Charcot-Marie-tooth disease : muscle morphological and neurophysiological aspects

Sammanfattning: Charcot-Marie-Tooth disease (CMT) is a common inherited disorder of the peripheral nervous system characterised by distal weakness and muscular atrophy, sensory disturbance of the distal limbs, diminished or absent deep tendon reflexes and often pes cavus. CMT is divided into two major groups based on clinical and electrophysiological findings. CMT I is characterised by demyelination and markedly reduced nerve conduction velocity, whereas in CMT2 there is an axonal neuropathy with normal to near-normal nerve conduction velocitity. The aim of the present study was to characterise muscle biopsy histopathology and morphometry, in distal and proximal muscles, muscle strength by means of isokinetic measurement, macro EMG parameters as indicators of the denervation-reinnervation activity, and sensory function by means of sensory screening and quantitative determination of somatosensory thresholds. The difference regarding these parameters between the two major forms of CMT, CMT I and CMT2 was elucidated. Different histopathological findings were seen in muscle biopsies from the two groups. Muscle biopsies of the CMT I patients exhibited angular atrophic fibres that were scattered or in groups; findings commonly described as "neuropathic". In the biopsies of the CMT2 patients there was a variation of muscle fibre sizes with highly hypertrophic and atrophic fibres. The hypertrophic fibres had numerous internalised nuclei, fibre splitting, and some fibres had the appearance of "whorled fibres"; findings commonly regarded as "myopathic". An increase of type I (slow-twitch) muscle fibre percentage was found both in CMT1 (p<0.01) and CMT2 (p<0.05) patients when compared with normal controls. The type I muscle fibre area was significantly increased in CMT2 patients (p<0.05) but not in the CMT1 patients when compared with the controls. The immunohistochemical stainings showed that both CMT groups had a normal muscle fibre cytoskeletal structure. Signs of regeneration visualised by antibodies directed against Leu-19, a satellite cell antigen, further supported that the muscle biopsy findings in CMT2 were of myopathic type. Since the muscle affection of the two disorders has a primarily distal distribution with a distal to proximal gradient, muscle biopsy was performed in proximal muscles in order to study early changes. The CMT I patients had muscle fibre abnormalities of "neuropathic" type both in distal and proximal muscles. CMT2 patients, on the other hand, had muscle fibre abnormalities of a "myopathic" character in distal muscles and of both types in proximal muscles. The neuropathic muscle biopsy abnormalities found in the CMT I were inversely correlated to motor nerve conduction velocity, i.e. to the severity of the disorder. The myopathic abnormalities found in the CMT2 patients were inversely correlated to muscle strength. This indicates that the neuropathic histopathological changes in the CMT1 patients are primary, while the myopathic in the CMT2 patients are secondary, i.e. compensatory to the loss of muscle power. In order to analyse the denervation-reinnervation activity, macro EMG was performed. It showed an increase of amplitudes in CMT I patients, indicating an active denervation-reinnervation process. The amplitudes of the CMT2 patients were normal, indicating a lower reinnervation capacity when compared with the CMT I patients. In summary, the CMT I patients compensate for the on-going denervation by collateral reinnervation and when this does not keep up with a continuous loss of motoneurons, permanent denervation of an increasing number of muscle fibres occurs leading to a decrease in muscle strength. CMT2 patients have a lower collateral reinnervation capacity and the loss of motor units is mainly compensated for by an increase of the contractile tissue seen as significant hypertrophy of muscle fibres which are still innervated. The duration of the disorder and the functional muscle strength were almost the same in the CMT I and CMT2 patients. Therefore the difference in compensation of the denervation is suggested to be due to the differences in nerve dysfunction between CMT I and CMT2, demyelination and axonal disturbance respectively. Sensibility impairment found in CMT1 and CMT2 patients indicated involvement of both unmyelinated and myelinated nerve fibres, and the sensory dysfunction appeared more frequently in the CMT I than in the CMT2 patients. According to the different nerve dysfunctions, demyelination and axonal dysfunction respectively, the impairment of nerve function was mediated via myelinated nerve fibres, i.e. vibration dominated in CMT I, and via unmyelinated nerve fibres, i.e. thermal sensibility in CMT2. The genetically defined subgroup of CMT1A did not differ from the other CMT1 patients regarding muscle biopsy findings. However, there was a tendency that the CMT I A patients had a more severe sensory dysfunction. ISBN 91-628-3881-4