[Neuromuscular Ultrasound: Diagnosis and Evaluation in Neuromuscular Diseases].

Neuromuscular ultrasound has become an integral part of the diagnostic workup of neuromuscular diseases in neurology. Neuromuscular ultrasound can detect nerve enlargement, selective muscle damage, and fasciculation easily and non-invasively, which allows differentiation between auto-immune/inflammatory and degenerative/hereditary diseases. It is significant and essential for all neurologists to master the neuromuscular ultrasound technique.

Neurophysiological and imaging biomarkers of lower motor neuron dysfunction in motor neuron diseases/amyotrophic lateral sclerosis: IFCN handbook chapter.

This chapter discusses comprehensive neurophysiological biomarkers utilised in motor neuron disease (MND) and, in particular, its commonest form, amyotrophic lateral sclerosis (ALS). These encompass the conventional techniques including nerve conduction studies (NCS), needle and high-density surface electromyography (EMG) and H-reflex studies as well as novel techniques. In the last two decades, new methods of assessing the loss of motor units in a muscle have been developed, that are more convenient than earlier methods of motor unit number estimation (MUNE),and may use either electrical stimulation (e.g. MScanFit MUNE) or voluntary activation (MUNIX). Electrical impedance myography (EIM) is another novel approach for the evaluation that relies upon the application and measurement of high-frequency, low-intensity electrical current. Nerve excitability techniques (NET) also provide insights into the function of an axon and reflect the changes in resting membrane potential, ion channel dysfunction and the structural integrity of the axon and myelin sheath. Furthermore, imaging ultrasound techniques as well as magnetic resonance imaging are capable of detecting the constituents of morphological changes in the nerve and muscle. The chapter provides a critical description of the ability of each technique to provide neurophysiological insight into the complex pathophysiology of MND/ALS. However, it is important to recognise the strengths and limitations of each approach in order to clarify utility. These neurophysiological biomarkers have demonstrated reliability, specificity and provide additional information to validate and assess lower motor neuron dysfunction. Their use has expanded the knowledge about MND/ALS and enhanced our understanding of the relationship between motor units, axons, reflexes and other neural circuits in relation to clinical features of patients with MND/ALS at different stages of the disease. Taken together, the ultimate goal is to aid early diagnosis, distinguish potential disease mimics, monitor and stage disease progression, quantify response to treatment and develop potential therapeutic interventions.

Diagnostic utility of Gold Coast criteria for amyotrophic lateral sclerosis in Asia.

Objective: This study aimed to reveal the diagnostic utility of Gold Coast (GC) criteria in Japanese patients with amyotrophic lateral sclerosis (ALS) by comparing the sensitivity/specificity with revised El Escorial (R-EE) and Awaji criteria, because its utility has not been studied in Asian ALS. Methods: Consecutive 639 patients (529 with ALS and 110 with ALS mimics), who were suspected of ALS and referred to three Japanese ALS centers, were enrolled. Diagnostic accuracy and characteristics of false positive and negative in GC criteria were compared with those of the Awaji and R-EE criteria. Patients were categorized as definite, probable or possible ALS according to each criterion. Results: The sensitivity of GC criteria (96.8%, 95% confidence interval [CI]: 95.3-98.3%) was higher than that of Awaji (89.6%, 95% CI: 87.0-92.2%) and R-EEC (89.2, 95% CI: 86.6-91.8%) criteria (both, p < 0.001). The specificity was also higher with GC criteria (77.3%, 95% CI: 69.5-85.1%) than Awaji (65.5%, 95% CI: 56.6-74.4%) and R-EEC (66.4, 95% CI: 57.6-75.2%) criteria (both, p < 0.01). Using GC criteria, patients with cervical spondylosis and Parkinson's syndrome tended to be diagnosed with ALS (i.e. "false positive"). Additionally, ALS patients diagnosed only by GC criteria less frequently had upper motor neuron (UMN) signs, compared with the other two criteria. Conclusion: Gold Coast criteria improve diagnostic accuracy for ALS in an Asian population, especially in patients with subtle UMN signs.

