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The Charcot-Marie-Tooth-1E (CMT1E) disease is typically described as a peripheral neuropathy in humans, causing decreased nerve conduction, spastic paralysis, and tremor. The Trembler-J (TrJ) mice serve as a high fidelity model of this disease. Here, we use functional ultrasound (fUS) and functional connectivity (FC) to analyze TrJ mice's brain activity during sensory stimulation and resting state experiments against wild type (WT) mice - the healthy counterpart. fUS is an imaging technique that measures cerebral blood volume (CBV) temporal changes. We study these changes in the primary somatosensory cortex barrel field (S1BF) of both mice populations during periodic vibrissae stimulation, measuring the number of pixels that correlate to the stimulation (i.e., the size of the activation area), the average correlation of these pixels (i.e., the response strength), and the CBV's rate of change for each stimulation (i.e., the hemodynamic response). Then, we construct a FC matrix for each genotype and experiment by correlating the CBV signals from the eight cortical regions defined by the Paxinos and Franklin atlas. Our results show that TrJ mice have significantly diminished neurovascular responses and altered brain connectivity with respect to WT mice, pointing to central nervous system effects that could shift our understanding of the CMT1E disease., Competing Interests: Declarations. Competing interests: M.T. is co-founder and shareholder of Iconeous, a company which commercializes ultrasonic neuroimaging scanners. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Introduction/aims: In a recent study, we showed that nerve ultrasound of the upper limbs could distinguish inherited sensory neuronopathy from inherited axonopathy; surprisingly, no differences were found in the lower limb nerves. In this study, we compared lower limb nerve ultrasound measurements in inherited neuronopathy, inherited axonopathy, and acquired axonopathy., Methods: Tibial and sural nerve ultrasound cross-sectional areas (CSAs) of 34 healthy controls were retrospectively compared with those of three patient groups: 17 with cerebellar ataxia with neuronopathy and vestibular areflexia syndrome (CANVAS), 18 with Charcot-Marie-Tooth type 2 (CMT2), and 18 with acquired length-dependent sensorimotor axonal neuropathy, using ANOVA with post-hoc Tukey honestly significance difference (HSD) (significance level set at p < .05)., Results: The nerve CSAs of CANVAS and CMT2 patients were not significantly different. Both the tibial and the sural nerve CSAs were significantly smaller in CANVAS and CMT2 compared with the acquired axonal neuropathy group. Tibial nerve CSAs of CANVAS and CMT2 were significantly smaller than controls. Tibial and sural nerve CSAs of the acquired axonal neuropathy group were also significantly larger than the controls'., Discussion: Ultrasound of the lower limb nerves distinguished inherited from acquired axonopathy with the nerve size respectively reduced and increased in these two groups. This has potential implication for the differential diagnosis of these diseases in clinical practice., (© 2024 Wiley Periodicals LLC.)

Background and Objectives: Intramuscular fat fraction (FF), assessed with quantitative MRI (qMRI), has emerged as one of the few responsive outcome measures in CMT1A patients. The main limitation for its use in future therapeutic trials is the time required for the manual segmentation of individual muscles. This study aimed to evaluate the accuracy and responsiveness of a fully automatic artificial intelligence (AI)-based segmentation pipeline to assess disease progression in a cohort of CMT1A patients over 1 year., Methods: Twenty CMT1A patients were included in this observational, prospective, longitudinal study. FF was measured twice a year apart using qMRI in the lower limbs. Individual muscle segmentation was performed fully automatically using a trained convolutional neural network with or without human quality check (QC). The corresponding results were compared with those obtained by fully manual (FM) segmentation using the Dice similarity coefficient (DSC). FF progression and its standardized response mean (SRM) were also computed in individual muscles over the single central slice and a 3D volume to define the most sensitive region of interest., Results: AI-based segmentation showed excellent DSC values (>0.90). Significant global FF progression was observed at thigh (+0.71% ± 1.28%; p = 0.016) and leg (+1.73% ± 2.88%, p = 0.007) levels, similarly to that calculated using the FM technique ( p = 0.363 and p = 0.634). FF progression of each individual muscle was comparable when computed from either the central slice or the 3D volume. The best SRM value (0.70) was obtained for the FF progression computed using the AI-based technique with human QC in the 3D volume at the leg level. The time required for fully automatic segmentation using AI with a QC was 10 hours for the entire data set compared with 90 hours for the FM., Discussion: qMRI combined with AI-based segmentation can be considered as a process ready for assessing longitudinal FF changes in CMT1A patients. Given the slow FF progression at a thigh level and the large heterogeneity between muscles and individuals, FF should be quantified from a 3D volume at the leg level for longitudinal analyses. A QC performed after the AI-based segmentation is still advised given the increased SRM value.

