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

DOI: 10.1093/brain/awh020 Advanced Access publication November 7, 2003 Brain (2004), 127, 203±211 Nerve excitability properties in Charcot±Marie± Tooth disease type 1A Hiroyuki Nodera,1 Hugh Bostock,4 Satoshi Kuwabara,2 Takashi Sakamoto,1 Kotaro Asanuma,1 Sung Jia-Ying,2 Kazue Ogawara,2 Naoki Hattori,3 Masaaki Hirayama,3 Gen Sobue3 and Ryuji Kaji1 1Department of Clinical Neuroscience, Graduate School of Medicine, University of Tokushima, Tokushima, 2Department of Neurology, Chiba University, Chiba, 3Department of Neurology, Nagoya University, Nagoya, Japan and 4Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, London, UK Summary 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 recti®cation to hyperpolarizing currents and unusually fast accommodation to depolarizing currents. Strength±dur- Correspondence to: Ryuji Kaji, MD, PhD, Department of Clinical Neuroscience, University of Tokushima, 2-50-1 Kuramotocho, Tokushima City, 770-8503 Japan E-mail: ation 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. Keywords: Charcot±Marie±Tooth disease type 1A; paranode; membrane properties; threshold tracking; potassium channel Abbreviations: CIDP = chronic in¯ammatory demyelinating polyneuropathy; CMAP = compound muscle action potential; CMT1A = Charcot±Marie±Tooth disease type 1A; CV = conduction velocity; DL = distal motor latency; PMP22 = peripheral myelin protein 22; SNAP = sensory nerve action potential; TE = threshold electrotonus Introduction Charcot±Marie±Tooth disease type 1A (CMT1A) is the most common form of hereditary motor and sensory neuropathy and its hallmark is diffuse demyelination (Dyck et al., 1993; Birouk et al., 1997). However, secondary axonal degeneration is common and its degree determines the patient's functional disability (Hattori et al., 2003; Krajewski et al., 2000; Hanemann and Gabreels-Festen, 2002). To date, the pathophysiology of the secondary axonal degeneration in CMT1 is unknown, although abnormal axon±Schwann cell interaction has been considered to play a major role (Sahenk and Mendell, 1999a; Kamholz et al., 2000; Maier et al., 2002). Intact Schwann cells are important in maintaining axonal integrity and development (Peles and Salzer, 2000; Martini, 2001; Scherer and Arroyo, 2002), so it would be reasonable to assume that in CMT1A abnormalities exist in axonal membrane properties, as well as in myelin. Measurements of axonal excitability properties by threshold tracking have recently shed light on a variety of conditions affecting peripheral nerves (Bostock et al., 1998; Burke et al., 2001). The excitability properties are particularly sensitive to membrane potential, but also depend on nodal and internodal ion channels, as well as the passive Brain Vol. 127 No. 1 ã Guarantors of Brain 2003; all rights reserved 204 H. Nodera et al. membrane properties, such a nodal width, and the extent to which the internodal axonal compartment is electrically isolated from the nodal compartment (Bostock et al., 1998). Although many of these parameters are expected to be altered in demyelinating disease, several clinical studies have failed to reveal a clear-cut pattern of excitability changes related to demyelination. Thus a study of chronic in¯ammatory demyelinating polyneuropathy (CIDP) found raised thresholds but a shorter strength±duration time constant and no consistent changes in threshold electrotonus (Cappelen-Smith et al., 2001). Studies of multifocal motor neuropathy have found evidence of membrane hyperpolarization distal to sites of conduction block (Kiernan et al., 2002b), reduced Na+ conductance (Priori et al., 2002) and normal membrane properties proximal to sites of block (Cappelen-Smith et al., 2002), but at the sites of conduction block, where demyelination has been reported (Kaji et al., 1993), thresholds are very high and speci®c excitability changes relatable to demyelination have not been reported. A study of axonal and demyelinating forms of Guillain±Barre syndrome (Kuwabara et al., 2002a) also failed to ®nd any changes in nerve excitability properties at the wrist that could be directly related to the demyelination, probably because the major pathology occurred more distally in these patients. It has previously been argued that the reason why threshold electrotonus studies have failed to reveal consistent abnormalities in demyelinating neuropathies is because axons and nodes are affected non-uniformly, and ®bres demyelinated at the point of stimulation will preferentially be excited at adjacent normal nodes, or other, more normal ®bres will be excited in their place (Bostock et al., 1998). This argument should be less applicable to CMT1A, in which it is possible to limit cases to a well-de®ned genetic defect [duplication of the PMP22 (peripheral myelin protein 22) gene] and axons are affected relatively uniformly. This study was therefore undertaken to test the hypothesis that CMT1A patients, unlike those with previously studied acquired demyelinating diseases, would exhibit a consistent pattern of abnormal excitability measures. A further aim was to test for secondary changes in axonal membrane properties, such as changes in membrane potential, which could not be related directly to altered myelination but which might be related to the secondary axonal degeneration. In the event, a consistent pattern of abnormal nerve excitability properties was found, which was consistent with demyelination, but there was litt (...truncated)