[Charcot-Marie-Tooth disease Patient Registry in Japan].

To clarify the natural courses, medical conditions, and problems in daily life and medical care of the patients with Charcot-Marie-Tooth disease (CMT) in Japan, we have developed a patient registration system (CMT Patient Registry (CMTPR)). We analyzed data of questionnaires from 303 patients (males: 162, females: 141, mean age: 45.9 years old) who registered for CMTPR. The age of onset was less than 15 years old in 45% and more than 60 years old in 5% of the patients. Genetic testing was performed in 65%, and about half of the patients with genetic testing had a duplication of the PMP22 gene. Seventy-six percent of the patients had regular visits to medical facilities. Five percent of patients had no history of hospital visits. Fifteen percent of all patients needed assistance with daily activities due to motor function impairment in the upper extremities, and 25% required assistance due to lower limb impairment. There were no significant differences in the need for assistance by gender or age. Of the 267 adult patients, 18% had difficulty working due to reasons related to the disease, although none of the junior patients reported any problem attending school. This was the first nationwide epidemiological study with healthcare and welfare information on patients with CMT in Japan. We hope the results of this study will lead to better welfare and medical care in CMT patients.

Assessment of motor unit firing by high-density surface electromyography detects motor neuronal hyperexcitable state in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), the impact of motor neuron dysfunction on the motor unit (MU) firing pattern remains to be elucidated. The aim of this study was to clarify the characteristics of the MU firing rate and its association with clinical factors in ALS patients using high-density surface electromyography (HDSEMG) and MU decomposition analysis. METHODS: Nineteen ALS patients and 20 controls prospectively underwent HDSEMG recording of the vastus lateralis muscle during ramp-up (30% of maximum voluntary contraction) and sustained (10% of maximal voluntary contraction for 60 seconds) contractions on performing isometric knee extension. After decomposition analysis, instantaneous firing rates (IFRs) of individually identified MUs were calculated. Comparison of IFRs and clinical variables between ALS patients and controls and analysis of the correlation between individual mean IFR and clinical variables in ALS patients were performed. RESULTS: The number of identified MUs was lower in ALS patients than in controls (P = .017). Mean IFRs of MUs (i.e., mean MU firing rates) were higher in ALS patients than in controls at some force levels on ramp-up contraction (P < .05) and at 50 to 60 seconds during sustained contraction (9.1 [ALS] vs 8.3 [controls] pulses per second; P = .036). There was no correlation between the clinical parameters and mean IFR of each patient. DISCUSSION: ALS patients had a higher MU firing rate during muscle contraction at a low force level. Noninvasive assessment of the MU firing rate by HDSEMG can detect a motor neuronal hyperexcitable state in ALS patients.

Compound muscle action potential duration ratio for differentiation between Charcot-Marie-Tooth disease and CIDP.

OBJECTIVE: To elucidate the utility of the proximal to distal compound muscle action potential (CMAP) duration ratio to distinguish between demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) compared with nerve ultrasound. METHODS: Thirty-nine demyelinating CMT patients and 19 CIDP patients underwent nerve conduction studies (NCS) and nerve ultrasound. NCS parameters including CMAP duration ratio calculated by dividing the value at the proximal site by that at the distal site and nerve cross-sectional area (CSA) measured by ultrasound were compared between the two groups. The diagnostic sensitivity and specificity of each parameter were analysed. RESULTS: CMT patients showed a significantly lower CMAP duration ratio than CIDP patients (p < 0.05). The area under the curve (AUC) value of the CMAP duration ratio exceeded 0.95 when CMT was considered "positive", and a cut-off value of 1.13 resulted in high diagnostic sensitivity and specificity (84.6 and 100 % for median nerve, 97.4 and 85.7 % for ulnar nerve, respectively), whereas the AUC value of nerve CSA ranged from 0.70 to 0.81. CONCLUSIONS: The CMAP duration ratio could effectively distinguish between demyelinating CMT and CIDP. SIGNIFICANCE: Adding the CMAP duration ratio to a routine NCS may improve the accuracy of the diagnosis of demyelinating CMT.