Objective: Neuromuscular evaluation increasingly employs muscle ultrasonography to determine muscle thickness, mean grayscale echointensity, and visual semiquantitative echotexture attenuation. However, these measures provide low sensitivity for detection of mild muscle abnormality. Exercise-induced intramuscular blood flow is a physiologic phenomenon, which may be impaired in mildly affected muscles, particularly in dystrophinopathies, and may indicate functional muscle ischemia. We aimed to determine if muscle blood flow is reduced in patients with neuromuscular disorders and preserved muscle strength, and if it correlates with echointensity and digital echotexture measurements., Methods: Peak exercise-induced blood flow, echointensity, and echotexture were quantified in the elbow flexor muscles of 15 adult patients with Becker muscular dystrophy (BMD) and 13 patients with other muscular dystrophies (OMD). These were compared to 17 patients with Charcot-Marie-Tooth type 1 (CMT1) neuropathy and 21 healthy adults from a previous study., Results: Muscle blood flow was reduced in all patient groups compared to controls, most prominently in BMD patients (p < 0.0001). Echointensity was similarly increased in all patient groups (p < 0.05), while echotexture was reduced only in muscular dystrophy patients (p ≤ 0.002). In BMD, blood flow correlated with echotexture (Pearson r = 0.6098, p = 0.0158) and strength (Spearman r = 0.5471; p = 0.0370). In patients with normal muscle strength, reduced muscle blood flow was evident in all patient groups (p < 0.001), echotexture was reduced in BMD and OMD (p < 0.01), and echointensity was increased in CMT (p < 0.05)., Interpretation: Muscle blood flow is a sensitive measure to detect abnormality, even in muscles with normal strength. Increased echointensity may indicate a neurogenic disorder when strength is preserved, while low echotexture suggests a dystrophic disease., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Abstract: Neuromuscular ultrasound has emerged as a beneficial, complementary tool to electromyography (EMG) in the diagnosis of neuromuscular diseases as it provides high-resolution anatomic imaging of peripheral nerves and muscles. It has been used previously as an adjunct to EMG to diagnose Charcot-Marie-Tooth disease. Here, we present a case of a 64-yr-old man with bilateral sensorineural hearing loss of 14 yrs who presented to an outpatient neuromuscular clinic at a tertiary medical center with very slow progressive paresthesias. This case highlights the application of neuromuscular ultrasound to help confirm the presence of a likely Charcot-Marie-Tooth disease type 4C despite indeterminate genetic testing results and challenging EMG results. He had genetic testing which revealed a normal PMP22 gene; however, he had a variant of uncertain significance in the SH3TC2 gene which has shown associations with autosomal recessive CMT4C. Neuromuscular ultrasound revealed mild median and significant tibial nerve uniform enlargement throughout their course. There may also be utility in performing neuromuscular ultrasound on similarly affected family members if the same variant of uncertain significance returns for SH3TC2 , with consideration of both peripheral nerve and nerve root assessment., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: Pathogenic variants of the glycyl-tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot-Marie-Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy., Methods: This cross-sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed., Results: The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients., Conclusions: GARS1 variants may produce a dHMN phenotype with "split hand" and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

We aimed to develop efficient data labeling strategies for ground truth segmentation in lower-leg magnetic resonance imaging (MRI) of patients with Charcot-Marie-Tooth disease (CMT) and to develop an automated muscle segmentation model using different labeling approaches. The impact of using unlabeled data on model performance was further examined. Using axial T1-weighted MRIs of 120 patients with CMT (60 each with mild and severe intramuscular fat infiltration), we compared the performance of segmentation models obtained using several different labeling strategies. The effect of leveraging unlabeled data on segmentation performance was evaluated by comparing the performances of few-supervised, semi-supervised (mean teacher model), and fully-supervised learning models. We employed a 2D U-Net architecture and assessed its performance by comparing the average Dice coefficients (ADC) using paired t-tests with Bonferroni correction. Among few-supervised models utilizing 10% labeled data, labeling three slices (the uppermost, central, and lowermost slices) per subject exhibited a significantly higher ADC (90.84±3.46%) compared with other strategies using a single image slice per subject (uppermost, 87.79±4.41%; central, 89.42±4.07%; lowermost, 89.29±4.71%, p < 0.0001) or all slices per subject (85.97±9.82%, p < 0.0001). Moreover, semi-supervised learning significantly enhanced the segmentation performance. The semi-supervised model using the three-slices strategy showed the highest segmentation performance (91.03±3.67%) among 10% labeled set models. Fully-supervised model showed an ADC of 91.39±3.76. A three-slice-based labeling strategy for ground truth segmentation is the most efficient method for developing automated muscle segmentation models of CMT lower leg MRI. Additionally, semi-supervised learning with unlabeled data significantly enhances segmentation performance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.9 ± 20.3% in CMT1A patients, and the 365-day FF (n = 15) increased by 2.0 ± 2.4% (p < 0.001 vs controls). Intrinsic foot-level FF demonstrated large responsiveness (12-month