Neurological Dysfunction And Axonal Degeneration In Charcot‐Marie‐Tooth Disease Type 1A

Abstract

Charcot‐Marie‐Tooth disease type 1A (CMT1A), the most frequent form of GAIT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and regeneration, motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.

Clinical progression in Charcot–Marie-Tooth disease type 1A duplication: clinico-electrophysiological and MRI longitudinal study of a family

“…Selective fatty atrophy of intrinsic foot muscles is the characteristic pattern of patients with minimal disease; afterwards this pattern usually combines variable involvement of lower-leg muscles. In keeping with these observations, we found here that in patients IV-3 and IV-4 with mild CMTNS [29], MRI showed subtle distally accentuated fatty infiltration of anterior and lateral lower-leg muscle compartments with massive fatty atrophy of foot musculature in the scanned patient (case IV-4); this proximal-to-distal gradient of muscle changes concurs with the proposal of a length-dependent axonal degeneration as the mechanism of muscle denervation in CMT1A patients [2,13,23,31].…”

“…Edema with contrast enhancement was found in lower-leg musculature, and in anterior and posterior femoral musculature. Such imaging lesions correlate well with our electrophysiological findings, including progressive CMAP attenuation on the TA muscle, and presence of spontaneous muscle activity, indicative of axonal dysfunction with active denervation [2,6,15,23,31]. In a chronic disorder with minimal clinical progression over decades, such as CMT1A, the presence of these imaging lesions is difficult to interpret.…”

“…The clinical course is quiescent in adults [20], although a considerable agedependent increase in either mean weakness score [1,19] or neuropathic deficit [10] has been reported in cross-sectional studies; furthermore, functional disability increases with disease duration [3]. With regard to the disease course in adult CMT1A patients, cross-sectional studies indicate that clinical disability at the impairment and severity level is related to axonal dysfunction [23,31]. Because of the cross-sectional design, these studies cannot answer the question of whether and to what extent there is clinically and electrophysiologically disease progression in adult patients [32].…”

Screening of the 17p11.2–p12 region in a large cohort of patients with Charcot-Marie-Tooth (CMT) disease or hereditary neuropathy with liability to pressure palsies (HNPP)

“…Similarly, in CMT1A patients harboring the 17p11.2-p12 duplication, decreased compound action potential amplitudes (CMAPs) in distal nerves were recorded (Krajewski et al 2000). Thus, patients affected with CMT1A have been shown to manifest with axonal changes.…”

The causes of Charcot-Marie-Tooth disease

“…With regard to disease mechanisms, the crucial interplay between neurons (axons) and myelinating Schwann cells has turned into a prominent factor [6]. This has become particularly obvious with the finding that the disability in most if not all inherited neuropathies, axonal and demyelinating forms, is correlated with axonal loss [33,35,74,204]. Myelin deficiency also leads to a decrease in axonal caliber, axonal transport, and affects neurofilaments and microtubules [205].…”