Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response.
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The small Maf proteins form heterodimers with CNC and Bach family proteins to elicit transcriptional responses from Maf recognition elements (MAREs). We previously reported germ line-targeted deficiencies in mafG plus mafK compound mutant mice. The most prominent mutant phenotype was a progressive maf dosage-dependent neuromuscular dysfunction. However, there has been no previous report regarding the effects of altered small-maf gene expression on neurological dysfunction. We show here that MafG and MafK are expressed in discrete central nervous system (CNS) neurons and that mafG::mafK compound mutants display neuronal degeneration coincident with surprisingly selective MARE-dependent transcriptional abnormalities. The CNS morphological changes are concurrent with the onset of a neurological disorder in the mutants, and the behavioral changes are accompanied by reduced glycine receptor subunit accumulation. Bach/small Maf heterodimers, which normally generate transcriptional repressors, were significantly underrepresented in nuclear extracts prepared from maf mutant brains, and Bach proteins fail to accumulate normally in nuclei. Thus compound mafG::mafK mutants develop age- and maf gene dosage-dependent cell-autonomous neuronal deficiencies that lead to profound neurological defects. (+info)
Muscle spindle activity in alternating tremor of Parkinsonism and in clonus.
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Single unit activity in spindle afferent nerve fibres from the finger flexors, the anterior tibial muscle, and the calf muscles was recorded intraneurally with tungsten microelectrodes in patients with Parkinsonism with resting tremor and in spastic patients with clonus. During tremor of Parkinsonism, involving the receptor bearing muscles, the Ia afferent fibre discharge patterns were similar to those seen previously in healthy subjects during voluntary fast alternating finger or foot movements: besides the stretch discharges occurring during the relaxation phases, discharges also occurred during the contraction phases. Such contraction discharges, presumed to originate from intrafusal muscle fibre contractions, were not seen in the spastic patients during clonus. During the clonic oscillations each afferent stretch discharge was regularly followed by a stretch reflex contraction which on its falling phase elicited a new volley of impulses in the Ia afferent fibres. The findings are considered to support the notion that, like the contractions in normal voluntary alternating movements, the contractions in tremor of Parkinsonism are organized according to the principle of alpha-gamma coactivation, whereas the contractions in clonus are stretch reflexes causing pure alpha contractions. (+info)
The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted.
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Myoclonus-dystonia syndrome (MDS) is a non-degenerative neurological disorder that has been described to be inherited in an autosomal dominant mode with incomplete penetrance. MDS is caused by loss of function mutations in the epsilon-sarcoglycan gene. Reinvestigation of MDS pedigrees provided evidence for a maternal imprinting mechanism. As differential methylated regions (DMRs) are a characteristic feature of imprinted genes, we studied the methylation pattern of CpG dinucleotides within the CpG island containing the promoter region and the first exon of the SGCE gene by bisulphite genomic sequencing. Our findings revealed that in peripheral blood leukocytes the maternal allele is methylated, while the paternal allele is unmethylated. We also showed that most likely the maternal allele is completely methylated in brain tissue. Furthermore, CpG dinucleotides in maternal and paternal uniparental disomy 7 (UPD7) lymphoblastoid cell lines show a corresponding parent-of-origin specific methylation pattern. The effect of differential methylation on the expression of the SGCE gene was tested in UPD7 cell lines with only a weak RT-PCR signal observed in matUPD7 and a strong signal in patUPD7. These results provide strong evidence for a maternal imprinting of the SGCE gene. The inheritance pattern in MDS families is in agreement with such an imprinting mechanism with the exception of a few cases. We investigated one affected female that inherited the mutated allele from her mother. Surprisingly, we found the paternal wild type allele expressed whereas the mutated maternal allele was not detectable in peripheral blood cDNA. (+info)
The use of the ketogenic diet in a patient with subacute sclerosing panencephalitis.
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OBJECTIVE: To report on the effects of the ketogenic diet on a 9-year-old boy with myoclonic jerks due to subacute sclerosing panencephalitis (SSPE). METHODS: A 9-year-old boy presented with progressively worsening myoclonus unresponsive to valproic acid and clonazepam. He was started on the ketogenic diet maintaining urine ketones at greater than 80 mg x dl(-1). RESULTS: Within 2 weeks of dietary initiation, myoclonic jerks stopped. Four weeks later he developed cognitive slowing. Results of electroencephalogram and cerebrospinal fluid analysis were consistent with SSPE. Three months after ketogenic diet initiation, myoclonic jerks reappeared and were refractory to treatment. CONCLUSION: The ketogenic diet may be useful in controlling, even temporarily, the myoclonic jerks of SSPE. (+info)
A case of primary spinal myoclonus: clinical presentation and possible mechanisms involved.
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Spinal myoclonus is a rare movement disorder characterized by myoclonic involvement of a group of muscles supplied by a few contiguous segments of the spinal cord. Structural lesions are usually the cause, but in primary spinal myoclonus the etiology remains unknown. We present the case of a 26-year-old woman with cervical spinal myoclonus in which both clinical and electromyographic findings pointed to the segment C1-C3 as the origin of the myoclonus. Laboratorial examinations were normal and no structural lesion was found in magnetic resonance imaging (MRI). Botulinum toxin type A was injected in infrahyoid muscles and cervical paraspinal musculature. The patient remained free of symptoms for almost five months. The pathophysiology of spinal myoclonus remains speculative, but there is evidence that various possible mechanisms can be involved: loss of inhibitory function of local dorsal horn interneurons, abnormal hyperactivity of local anterior horn neurons, aberrant local axons re-excitations and loss of inhibition from suprasegmentar descending pathways. (+info)
Metabolic alkalosis and myoclonus.
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This is the first case reported of vomiting-induced metabolic alkalosis associated with myoclonus. The report describes an unusual presentation of myoclonus secondary to acid-base disturbance caused by recreational drug-induced vomiting. The severe derangement of hyponatraemia, hypokalaemia, and alkalosis appears to have been reasonably well tolerated due to the gradual onset and relatively long history. The causes, mechanism, and management of metabolic alkalosis are discussed. (+info)
The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
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BACKGROUND: There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. AIM: To improve the criteria for diagnosing clinically significant serotonin toxicity. DESIGN: Retrospective analysis of prospectively collected data METHODS: We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions. RESULTS: Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria. DISCUSSION: These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives. (+info)
SUBACUTE INCLUSION ENCEPHALITIS: A CLINICAL AND PATHOLOGICAL REVIEW.
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Subacute inclusion encephalitis has been reported most frequently from Western Europe; only 16 cases have been described in North America. During the past eight years the authors have encountered 14 cases in the Toronto area, and histological confirmation has been obtained in seven of these.The disease most often presents as a combination of progressive personality and intellectual deterioration combined with myoclonic seizures or drop attacks and focal neurological deficits, although extrapyramidal symptoms or evidence of raised intracranial pressure may also occur.At the time of the initial presentation the EEG was characteristic in only nine of the 14 cases, but a first-zone rise in the colloidal gold curve was present in all cases in which it was carried out.From the pathological features of the disease, as described, and its absence of familial occurrence, it is concluded that a viral origin is most probable, although its rarity and predilection for a particular age group are unusual. (+info)