standardized response mean (SRM) of 0.86) and correlated with the CMT examination score (ρ = 0.58, P = 0.01). Intrinsic foot-level FF has the potential to be used as a biomarker in future clinical trials involving younger CMT1A patients. ANN NEUROL 2024;96:170-174., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The cavovarus foot is a complex 3-dimensional deformity. Although a multitude of techniques are described for its surgical management, few of these are evidence based or guided by classification systems. Surgical management involves realignment of the hindfoot and soft tissue balancing, followed by forefoot balancing. Our aim was to analyze the pattern of residual forefoot deformities once the hindfoot is corrected, to guide forefoot correction., Methods: We included 20 cavovarus feet from 16 adult patients with Charcot-Marie-Tooth who underwent weightbearing CT (mean age 43.4 years, range: 22-78 years, 14 males). Patients included had flexible deformities, with no previous surgery. Using specialized software (Bonelogic 2.1, Disior) a 3-dimensional, virtual model was created. Using morphologic data captured from normal feet in patients without pathology as a guide, the talonavicular joint of the cavovarus foot was digitally reduced to a "normal" position to simulate the correction that would be achieved during surgical correction. Models of the corrected position were exported and geometrically analyzed using Blender 3.64 to identify anatomical trends., Results: We identified 4 types of cavovarus forefoot morphotypes. Type 0 was defined as a balanced forefoot (2 cases, 10%). Type 1 was defined as a forefoot where the first metatarsal was relatively plantarflexed to the rest of the foot, with no significant residual adduction after talonavicular joint correction (12 cases, 60%). Type 2 was defined as a forefoot where the second and first metatarsals were progressively plantarflexed, with no significant adduction (4 cases, 20%). Type 3 was defined as a forefoot where the metatarsals were adducted after talonavicular derotation (2 cases, 10%)., Conclusion: In this relatively small cohort, we identified 4 forefoot morphotypes in cavovarus feet that might help surgeons to recognize and anticipate the residual forefoot deformities after hindfoot correction. Different treatment strategies may be required for different morphotypes to achieve balanced correction., Level of Evidence: Level IV, retrospective case series., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure forms for all authors are available online.

Increasingly Charcot neuroarthropathy (CN) is being recognized in patients with Charcot-Marie-Tooth (CMT) disease. In this report, we describe a case of CN in a CMT patient, adding to the very scarce literature describing this association. We additionally report his unique evaluation with fluorodeoxyglucose (FDG) and sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) scanning, the study of which is limited in CN despite its promising role. A 54-year-old known case of CMT, presented with left foot pain, and swelling for 4 months. Weakness and sensory deficits as a result of CMT were evident in both lower and upper limbs. His x-ray was suggestive of CN. Both FDG and NaF PET/CT scanning demonstrated increased tracer uptake in the first tarsometatarsal joint (TMTJ), in keeping with CN. Recognition of the association of CMT with CN is of vital importance as early diagnosis relies on high clinical suspicion. Characterizing risk factors of CN in CMT patients is still under study. Moreover, there is lack of data evaluating the role of PET/CT in CN and specifically in the context of CMT., Competing Interests: The authors have no conflict of interest.

Background: The complex deformities in cavovarus feet of Charcot-Marie-Tooth (CMT) disease are difficult to evaluate. The aim of this study was to quantify the initial standing alignment correction achieved after joint-sparing CMT cavovarus reconstruction using pre- and postoperative weightbearing computed tomography (WBCT)., Methods: Twenty-nine CMT cavovarus reconstructions were retrospectively analyzed. Three-dimensional measurements were performed using semiautomated software (Bonelogic 2.1) to investigate changes in sagittal, axial, and coronal parameters. Pre- and postoperative data were compared, along with normative data. Correlation among the preoperative measurements and the amount of correction in sagittal, axial, and coronal parameters were analyzed., Results: The sagittal, axial, and coronal malalignment of the hindfoot, and the sagittal and axial malalignment of the forefoot, was significantly improved after corrective surgery ( P < .05). Sagittal Meary angle (from 14.8 to 0.1 degrees), axial talonavicular angle (TNA, from 3.6 to 19.2 degrees), and coronal hindfoot alignment (from 11.0 to -11.1 degrees) showed significant changes postoperatively ( P < .001). Hindfoot, forefoot sagittal, and forefoot axial parameters reached comparable outcomes compared with normative value ( P > .05). Regarding amount of correction, Spearman correlation demonstrated that axial Meary angle and TNA were most strongly related to improvement in sagittal Meary angle and coronal hindfoot alignment., Conclusion: Preoperative and postoperative WBCT measurements demonstrated that joint sparing CMT cavovarus reconstruction significantly improved sagittal, axial, and coronal deformities of CMT, and sagittal Meary angle was restored toward normative values. Apparent axial plane correction, the majority of which occurred at the talonavicular joint, had the strongest correlation with deformity correction in multiple planes. This suggests that soft tissue releases and correction of the talonavicular joint may be a key component of a cavovarus foot correction., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure forms for all authors are available online.