Serum pentraxin 3 concentration correlates with disease severity in patients with myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is an antibody-mediated inflammatory disease affecting post-synaptic membranes of neuromuscular junctions, and objective biomarkers of MG disease activity are lacking. Pentraxin 3 (PTX3) is an acute-phase inflammatory glycoprotein in the same family as C-reactive protein that is associated with disease activity in several autoimmune disorders. Thus, we investigated whether circulating PTX3 is a useful biomarker of MG activity. METHODS: Serum PTX3 was measured in 40 patients with MG who were positive for anti-acetylcholine receptor antibody, and in 30 healthy and disease controls, using a commercial enzyme-linked immunosorbent assay kit. In patients with MG, the correlation of serum PTX3 levels with disease severity scales at serum sampling, including MG Foundation of America (MGFA) classification, MG activity of daily living (MG-ADL) score, and quantitative MG (QMG) score, were investigated. RESULTS: Although there was no significant difference in serum PTX3 between the MG and control groups (mean, 3346 pg/mL in MG group vs. 2870 pg/mL in control group, P = 0.56), serum PTX3 moderately correlated with all disease severity scores (MGFA classification: Spearman's ρ = 0.53, P = 0.0004; MG-ADL score: Spearman's ρ = 0.45, P = 0.004; QMG score: Spearman's ρ = 0.50, P = 0.004). CONCLUSION: Our results suggest that circulating PTX3 may reflect the extent of neuromuscular junction damage and might be involved in the pathogenesis of MG.

Amyotrophic lateral sclerosis: Correlations between fluid biomarkers of NfL, TDP-43, and tau, and clinical characteristics.

OBJECTIVES: We previously reported the diagnostic and prognostic performance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma as amyotrophic lateral sclerosis (ALS) biomarkers. The present study aimed to elucidate associations between clinical characteristics and the markers as well as mutual associations of the markers in ALS patients using the same dataset. METHODS: NfL, TDP-43, and t-tau levels in CSF and plasma in 75 ALS patients were analyzed. The associations between those markers and clinical details were investigated by uni- and multivariate analyses. Correlations between the markers were analyzed univariately. RESULTS: In multivariate analysis of CSF proteins, the disease progression rate (DPR) was positively correlated with NfL (ß: 0.51, p = 0.007) and t-tau (ß: 0.37, p = 0.03). Plasma NfL was correlated with age (ß: 0.53, p = 0.005) and diagnostic grade (ß: -0.42, p = 0.02) in multivariate analysis. Plasma TDP-43 was correlated negatively with split hand index (ß: -0.48, p = 0.04) and positively with % vital capacity (ß: 0.64, p = 0.03) in multivariate analysis. Regarding mutual biomarker analysis, a negative correlation between CSF-NfL and TDP-43 was identified (r: -0.36, p = 0.002). CONCLUSIONS: Elevated NfL and t-tau levels in CSF may be biomarkers to predict rapid DPR from onset to sample collection. The negative relationship between CSF NfL and TDP-43 suggests that elevation of CSF TDP-43 in ALS is not a simple consequence of its release into CSF during neurodegeneration. The negative correlation between plasma TDP-43 and split hand index may support the pathophysiological association between plasma TDP-43 and ALS.

A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene. CASE PRESENTATION: A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD. CONCLUSION: We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.

Quantitative assessment of muscle echogenicity in Charcot-Marie-Tooth disease type 1A by automatic thresholding methods.

