Nerve excitability properties in Charcot-Marie-Tooth disease type 1A

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the in vivo assessment of multiple axonal excitability properties at the median nerve in nine CMT1A patients with PMP22 (peripheral myelin protein 22) gene duplication and 53 controls. The thresholds of CMT1A patients were much higher than normal, and threshold electrotonus (TE) exhibited a consistent pattern of abnormalities: early steep changes (fanning out) of both hyperpolarizing and depolarizing responses were followed by increased inward rectification to hyperpolarizing currents and unusually fast accommodation to depolarizing currents. Strength-duration time constants and the shapes of recovery cycles were normal, although refractoriness and superexcitability were reduced relative to controls. The high thresholds and early fanning out of electrotonus indicated altered cable properties, such that a greater proportion than normal of applied currents reached internodal rather than nodal axolemma. The rapid accommodation to depolarizing currents suggested activation of fast K+ channels, which are normally sequestered from the nodal membrane. The excitability abnormalities are therefore consistent with a demyelinating pathology and exposure or spread of K+ channels from under the myelin. It remains to be seen whether the TE abnormalities in CMT1A, which resemble previous recordings from normal immature rats, can be distinguished from those in acquired demyelinating neuropathies.

Axonal function in a family with episodic ataxia type 2 due to a novel mutation

“…The nerve excitability changes in these patients did not correspond to those previously described for membrane depolarization or hyperpolarization [6], for demyelination in CMT1A [18], or for block of sodium channels [9]. While alteration in neuromuscular transmission may alter recovery cycle measures, it is unlikely to cause the prominent changes in threshold electrotonus, the major finding of this study, which assesses local changes underlying the stimulating electrode.…”

Terminal latency index in neuropathy with antibodies against myelin‐associated glycoproteins

“…33,35 Electrophysiologically, conduction blocks characterize CIDP, whereas in MAG/SGPG-N conduction block is rarely observed. MAG/SGPG-N and hereditary sensorimotor neuropathy type 1 (HMSN1) have similar demyelinating features on nerve conduction studies and a slow progressive course, 26 although they can usually be distinguished clinically by the predominance of sensory symptoms and older age of onset of MAG/ SGPG-N compared to HMSN1. 3,9 HMSN1A is the most common subtype of HMSN1 and is caused by mutations in the gene encoding for peripheral myelin protein 22 , whereas HMSN1B results from genetic abnormalities in myelin protein zero.…”

Differences in Membrane Properties in Simulated Cases of Demyelinating Neuropathies: Internodal Focal Demyelinations without Conduction Block

“…Accuracy in establishing the diagnosis in CMT1A and GBS is related, in part, to the appropriate application of electrodiagnostic techniques. Using a noninvasive technique of threshold tracking, the indices of the axonal excitability, such as threshold electrotonus, strength-duration time constants, rheobases and recovery cycles can now be measured in healthy subjects and patients with GBS and CMT1A [6][7][8]. These indices depend on the biophysical properties of the axonal membrane and myelin sheath.…”