Background and Aims: Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause axonal or demyelinating Charcot-Marie-Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1-related CMT in a Chinese cohort., Methods: Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected., Results: We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis., Conclusions: In this study, we conducted an analysis of clinical features of the GDAP1-related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes., (© 2024 Peripheral Nerve Society.)

Background and Purpose: We previously reported that nerve enlargement assessment by nerve ultrasonography of the intermediate upper limb is applicable for distinguishing demyelinating Charcot-Marie-Tooth disease (CMT) from chronic inflammatory demyelinating polyneuropathy (CIDP). However, differences in the severity and distribution patterns of lower extremity nerve enlargement have not been established for either disease. Therefore, we examined the utility of lower extremity nerve ultrasonography for differentiating between CMT and CIDP., Methods: Twelve patients with demyelinating CMT and 17 patients with CIDP were evaluated. The median, ulnar, tibial, and fibular nerves were evaluated in three regions: the distal upper extremity, intermediate upper extremity, and lower extremity. Of the 14 selected screening sites, the number of sites that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined., Results: The screening ESNs in the intermediate region and lower extremities were greater in patients with demyelinating CMT than in patients with CIDP and greater than the ESN in the distal region (p = 0.010, p = 0.001, and p = 0.101, respectively). The ESNs in the intermediate region and lower extremities significantly differed among patients with typical CIDP, CIDP variants, and demyelinating CMT (p = 0.084 and p < 0.001). Among the 14 selected screening sites, the combined upper and lower extremity ESNs exhibited the highest AUC (0.92; p < 0.001)., Conclusions: Combining the upper and lower extremities for ultrasonographic nerve measurement more accurately distinguishes CIDP from demyelinating CMT., Competing Interests: Declaration of competing interest The authors declare that they have no potential conflicts of interest in relation to this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Lower limb muscle magnetic resonance imaging (MRI) obtained fat fraction (FF) can detect disease progression in patients with Charcot-Marie-Tooth disease 1A (CMT1A). However, analysis is time-consuming and requires manual segmentation of lower limb muscles. We aimed to assess the responsiveness, efficiency and accuracy of acquiring FF MRI using an artificial intelligence-enabled automated segmentation technique., Methods: We recruited 20 CMT1A patients and 7 controls for assessment at baseline and 12 months. The three-point-Dixon fat water separation technique was used to determine thigh-level and calf-level muscle FF at a single slice using regions of interest defined using Musclesense, a trained artificial neural network for lower limb muscle image segmentation. A quality control (QC) check and correction of the automated segmentations was undertaken by a trained observer., Results: The QC check took on average 30 seconds per slice to complete. Using QC checked segmentations, the mean calf-level FF increased significantly in CMT1A patients from baseline over an average follow-up of 12.5 months (1.15%±1.77%, paired t-test p=0.016). Standardised response mean (SRM) in patients was 0.65. Without QC checks, the mean FF change between baseline and follow-up, at 1.15%±1.68% (paired t-test p=0.01), was almost identical to that seen in the corrected data, with a similar overall SRM at 0.69., Conclusions: Using automated image segmentation for the first time in a longitudinal study in CMT, we have demonstrated that calf FF has similar responsiveness to previously published data, is efficient with minimal time needed for QC checks and is accurate with minimal corrections needed., Competing Interests: Competing interests: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work)., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: With potential therapies for many forms of Charcot-Marie-Tooth disease (CMT), responsive outcome measures are urgently needed for clinical trials. Quantitative lower limb MRI demonstrated progressive calf intramuscular fat accumulation in the commonest form, CMT1A with large responsiveness. In this study, we evaluated the responsiveness and validity in the three other common forms, due to variants in GJB1 (CMTX1), MPZ (CMT1B) and MFN2 (CMT2A)., Methods: 22 CMTX1, 21 CMT1B and 21 CMT2A patients and matched controls were assessed at a 1-year interval. Intramuscular fat fraction (FF) was evaluated