1. Introduction
Charcot-Marie-Tooth disease (CMT), also known as progressive peroneal muscular atrophy or hereditary motor and sensory neuropathy (HMSN), was initially reported in 1886 by Charcot and Marie (France), and Tooth (UK). The disease is characterized by peroneal muscle atrophy as the primary manifestation. Since the initial description, it has been studied by researchers to understand its etiology and pathophysiology [
1,
2,
3,
4,
5]. However, the exact cause and mechanisms of the disease remain elusive [
6].
Charcot-Marie-Tooth disease is primarily an autosomal dominant, progressive, symmetric disorder of motor and sensory nerves, which predominantly manifests in the lower extremities. It is classified as a disorder of peripheral nerve, and the clinical presentation includes the symptoms of gradual muscular atrophy and sensory deficits, starting from the distal portions of the feet and hand and progressing towards the proximal extremities. The severity of the symptoms is assumed to correlate with the degree of axonal degeneration [
7,
8]. It is classified into seven categories based on manifestations, genetic inheritance patterns, electrophysiology, or results of pathologic changes from nerve biopsy [
9]. Over the past few decades, with the discovery of various genes contributing to variability, molecular genetic examination has become an important diagnostic method for CMT disease. CMT Type 1 is demyelinating, and autosomal dominant phenotype currently subdivided into A, B, C, D, E, F, G, and HNPP based on the specific gene mutation and related phenotypes.
The most common subtype, constituting about 70% of cases of this disorder, is CMT1A. Its initial clinical presentation involves pain, muscle weakness, and foot deformities [
10], followed by progression of weakness to affect leg muscles [
11]. Such clinical progression leads to abnormal gait patterns and, in some cases, even results in the loss of ambulation. However, it is widely acknowledged that in the majority of cases, the clinical course is known to advance slowly. Krajewski et al. reported that out of forty-two walkable CMT patients, only three required the use of a wheelchair in the later time [
7]. However, Pfeiffer et al., when analyzing the walking patterns of fifty patients, found that a mere five individuals exhibited a normal gait pattern [
12].
Previous research studies on gait impairment and patterns in the context of CMT disease have predominantly focused on describing gait patterns within patient groups based on the individual presentation or genetic traits without objective measurements [
13,
14]. Additionally, some studies only involved a comparison of gait patterns between a control group and the CMT population [
15,
16]. Despite the significance of gait abnormalities in CMT disease, currently, there is a lack of studies analyzing differences in gait abnormalities among patient subgroups based on the disease severity. One study described the abnormal gait patterns among CMT disease subgroups, however, the subjects of the study were limited to children [
17].
The objective of this study was to investigate the characteristics of gait patterns among a cohort of 22 individuals diagnosed with CMT1A. This investigation was conducted through the application of motion analysis, encompassing the measurement of kinematic and kinetic parameters. Additionally, a comparative analysis was performed between the gait patterns of CMT1A patients and those of the control group of individuals without CMT, to identify distinct gait features.
4. Discussion
In this study, through three-dimensional gait analysis, a comprehensive comparison of temporospatial, kinematic, and kinetic characteristics of gait differences between the control group and the CMT1A disease group, and between the CMT1A disease subgroups based on disease severity was conducted. Gait speed exhibited a significant decrease in the CMT1A disease group compared to the control group, which can be attributed to the deviations in the kinematic and kinetics of gait patterns. Specifically, the reduced ankle plantarflexor force at push-off in CMT patients is believed to contribute to this discrepancy [
16]. On the contrary, the slower gait speed could potentially influence the kinematic and kinetic changes in walking. However, the observed deviations in the gait pattern of the CMT1A disease group in this study were not consistent with the alterations seen in walking due to a slower gait speed in the control group [
22]. Instead, these deviations more closely resembled the gait deviations resulting from weakened hip and ankle muscle powers, rather than those occurring with a slower gait pattern in healthy individuals [
23]. Furthermore, a decrease in various ankle joint angles was observed in the CMT1A disease group, including the maximal ankle dorsiflexion angle, the dorsiflexion angle at 98% of the gait cycle, the ankle dorsiflexion at initial contact, and the maximal ankle plantarflexion at push-off with an increase in the maximal ankle rotation in stance. These findings explain the occurrence of foot drop due to the impairment of ankle dorsiflexor muscles. Consequently, this phenomenon leads to an increased ankle plantarflexion angle at initial contact. The compromised function of the gastrocnemius and soleus muscles result in reduced ankle plantarflexion at push-off and diminished dorsiflexion power during the late stance phase. This inadequate ankle dorsiflexion, along with insufficient ankle plantarflexion, resembles the pattern observed by Vinci and Perelli [
11] in CMT patients, where there was nerve degeneration progresses from distal to proximal within the lower extremities, leading to symptomatic changes in ankle kinematics due to muscle weakness and atrophy. They attributed these alterations to an imbalanced function of the ankle evertor muscles, causing a supination deformity of the ankle joint. This explanation aligns with the findings of this study, which showed increased ankle internal rotation moment [
24,
25].