OBJECTIVE: To investigate the utility of automatic thresholding methods for quantitative muscle echogenicity assessment as a marker of disease severity in Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Muscle ultrasound was performed in 15 CMT1A patients and 7 healthy controls. Muscle echogenicity of six limb muscles in each subject was assessed by 16 automatic thresholding methods and conventional grey-scale analysis. Echogenicity of each method in CMT1A patients was compared with that in controls. A correlation between the echogenicity and CMT neuropathy score (CMTNS) was also analysed in CMT1A patients. RESULTS: Significant differences in mean echogenicity of the 6 muscles between CMT1A patients and controls were found both in grey-scale analysis (p < 0.01) and 11 of the 16 automatic thresholding methods (p < 0.05 in each method). In CMT1A patients, mean echogenicity of the 6 muscles was positively correlated with CMTNS in 8 of the 16 automatic thresholding methods, but not in grey-scale analysis. CONCLUSION: Automatic thresholding methods can be used to detect the difference in muscle echogenicity between CMT1A patients and controls. Echogenicity parameters correlate with the disease severity. SIGNIFICANCE: Quantitative muscle echogenicity assessment by automatic thresholding methods shows potential as a surrogate marker of disease progression in CMT1A.

Rate of change in acetylcholine receptor antibody levels predicts myasthenia gravis outcome.

OBJECTIVE: To investigate the association between changes in anti-acetylcholine receptor antibody (AChR Ab) levels induced by immunosuppressive treatment and myasthenia gravis (MG) prognosis at 1-year post-treatment in patients with MG. METHODS: We included 53 consecutive AChR Ab-positive patients with MG whose AChR Ab levels were remeasured within 100 days of initiating immunosuppressive treatment (median remeasuring time post-treatment: 71 (55-84) days). The AChR Ab level reduction rate (RR-AChRAb, %/day) adjusted for the time between treatment initiation, and AChR Ab level remeasurement was calculated as follows: (pretreatment-post-treatment AChR Ab level)/pretreatment AChR Ab level/days between therapy initiation and AChR Ab level remeasurement ×100. Participants were divided into two groups based on the cut-off value of RR-AChR Ab, determined using receiver operating characteristic analyses for achieving minimal manifestation (MM) or better status at 1-year postimmunosuppressive treatment. The Myasthenia Gravis Foundation of America postintervention status and MG activity of daily living (MG-ADL) score at 1-year post-treatment were compared between the two groups. RESULTS: The RR-AChRAb cut-off value was 0.64%/day. The high RR-AChRAb group had a higher ratio of MM or better status (90% vs 65%, p=0.03) and lower MG-ADL score (median; 1 vs 2, p=0.04) than the low RR-AChRAb group. Kaplan-Meier analyses showed the early MM achievement in the high RR-AChRAb group (p=0.002, log-rank test). CONCLUSIONS: High RR-AChRAb is associated with a favourable outcome at 1-year post-treatment. AChR Ab remeasurement within 100 days of therapy may be useful for predicting AChR Ab-positive MG outcomes at 1-year post-treatment.

Dispersion of mean consecutive differences in single-fiber electromyography increases diagnostic sensitivity for myasthenia gravis.

INTRODUCTION: In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG. METHODS: One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses. RESULTS: MG patients showed a significantly greater MCD mean (MG: control, 26.3 µs; 13.5 µs [median]; P < .0001), MCD SD (MG: control, 12.8 µs; 5.1 µs [median]; P < .0001), and MCD CV (MG: control, 46.1; 37.5 [median]; P < .001) than those without MG. An ROC curve of SD showed a large area under the curve (0.88), and a cut-off value of 7.2 µs, which was calculated by maximum Youden index, exhibited high diagnostic sensitivity (86%) for MG. Combined MCD mean, outliers, and SD criteria showed higher sensitivity (88%) than conventional criteria alone (82%), at the expense of lower specificity. Five MG patients with normal MCD mean and abnormal MCD SD had only ocular symptoms. DISCUSSION: The dispersion of MCD as measured by MCD SD greater than 7.2 µs is significantly increased in patients with MG and may be a useful measure of abnormal jitter in the diagnosis of MG, especially for identifying patients with mild disease.