using three-point Dixon MRI at thigh and calf level along with clinical measures including CMT examination score, clinical strength assessment, CMT-HI and plasma neurofilament light chain., Results: All patient groups had elevated muscle fat fraction at thigh and calf levels, with highest thigh FF and atrophy in CMT2A. There was moderate correlation between calf muscle FF and clinical measures (CMTESv2 rho = 0.405; p = 0.001, ankle MRC strength rho = -0.481; p < 0.001). Significant annualised progression in calf muscle FF was seen in all patient groups (CMTX1 2.0 ± 2.0%, p < 0.001, CMT1B 1.6 ± 2.1% p = 0.004 and CMT2A 1.6 ± 2.1% p = 0.002). Greatest increase was seen in patients with 10-70% FF at baseline (calf 2.7 ± 2.3%, p < 0.0001 and thigh 1.7 ± 2.1%, p = 0.01)., Interpretation: Our results confirm that calf muscle FF is highly responsive over 12 months in three additional common forms of CMT which together with CMT1A account for 90% of genetically confirmed cases. Calf muscle MRI FF should be a valuable outcome measure in upcoming CMT clinical trials., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: This study assesses the coronal-plane deformities in cavovarus feet secondary to Charcot-Marie-Tooth disease (CMT) using Weightbearing-CT (WBCT) and semi-automated 3D-segmentation software., Methods: WBCTs from 30 CMT-cavovarus feet were matched to 30 controls and analysed using semi-automatic 3D-segmentation (Bonelogic, DISIOR). The software used automated cross-section sampling with subsequent straight-line representation of weighted centre points to calculate 3D axes of bones in the hindfoot, midfoot and forefoot. Coronal relationships of these axes were analysed. Supination/pronation of the bones in relation to the ground and within each joint were measured and reported., Results: The most significant deformity in CMT-cavovarus feet occurred at the talonavicular joint (TNJ) with 23 degrees more supination than normal feet (6.4 ± 14.5 versus 29.4 ± 7.0 degrees, p < 0.001). This was countered by relative pronation at the naviculo-cuneiform joints (NCJ) of 7.0 degrees (-36.0 ± 6.6 versus -43.0 ± 5.3 degrees, p < 0.001). Combined hindfoot varus and TNJ supination resulted in an additive supination effect not compensated by NCJ pronation. The cuneiforms in CMT-cavovarus feet were therefore supinated by 19.8 degrees to the ground relative to normal feet (36.0 ± 12.1 versus 16.2 ± 6.8 degrees, p < 0.001). The forefoot-arch and 1st metatarsal-ground angles demon st rated similar supination to the cuneiforms suggesting no further significant rotation occurred distally., Conclusion: Our results demonstrate coronal plane deformity occurs at multiple levels in CMT-cavovarus feet. Majority of the supination arises at the TNJ, and this is partially countered by pronation distally, mainly at the NCJ. An understanding of the location of coronal deformities may help when planning surgical correction., Level of Evidence: Level III, retrospective comparative study., (Copyright © 2023 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Aims: Charcot-Marie-Tooth disease type 1A (CMT1A) is characterized by enlargement and stiffness of peripheral nerves due to edema with large numbers of "onion bulbs" in the endoneurium. Ultrasound elastography seems to be an ideal method to detect this condition. The aim of this study was to analyze the shear wave elastography (SWE) features of peripheral nerves in patients with CMT1A., Material and Methods: We included 24 CMT1A patients with a mean age of 28 years, along with 24 age- and gender-matched controls. All patients presented with mutations of the PMP22 gene and showed length-dependent polyneuropathy. The motor nerve conduction velocity (MNCV) of the median nerve ranged from 5.2 to 37.4 m/s. SWE and cross-sectional area (CSA) were used to evaluate the bilateral median nerves at predefined sites in both patients and con-trols., Results: The average elastography value (EV) of the median nerve was 73.5±11.7 kPa in patients with CMT1A and 37.5±6.1 kPa in control subjects. The difference between the two groups was statistically significant (P<0.05). In CMT1A pa-tients, the average EV at the proximal and distal parts of the median nerve were 81.4±9.4 kPa and 65.2±8.1 kPa, respectively. The average CSAs at the proximal and distal parts of the median nerve were 0.29±0.06 cm2 and 0.20±0.05 cm2, respectively. The EV on SWE was positively correlated with CSA (p< 0.01) and negatively correlated with MNCV in the median nerve (p< 0.01)., Conclusions: Peripheral nerve stiffness dramatically increases in CMT1A and is correlated with the severity of nerve involvement.