Motor unit number index correlates with disability in Charcot-Marie-Tooth disease
Introduction
Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of hereditary motor and sensory neuropathies that can be transmitted through all forms of Mendelian inheritance (Szigeti and Lupski, 2009). It is the most frequent inherited neuropathy with a prevalence of 1:2,500 people (Barreto et al., 2016, Kochański, 2005, Patzkó and Shy, 2011). The initial pathological process induces either demyelination or axonal dysfunction, but in both cases, disability correlates with the extent of axonal loss (Krajewski et al., 2000).
Clinical features are a combination of length-dependent motor deficits and sensory signs and symptoms (Colomban et al., 2014, Pareyson and Marchesi, 2009). The first signs typically occur during the first or second decade of life. Paresis and muscle atrophy prevails in feet and legs, while involvement of the hands may follow later. Foot deformities with high arch and hammer toes depict the chronic nature of the motor neuropathy. Sensory signs and symptoms consist of loss of vibration and joint position sense and decreased pain and temperature sensation in stocking-glove pattern.
Electrophysiological studies distinguish two main types of CMT (Pareyson et al., 2006): the demyelinating form (CMT1), characterized by diffuse slowed nerve conduction velocity (NCV), typically <38 m/s (Manganelli et al., 2016), and the axonal form (CMT2), in which reduced compound muscle action potentials (CMAP) contrast with subnormal NCV. An intermediate form was also described with NCV ranging from 30 to 45 m/s and X-linked transmission.
During the last decade, seven clinical trials have been published in CMT1A disease to test the efficacy of either ascorbic acid (Burns et al., 2009, Lewis et al., 2013, Micallef et al., 2009, Pareyson et al., 2011, Verhamme et al., 2009) or a combination of baclofen, naltrexone and sorbitol at low dose (PXT3003) (Attarian et al., 2014, Chumakov et al., 2014). As CMT1A is a slowly progressive disease, the choice of endpoints that can monitor small changes over time remains a primary concern for future clinical development.
Classic electromyographic data are essential to the diagnosis process but are not relevant for following up patients or for the use as outcome measures in therapeutic trials.
It was reported that clinical disability is linked to axonal loss (Krajewski et al., 2000, Verhamme et al., 2004), but routine electrophysiological study cannot precisely evaluate its extent; in such slowly progressive neuropathies, collateral sprouting occurs from remaining axons and may increase the amplitude of individual motor unit action potentials, leading to a normal compound muscle action potential (CMAP) despite axonal loss (Shefner, 2001).
Motor unit number estimation (MUNE) techniques are interesting to assess axonal loss and the number of functional motor units. They were widely applied in amyotrophic lateral sclerosis (ALS) (Neuwirth et al., 2015). Motor Unit Number Index (MUNIX) estimation is a novel electrophysiological method to assess motor axonal dysfunction. It was first described by Nandedkar et al. (Nandedkar et al., 2004) and provides an index linked to the number of functional motor units in one muscle. MUNIX technique has been studied in ALS (Ahn et al., 2010, Boekestein et al., 2012, Furtula et al., 2013, Nandedkar et al., 2011, Neuwirth et al., 2011), chronic inflammatory demyelinating polyneuropathy (CIDP) (Delmont et al., 2016, Paramanathan et al., 2016) and multifocal motor neuropathy (Philibert et al., 2017) but has not yet been reported in CMT disease.
In this study, MUNIX technique was performed in patients with CMT disease and healthy controls. The data were compared between both groups and to clinical assessment to evaluate their correlation with clinical scales.
Section snippets
Methods
Adult patients with CMT disease were assessed during a consultation in the Referral Center for Neuromuscular Diseases and ALS, Marseille, France. This study was conducted over a period of one year. Demographic characteristics and clinical data were collected during the consultation, including several clinical scores such as CMT neuropathy score version 2 (CMTNSv2) (Murphy et al., 2011), CMT examination score (CMTES) version 2, overall neuropathy limitations scale (ONLS) (Graham and Hughes, 2006
Results
A total of 56 patients with CMT disease were included. Genetic diagnosis was available for 41 patients: 34 CMT1A with known duplication of PMP22 gene, 1 Dejerine-Sottas neuropathy with an identified mutation of PMP22 gene, 4 CMT1b with an identified mutation of P0 gene, 1 CMT4C with SH3TC2 gene mutation and 1 patient with ARHGEF10 gene mutation. Genetic diagnosis was not available for other patients: 1 sporadic demyelinating CMT, 9 axonal CMT (3 autosomal recessive, 3 autosomal dominant and 3
Discussion
In this study, we demonstrated the usefulness of the MUNIX technique in CMT disease. We found a good correlation between MUNIX and manual muscle testing and between MUNIX sum score and clinical scales.
MUNE techniques demonstrated that disability in CMT disease correlated with axonal loss, which was better reflected by the estimation of the number of motor units rather than by the CMAP amplitude (Lawson et al., 2003, Lewis et al., 2003, Videler et al., 2008). The estimation of the number of
Conclusion
This study showed that MUNIX correlated with motor impairment and clinical disability in patients with CMT disease, and could provide a new tool to follow up these patients in trials. Further studies are required to confirm our results in larger cohorts and to assess its sensitivity to change.
Acknowledgements
The results of this study were presented on a poster at the peripheral nerve society annual meeting in Sitges, Spain, july 2017.
Conflict of interest
None of the authors have potential conflicts of interest to be disclosed.
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