in postanoxic, post-encephalitic and progressive myoclonus. Although random-ized controlled studies of patients with generalized seizures have not yet been conducted, on the basis of available information, levetiracetam may be prom-ising in the treatment of generalized seizures.
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PMID:Levetiracetam: preliminary efficacy in generalized seizures. 1291 40

In a cohort of 275 Caucasians with a broad IGE phenotype, patients with absences were classified. Criteria of the 1989 Commission on Classification of the International League Against Epilepsy for Childhood Absence Epilepsy (CAE 1989 criteria) were compared with the stricter criteria of the ILAE Task Force for Classification and Terminology (CAE 2005 criteria). Among the 129 patients with absences without significant myoclonus, 50 had juvenile absence epilepsy 44 had CAE according to the CAE 1989 criteria and only 30 had CAE according to the CAE 2005 criteria. We found a significantly better outcome in patients considered as CAE by the CAE 2005 criteria, compared with those excluded. Strict criteria for classification of absence syndromes leave many patients unclassified. However, diagnostic criteria used to classify CAE patients have prognostic significance. We propose that patients are classified as having benign CAE or as having CAE with the adverse prognostic factors indicated.
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PMID:Idiopathic generalized epilepsy with absences: syndrome classification. 1766 74


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