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy, resulting in length-dependent motor and sensory deficiencies. Asymmetric nerve involvement in the lower extremities creates a muscle imbalance, which manifests as a characteristic cavovarus deformity of the foot and ankle. This deformity is widely considered to be the most debilitating symptom of the disease, causing the patient to feel unstable and limiting mobility. Foot and ankle imaging in patients with CMT is critical for evaluation and treatment, as there is a wide range of phenotypic variation. Both radiography and weight-bearing CT should be used for assessment of this complex rotational deformity. Multimodality imaging including MRI and US is also important to help identify changes in the peripheral nerves, diagnose complications of abnormal alignment, and evaluate patients in the perioperative setting. The cavovarus foot is susceptible to distinctive pathologic conditions including soft-tissue calluses and ulceration, fractures of the fifth metatarsal, peroneal tendinopathy, and accelerated arthrosis of the tibiotalar joint. An externally applied brace can assist with balance and distribution of weight but may be appropriate for only a subset of patients. Many patients will require surgical correction, which may include soft-tissue releases, tendon transfers, osteotomies, and arthrodesis when necessary, with the goal of creating a more stable plantigrade foot. The authors focus on the cavovarus deformity of CMT. However, much of the information discussed may also be applied to a similar deformity that may result from idiopathic causes or other neuromuscular conditions. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Background: Hip dysplasia is a lack of femoral head coverage and disruption of hip and acetabular alignment and congruency, with severity ranging from mild subluxation in nascent at-risk hips to complete dislocation. Presentation of hip dysplasia in neuromuscular conditions can be sub-clinical or associated with a limp with or without hip pain, abductor and flexor weakness and reduced hip range of motion. Untreated hip dysplasia leads to early onset osteoarthritis requiring hip arthroplasty in early adulthood. Hip dysplasia occurs in 6-20% of children with Charcot-Marie-Tooth disease, however little is known about the reliability and sensitivity of detection on plain film pelvic radiographs., Methods: 14 common measures of hip dysplasia on anteroposterior pelvis radiographs were independently assessed by 2 orthopaedic specialists in 30 ambulant children with Charcot-Marie-Tooth disease. Hip health was also categorised based on clinical impression to assess the sensitivity of radiographic measures to identify hip dysplasia status., Results: 8 measures (acetabular index, head width, lateral centre-edge angle, lateral uncoverage, medial joint width, migration percentage, neck shaft angle, triradiate status) exhibited 'excellent' reliability between clinical evaluators. 5 of the 30 patients (17%) were identified as having nascent hip dysplasia. Reliable radiographic measures that significantly distinguished between nascent hip dysplasia and healthy hips were acetabular index, lateral centre edge angle, medial joint width and migration percentage., Conclusions: We have identified a subset of reliable and sensitive radiographic hip measures in children with Charcot-Marie-Tooth disease to prioritise during hip screening to mitigate the deleterious effects of hip dysplasia, pain and disability in adulthood.

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., Competing Interests: Conflict of interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Introduction/aims: Inclusion body myositis (IBM) is a myopathic condition but in some patients has been associated with an axonal length-dependent polyneuropathy. In this study, we quantified the cross-sectional area of the sciatic and tibial nerves in patients with IBM comparing with Charcot-Marie-Tooth disease type 1A (CMT1A) and healthy controls using magnetic resonance neurography (MRN)., Methods: MRN of the sciatic and tibial nerves was performed at 3T using MPRAGE and Dixon acquisitions. Nerve cross-sectional area (CSA) was measured at the mid-thigh and upper third calf regions by an observer blinded to the diagnosis. Correlations were performed between these measurements and clinical data., Results: A total of 20 patients with IBM, 20 CMT1A and 29 healthy controls (age- and sex-matched) were studied. Sciatic nerve CSA was significantly enlarged in patients with IBM and CMT1A compared to controls (sciatic nerve mean CSA 62.3 ± 22.9 mm 2 (IBM) vs. 35.5 ± 9.9 mm 2 (controls), p < 0.001; and 96.9 ± 35.5 mm 2 (CMT1A) vs. 35.5 ± 9.9 mm 2 (controls); p < 0.001). Tibial nerve CSA was also enlarged in IBM and CMT1 patients compared to controls., Discussion: MRN reveals significant hypertrophy of the sciatic and tibial nerves in patients with IBM and