Motor unit number index correlates with disability in Charcot-Marie-Tooth disease

https://doi.org/10.1016/j.clinph.2018.04.359Get rights and content

Highlights

  • The MUNIX technique estimates axonal loss and the number of remaining functional motor units.

  • The MUNIX sum score correlated with disability in Charcot-Marie-Tooth (CMT) disease as defined by clinical scales.

  • The MUNIX sum score may be proposed as an outcome measure in CMT disease.

Abstract

Objective

The aim of this study was to assess the usefulness of motor unit number index (MUNIX) technique in Charcot-Marie-Tooth disease and test the correlation between MUNIX and clinical impairment.

Methods

MUNIX technique was performed in the abductor pollicis brevis (APB), the abductor digiti minimi (ADM) and the tibialis anterior (TA) muscles in the nondominant side. A MUNIX sum score was calculated by adding the MUNIX of these 3 muscles. Muscle strength was measured using the MRC (medical research council) scale. Disability was evaluated using several functional scales, including CMT neuropathy score version 2 (CMTNSv2) and overall neuropathy limitation scale (ONLS).

Results

A total of 56 CMT patients were enrolled. The MUNIX scores of the ADM, APB and TA muscles correlated with the MRC score of the corresponding muscle (p < 0.01). The MUNIX sum score correlated with the clinical scales CMTNSv2 (r  =  −0.65, p < 0.01) and ONLS (r  =  −0.57, p < 0.01).

Conclusion

MUNIX correlates with muscle strength and clinical measurements of disability in patients with CMT disease.

Significance

The MUNIX technique evaluates motor axonal loss and correlates with disability. The MUNIX sum score may be a useful outcome measure of disease progression in CMT.

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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