High-density surface electromyography to assess motor unit firing rate in Charcot-Marie-Tooth disease type 1A patients.

OBJECTIVE: The aim of this study was to elucidate the characteristics of the motor unit (MU) firing rate in Charcot-Marie-Tooth disease type 1A (CMT1A) patients and its longitudinal change using high-density surface-electromyography (surface-EMG) and MU decomposition analysis. METHODS: Nineteen patients with CMT1A and 21 force-matched healthy controls prospectively underwent surface-EMG recording of the vastus lateralis muscle during ramp-up and sustained contractions on performing isometric knee extension. After decomposition analysis, instantaneous firing rates (IFRs) of individually identified MUs were calculated. In CMT1A patients, follow-up measurements were performed one year after the baseline. Comparison of IFRs and clinical variables between CMT1A patients and controls at the baseline and between the baseline and after one year in CMT1A patients was performed. RESULTS: Mean IFRs of MUs were lower in CMT1A patients than in controls. This was true at various force levels in ramp-up contractions (p < 0.01. e.g., 10.3 (CMT1A patients) vs. 12.2 (controls) pulses-per-second (pps) at 22.5-27.5% of maximal voluntary contraction (MVC) in MUs recruited at <7.5% of MVC) and at any time-point during sustained contractions (p < 0.001. e.g., 8.0 vs. 9.3 pps, respectively, at 10-20 seconds). In CMT1A patients, mean IFRs at 0-10 seconds of sustained contraction were significantly decreased over one year (from 8.06 to 7.52 pps; p = 0.027), whereas the disease severity score and MVC of knee extension did not change over time. CONCLUSION: CMT1A patients had a lower individual MU firing rate. SIGNIFICANCE: The MU firing rate is a potential short-term biomarker of axonal damage in CMT1A patients.

Sonographic Nerve Enlargement in a Patient with Sarcoidosis.

We herein report a 73-year-old woman case with sarcoid neuropathy showing nerve enlargement assessed by nerve ultrasound both before and after treatment. The site of conduction block in the left tibial nerve corresponded to the site of nerve enlargement with a hypo-echoic pattern. After treatment with prednisolone, nerve ultrasound detected the remission of the nerve enlargement, and the conduction block and clinical symptoms also improved. Nerve enlargement may reflect inflammation of the peripheral nerve. A follow-up study of sonographic nerve enlargement may be of clinical significance for assessing the effectiveness of treatment for sarcoid neuropathy.

Difference in distribution of fasciculations between multifocal motor neuropathy and amyotrophic lateral sclerosis.

OBJECTIVE: To examine differences in fasciculation distribution between patients with multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS) based on muscle ultrasound. METHODS: Forty-one muscles (tongue muscle and 40 muscles of the trunk and limbs on both sides) in 5 MMN patients and 21 muscles (tongue muscle and 20 muscles on the onset side) in 21 ALS patients were subjected to muscle ultrasound individually for 60 seconds to detect the presence of fasciculations. RESULTS: Fasciculation detection rates on the onset side were significantly higher in ALS (42.4 ± 18.3%, mean ± SD) than in MMN (21.9 ± 8.8%) patients (p < 0.05). In MMN patients, no fasciculation was detected in the tongue or truncal muscles. There was no difference in the fasciculation detection rate between the onset and non-onset sides or between upper and lower limbs in MMN patients. CONCLUSIONS: In MMN patients, fasciculations were detected extensively in the limbs. However, the detection rate in patients with MMN was lower than in those with ALS. SIGNIFICANCE: Demonstration of the absence of fasciculations in the tongue and truncal muscles in MMN patients by extensive muscle ultrasound examination may help distinguish MMN from ALS.