CMT1A compared to controls. Further studies are needed to correlate with neurophysiological measures and assess whether this finding is useful diagnostically., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare subtype associated with LITAF gene mutations. Until now, only a few studies have reported the clinical features of CMT1C., Objective: This study was performed to find CMT1C patients with mutation of LITAF in a Korean CMT cohort and to characterize their clinical features., Methods: In total, 1,143 unrelated Korean families with CMT were enrolled in a cohort. We performed whole exome sequencing to identify LITAF mutations, and examined clinical phenotypes including electrophysiological and MRI features for the identified CMT1C patients., Results: We identified 10 CMT1C patients from three unrelated families with p.G112S mutation in LITAF. The frequency of CMT1C among CMT1 patients was 0.59%, which is similar to reports from Western populations. CMT1C patients showed milder symptoms than CMT1A patients. The mean CMT neuropathy score version 2 was 7.7, and the mean functional disability scale was 1.0. Electrophysiological findings showed a conduction block in 22% of affected individuals. Lower extremity MRIs showed that the superficial posterior and anterolateral compartments of the calf were predominantly affected., Conclusions: We found a conduction block in Korean CMT1C patients with p.G112S mutation and first described the characteristic MRI findings of the lower extremities in patients with LITAF mutation. These findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Because of the insidious character and variations in presenting symptoms, Charcot-Marie-Tooth (CMT) disease is challenging to diagnose in children. Diagnosis is based on clinical and nerve conduction studies, as well as genetic examination. Therefore, competent nerve imaging techniques and non-invasive alternatives to nerve conduction studies are a necessity, especially in children. We performed a systematic review and meta-analysis to evaluate the current evidence and effectiveness of ultrasound in investigating nerve cross-sectional area (CSA) in those with CMT compared with healthy controls and to pool the CSA measurements. We included studies published in international peer-reviewed journals that measured nerve CSA by ultrasound in patients with CMT. We implemented double-arm meta-analyses to compare the mean CSA of nerves between patients with CMT and healthy controls by calculating the pooled mean difference in CSA. Moreover, we performed subgroup analyses by stratifying the studies according to the site of CSA measurement and examined the difference in nerve CSA between CMT1A and other CMT types. The included studies provide measurements of 12 nerve roots and nerves (vagus, C3, C4, C5, C6, greater auricular, phrenic, median, ulnar, fibular, tibial and sural nerves) in 628 patients with CMT and 586 healthy controls with a total of 6061 measured nerves. Meta-analyses of sonographic nerve CSA are provided to express nerve ultrasonography in the diagnosis of CMT patient., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Introduction/aims: Magnetic resonance imaging (MRI) of peripheral nerves can provide image-based anatomical information and quantitative measurement. The aim of this pilot study was to investigate the feasibility of high-resolution anatomical and quantitative MRI assessment of sciatic nerve fascicles in patients with Charcot-Marie-Tooth (CMT) 1A using 7T field strength., Methods: Six patients with CMT1A underwent imaging on a high-gradient 7T MRI scanner using a 28-channel knee coil. Two high-resolution axial images were simultaneously acquired using a quantitative double-echo in steady-state (DESS) sequence. By comparing the two DESS echoes, T2 and apparent diffusion coefficient (ADC) maps were calculated. The cross-sectional areas and mean T2 and ADC were measured in individual fascicles of the tibial and fibular (peroneal) portions of the sciatic nerve at its bifurcation and 10 mm distally. Disease severity was measured using Charcot-Marie-Tooth Examination Score (CMTES) version 2 and compared to imaging findings., Results: We demonstrated the feasibility of 7T MRI of the proximal sciatic nerve in patients with CMT1A. Using the higher field, it was possible to measure individual bundles in the tibial and fibular divisions of the sciatic nerve. There was no apparent correlation between diffusion measures and disease severity in this small cohort., Discussion: This pilot study indicated that high-resolution MRI that allows for combined anatomical and quantitative imaging in one scan is feasible at 7T field strengths and can be used to investigate the microstructure of individual nerve fascicles., (© 2022 Wiley Periodicals LLC.)

