ABSTRACT & COMMENTARY
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Unlike other neuromuscular disorders, physical exercise does not appear to worsen weakness in patients with Charcot-Marie-Tooth disease.
Source: Piscosquito G, et al. Is overwork weakness relevant in Charcot-Marie-Tooth disease? J Neurol Neurosurg Psychiatry 2014;85:1354-1358.
Overwork weakness, defined as increased disease progression as a result of muscle overload, has been demonstrated in Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, amyotrophic lateral sclerosis, and post-polio syndrome. As a result, patients are advised to relatively spare affected muscles during physical activity to prevent premature worsening. Does this apply to Charcot-Marie-Tooth disease (CMT)?
If overwork weakness were to play a role in CMT, hand strength would be expected to be superior in the non-dominant hand, because dominant hands do more work. Hence, to address this question, retrospective data review was undertaken on 271 CMT 1A patients, 108 men and 163 women, ages 18-70 years, recruited in the ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK) double-blind, randomized trial. Muscle strength was graded using the MRC scale and tested in distal muscles most affected in CMT, including the first dorsal interosseous and abductor pollicis brevis in both hands, and tibialis anterior and gastrocnemius/soleus complex in both legs. Using a 9-hole peg test, manual dexterity was tested and expressed in seconds. Side-to-side comparisons were made, with asymmetry defined as an MRC grade differential of 1 or more between sides. Statistical analysis included the chi-square and Fisher’s exact test, the Wilcoxon rank sum test or Kruskal-Wallis for comparisons, and the Shapiro-Wilk normality test, with statistical significance set at P < 0.05.
None of the patients demonstrated any significant side-to-side difference in hand or foot muscle strength for any muscle tested, while dexterity, as expected, was significantly better on the patient’s dominant side. In all muscles studied, strength significantly decreased with increasing disease severity and with age, with no significant difference seen between dominant or non-dominant hands, but with a mild but significant difference found in gastrocnemius/soleus strength in older patients, which was greater on the dominant side. Gender affected neither symmetry nor strength between sides. Overwork weakness does not appear to play a role in CMT 1A, and patients may be encouraged to exercise to their heart’s content.
Although more than 75 gene mutations may result in CMT, in most North American and European countries, the most frequent forms of CMT are autosomal dominant, with CMT1 accounting for more than 80%, most of whom have the classical CMT phenotype, with median motor nerve conduction velocities of 38 m/s and nerve biopsies demonstrating decreased numbers of myelinated axons with "onion bulbs," comprising several layers of basal lamina, Schwann cells, and connective tissue surrounding thinly myelinated axons. Presently, CMT1 is sub-classified as CMT1A to CMT1F, with CMT1A caused by a 1.4-Mb duplication of chromosome 17 containing the peripheral myelin protein 22 gene (PMP22). Together with mutations affecting myelin protein zero (MPZ), mitofusin 2 (MFN2), and gap junction beta-1 protein (GJB1, also referred to as connexin 32, Cx32), these abnormalities comprise more than 80% of CMT patients in Western countries. While a cure remains a distant hope, our understanding of the underlying pathophysiology is advancing dramatically.1
- Tazir M, et al. Hereditary motor and sensory neuropathies or Carcot-Marie-Tooth diseases: An update. J Neurol Sci 2014;347:14-22. http://dx.doi.org/10.1016/j.jns.2014.10.013.