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Myelin protein zero mutations were found to produce Charcot-Marie-Tooth disease phenotypes with various degrees of myelin impairment and axonal loss, ranging from the mild 'demyelinating' adult form to severe and early onset forms. Protein zero deficient homozygous mice ( ) show a severe and progressive dysmyelinating neuropathy from birth with compromised myelin compaction, hypomyelination and distal axonal degeneration. A previous study using immunofluorescence showed that motor nerves deficient of myelin protein zero upregulate the Na(V)1.8 voltage gated sodium channel isoform, which is normally present only in restricted populations of sensory axons. The aim of this study was to investigate the function of motor axons in protein zero-deficient mice with particular emphasis on ectopic Na(V)1.8 voltage gated sodium channel. We combined 'threshold tracking' excitability studies with conventional nerve conduction studies, behavioural studies using rotor-rod measurements, and histological measures to assess membrane dysfunction and its progression in protein zero deficient homozygous mutants as compared with age-matched wild-type controls. The involvement of Na(V)1.8 was investigated by pharmacologic block using the subtype-selective Na(V)1.8 blocker A-803467 and chronically in Na(V)1.8 knock-outs. We found that in the context of dysmyelination, abnormal potassium ion currents and membrane depolarization, the ectopic Na(V)1.8 channels further impair the motor axon excitability in protein zero deficient homozygous mutants to an extent that precipitates conduction failure in severely affected axons. Our data suggest that a Na(V)1.8 channelopathy contributed to the poor motor function of protein zero deficient homozygous mutants, and that the conduction failure was associated with partially reversible reduction of the electrically evoked muscle response and of the clinical function as indicated by the partial recovery of function at rotor-rod measurements. As a consequence of these findings of partially reversible dysfunction, we propose that the Na(V)1.8 voltage gated sodium channel should be considered as a novel therapeutic target for Charcot-Marie-Tooth disease. [ABSTRACT FROM AUTHOR]

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of theSPG4gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to theSPG4locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of theSPG4(spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with theSPG4mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations. [ABSTRACT FROM AUTHOR]

Study Objective: To assess the value of a history and physical examination findings in diagnosing the carpal tunnel syndrome, and to determine whether constellations of clinical findings identify patients at high or low risk for the carpal tunnel syndrome.Design: Comparison of diagnostic tests with neurophysiologic testing.Setting: Patients with upper extremity complaints of diverse causes referred to a neurophysiology laboratory for diagnostic studies.Methods: Before nerve conduction testing, a history, demographic and physical examination data, and a hand pain diagram were obtained from each patient. Diagrams were categorized as indicating the classic carpal tunnel syndrome, or as probable, possible, or unlikely to indicate the carpal tunnel syndrome. Associations between clinical data and nerve conduction results were examined in univariate and multivariate analyses.Results: Of 110 patients in the study, 44 (40%) had the carpal tunnel syndrome. Individually, the best predictors were hand pain diagram rating (positive predictive value, 0.59; 95% CI, 0.48 to 0.68) and Tinel sign (positive predictive value, 0.55, CI, 0.45 to 0.65). The combination of a positive Tinel sign and a probable or classic diagram rating had a positive predictive value of 0.71; CI, 0.53 to 0.85. Other findings from physical examination and the history were less useful. Just 9% of patients under 40 years of age with possible or unlikely diagram ratings had the carpal tunnel syndrome.Conclusions: With the exceptions of age, Tinel sign, and hand pain diagram rating, findings from the physical examination and the history had limited diagnostic utility. Patients under 40 years of age with possible or unlikely diagram ratings were at low risk for the carpal tunnel syndrome. This finding, which should be confirmed in an independent population, suggests that subsets of patients may be managed without nerve conduction studies. [ABSTRACT FROM AUTHOR]

The tension produced by the cramp evoked in the adductor pollicis muscle by repetitive stimuli to the nerve (20/s for 50 s) and by full voluntary effort in the brachial biceps was measured in a patient with McArdle's disease. The contracture was 17% of the peaktetanic tension, and was not associated with action potentials. Twitches superimposed on the contracture were at most diminished to half, as were their action potentials. Both slow and fast muscle fibres participated in the contracture. The contraction time of the twitches elicited after the tetanus was prolonged more in the patient than in a normal subject of the same age. There was evidence of delayed firing, first observed 90 seconds after the peak of the contracture. The patient had electromyographic and histological signs of myopathy. [ABSTRACT FROM AUTHOR]

Electrical and mechanical muscular responses to single and repetitive stimuli were recorded in 24 patients with myasthenia gravis. Findings in the platysma were compared with those in m. adductor pollicis (ADP). In the platysma, but not in the ADP, electrical and mechanical responses to single stimuli were often lower than normal, and could be normalised after tetanus and by endrophonium. The decrement of electrical and mechanical responses to repetitive stimuli was two to three times greater in the platysma than in the ADP; post-tetanic facilitation of the action potential was four times greater. The staircase phenomenon was abnormal in the platysma in patients with moderate and severe myasthenia, and also in the ADP in some patients without decrement in the action potential. Edrophonium was more effective in alleviating decrement in the platysma than in the ADP. In the platysma, block of neuromuscular transmission could account for most abnormalities. The finding in some patients of an abnormal staircase after correction for block of fibres indicates a lesion in excitation-contraction coupling. In six patients only the platysma showed abnormalities, in 10 patients abnormalities were more pronounced in the platysma than in the ADP, and in three patients more pronounced in the ADP than in the platysma; in five patients the platysma and the ADP were equally affected. [ABSTRACT FROM AUTHOR]

In the platysma of 34 normal subjects the amplitude of the action potential and twitch tension and tetanic tension were lower, the contraction time of the isometric twitch was 1.4 times shorter, and the potentiation of twitch tension in a staircase and after tetanus was two to four times greater than in m. adductor pollicis. Differences in twitch kinetics and potentiation were related to the four times higher incidence of fast fibres in the platysma than in the adductor pollicis muscle, as determined by histochemistry. Ninety-five per cent confidence limits were established for comparison with patients with myasthenia gravis. [ABSTRACT FROM AUTHOR]