This study identified a reduction in knee flexion angle in stance and an increase in knee extension power generation in stance. Kendall and McCreary et al. [
26] suggested that the biomechanism of knee joint hyperextension correlates with muscular dysfunction caused by compromised gastrocnemius and soleus muscle. These findings are parallel to the results observed in this study, where the deviations in knee kinematics could be attributed specifically to the weakened ankle plantarflexor muscles. The previous researchers expounded on compensatory mechanisms triggered by muscle imbalances around the ankle joint, leading to foot supination [
26,
27]. This compensation induces internal rotation of the shank relative to the thigh, aiding in enhancing foot progression during the loading response phase. The mechanism involving hip external rotation during shank progression, contributing to improved foot progression in foot supination position was also elucidated [
17]. In normal gait, the hip joint maintains an adducted position as the center of mass shifts over the weight-bearing lower limb in the stance phase [
22]. A decrease in hip adduction signifies a wider base of support in walking, a phenomenon observed in patients with neurological deficits like CMT or individuals with ankle instability [
28,
29]. This phenomenon is consistent with the findings in this study, where a decrease in the maximal hip adduction in CMT1A disease group aligns with the altered hip kinematics in the previous studies [
17,
30].
In this study, gait speed was significantly slower in the moderate group compared to the mild group, and in the swing phase, the maximal hip flexion angle was greater in the moderate group. Additionally, distinct characteristics were noted in the moderate group, including increased knee flexion angle at initial contact, the maximal knee flexion angle in swing, decreased ankle dorsiflexion angle at the 98% point of the gait cycle and initial contact, and a reduced peak ankle dorsiflexion moment in stance, all compared to the mild group. These gait patterns demonstrate that as the disease progresses, the severity of foot drop becomes more profound [
31,
32]. In cases where there is mild muscle weakening of the ankle dorsiflexors, particularly at initial contact, impaired eccentric contractions of the ankle dorsiflexor muscles can lead to foot slap. Moreover, in instances of more pronounced muscle weakness, gait imbalance with instability manifests at midstance, resulting in increased pronation and supination of the foot, coupled with dragging of the foot in the swing phase. This phenomenon is associated with a severe hip flexion and ankle plantarflexion, called steppage gait, which was also observed in this study and is explained by the progressive nature of the disease condition with the extent of food drop [
17,
30,
33,
34].
This study has several limitations. First, the cross-sectional design nature of this study may pose challenges in accurately assessing the changes in gait patterns over time. While this study investigated gait patterns and variations based on the severity of CMT1A disease in a cohort, it did not involve a prospective, longitudinal approach to track serial progression in gait abnormalities over an extended period individually. Therefore, the ability to precisely infer alteration linked to disease progression might be constrained. Second, the number of patients was relatively small even though we tried to recruit patients through a special clinic with the largest CMT cohort. This could be attributed to the fact that CMT is a rare disease. In forthcoming studies, it is anticipated that these considerations will be addressed, and a large-scale prospective, longitudinal study will be conducted for a more comprehensive analysis of the progressive nature of gait characteristics.