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. CMT patients typically show slowly progressive muscle weakness and sensory loss in a distal dominant pattern in childhood. The diagnosis of CMT is based on clinical symptoms, electrophysiological examinations, and genetic testing. Advances in genetic testing technology have revealed the genetic heterogeneity of CMT; more than 100 genes containing the disease causative mutations have been identified. Because a single genetic alteration in CMT leads to progressive neurodegeneration, studies of CMT patients and their respective models revealed the genotype-phenotype relationships of targeted genes. Conventionally, rodents and cell lines have often been used to study the pathogenesis of CMT. Recently, Drosophila has also attracted attention as a CMT model. In this review, we outline the clinical characteristics of CMT, describe the advantages and disadvantages of using Drosophila in CMT studies, and introduce recent advances in CMT research that successfully applied the use of Drosophila, in areas such as molecules associated with mitochondria, endosomes/lysosomes, transfer RNA, axonal transport, and glucose metabolism.

Charcot-Marie-Tooth disease type 1A: Longitudinal change in nerve ultrasound parameters.

BACKGROUND: This study aimed to elucidate the longitudinal changes in nerve ultrasound parameters of adult Charcot-Marie-Tooth disease type 1A (CMT1A) patients. METHODS: Fifteen adult patients with CMT1A prospectively underwent nerve ultrasound and clinical assessment (CMT neuropathy score [CMTNS]) at baseline and 5 y later. Nerve cross-sectional area (CSA) and echogenicity were measured in the median and sural nerves. Changes in ultrasound parameters and CMTNS and correlation between changes of ultrasound parameters and CMTNS were analyzed. RESULTS: Median and sural nerve CSAs did not change over 5 y, although CMTNS increased (P < .01). Nerve echogenicity in the sural nerve decreased over 5 y (P = .045). No correlations between changes in nerve ultrasound parameters and CMTNS were identified. CONCLUSIONS: No longitudinal changes in nerve size was detected in adult CMT1A. Exploring the factors that determine nerve size in childhood CMT1A may lead to the development of treatments.

Rate of Changes in CMT Neuropathy and Examination Scores in Japanese Adult CMT1A Patients.

Introduction: We aimed to clarify when adult patients with Charcot-Marie-Tooth disease type 1A (CMT1A), especially those diagnosed at middle or advanced ages, first showed symptoms and whether the rate of disease progression is accelerated by aging. Methods: Medical records of CMT1A outpatients between 2012 and 2019 were reviewed. The age at diagnosis, age when symptoms first appeared, and rate of disease progression, assessed based on clinical outcome measures including the CMT Neuropathy Score (CMTNS), Rasch-modified CMTNS (CMTNS-R), CMT Examination Score (CMTES), and Rasch-modified CMTES (CMTES-R) were analyzed. Results: Among 45 adult CMT1A patients, 42% had been diagnosed after 50 years of age, whereas 91% of all patients had exhibited some CMT-related symptoms before 20 years of age. The annual increase of all clinical outcome measures did not differ between patients under and over 50 years. Even when limited to patients whose initial CMTES-R showed mild to moderate severity, the rate of change in CMTES-R did not differ between the two age groups (the annual mean ± standard deviation, under 50 years: 1.1 ± 1.0, and over 50 years: 0.9 ± 1.1, p = 0.68). To determine whether patients with disabilities at a young age have a higher deterioration rate, they were classified into three groups according to their current age and age at diagnosis: patients under 50 years of age, patients over 50 years of age but diagnosed before 50, and patients diagnosed after 50 years of age. The mean annual increase of all clinical outcome measures, however, did not differ among these groups (CMTES-R: 1.03 ± 1.01 vs. 0.94 ± 1.57 vs. 0.81 ± 0.88, respectively, p = 0.87). Discussion: CMT1A patients develop symptoms in childhood and adolescence even if such symptoms are not noticeable until reaching an advanced age. Deterioration rates of clinical outcome measures are constant irrespective of the age in their adulthood, although we cannot rule out the limitation that the difference did not reach significance because of the small number of patients. Being aware of the existence of a considerable number of undiagnosed CMT patients will help promote the avoidance of inadequate medication.