Background: The complex deformities in cavovarus feet may be difficult to assess and understand. Weightbearing computed tomography (WBCT) is increasingly used in evaluating complex deformities. However, the bone axes may be difficult to calculate in the setting of severe deformity. Computer-assisted 3D axis calculation is a novel approach that may allow for more accurate assessment of foot alignment or deformity. This study aimed to assess differences in measurements done manually on 2D slices of WBCT vs 3D computer models in normal and cavus feet., Methods: We retrospectively analyzed WBCT scans from 16 normal and 16 cavus feet in patients with Charcot-Marie-Tooth disease. Six measurements were assessed: talar-first metatarsal angle (axial plane), forefoot arch angle (coronal plane), and Meary angle, calcaneal pitch, and cuneiform and navicular to floor distances (sagittal plane). 2D measurements were performed manually and 3D measurements were performed using specialized software (Bonelogic, DISIOR). Bland-Altman plots and linear regression were used to analyze differences., Results: There were no significant biases in measured variables in normal feet. In the cavovarus group, automated assessment calculated increased sagittal plane deformity (fixed bias 7.31 degrees for Meary angle, 2.39 degrees for calcaneal pitch) and less axial plane deformity (fixed bias 10.61 degrees for axial talar-first metatarsal angle). The latter also demonstrated proportional bias indicating greater discrepancy with increasing adduction., Conclusion: Measurements were comparable in normal feet suggesting automated techniques can reliably assess the alignment of bony axes. However, automated calculations show greater sagittal and less axial deformity in cavovarus feet than measured by manual techniques. This discrepancy may relate to rotational deformity seen in cavovarus feet, which may not be easily assessed manually. 3D automated measurements may therefore play a role in better assessing and classifying the cavovarus foot, which may ultimately inform treatment algorithms., Level of Evidence: Level III, retrospective comparative study.

Objective: Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) are caused by mutations to the peripheral myelin protein 22 (PMP22) gene. A need exists for sensitive and reliable biomarkers of progression and treatment response. Magnetic resonance imaging (MRI) metrics of nerve pathology and morphology were investigated for this purpose., Methods: MRI was performed at 3.0 T in the thigh of CMT1A (N = 11) and HNPP patients (N = 12) and controls (N = 23). Three potential imaging biomarkers of the sciatic nerve were investigated: 1) magnetization transfer ratio (MTR), which assays myelin content, and 2) cross-sectional area (CSA) and 3) circularity, which assay morphological changes. Potential imaging biomarkers were compared across cohorts and assessed for relationships with disability in the legs (CMTES L ), compound motor action potentials (CMAP), and motor conduction velocities (MCV). Inter-rater reliability and test-retest repeatability were established for each imaging metric., Results: Significant differences in MTR, CSA, and circularity were observed in CMT1A relative to controls (p = 0.02, p < 0.001, and p = 0.003, respectively, via Wilcoxon rank-sum tests). Differences were not observed in the HNPP cohort. Significant relationships were observed between MTR and clinical metrics (CMTES L : p = 0.003, CMAP: p = 0.03, MCV: p = 0.01); and between CSA and electrophysiology (CMAP: p = 0.002, MCV: p < 0.001). All metrics were reliable and repeatable with MTR the most reliable (intraclass correlation coefficient [ICC] >0.999, CV = 0.30%) and repeatable (ICC = 0.84, CV = 3.16%)., Interpretation: MTR, CSA, and circularity showed promise as reliable and sensitive biomarkers of CMT1A, but not HNPP. These warrant longitudinal investigation as response biomarkers in upcoming clinical trials of CMT1A, while other methods should be considered for HNPP., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Variants in SURF1 , encoding an assembly factor of mitochondrial respiratory chain complex IV, cause Leigh syndrome (LS) and Charcot-Marie-Tooth type 4K in children and young adolescents. Magnetic resonance imaging (MRI) appearance of enlarged nerve roots with postcontrastographic enhancement is a distinctive feature of hypertrophic neuropathy caused by onion-bulb formation and it has rarely been described in mitochondrial diseases (MDs). Spinal nerve roots abnormalities on MRI are novel findings in LS associated with variants in SURF1 . Here we report detailed neuroradiological and neurophysiologic findings in a child with LS and demyelinating neuropathy SURF1 -related. Our case underlines the potential contributive role of spinal neuroimaging together with neurophysiological examination to identify the full spectrum of patterns in MDs. It remains to elucidate if these observations remain peculiar of SURF1 variants or potentially detectable in other MDs with peripheral nervous system involvement., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: To evaluate the feasibility of proximal nerve MR neurography with diffusion tensor imaging (DTI) for differentiating Charcot-Marie-Tooth (CMT) 1A, CMT2, and healthy controls., Methods: The diameters, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of L4-L5 nerve roots, femoral nerve (FN), and sciatic nerve (SN) were compared. Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the diagnostic performance. DeLong's tests were applied to compare multiple ROC curves. Intraclass correlation coefficients were calculated for interobserver agreement assessment., Results: The diameters of the L4 nerve root, L5 nerve root, and SN of CMT1A patients were significantly larger than those of CMT2 patients and healthy controls. The FA values of all measured proximal nerves were significantly higher in controls (0.46 ± 0.09, 0.46 ± 0.08, 0.45 ± 0.07, and 0.48 ± 0.08) than in CMT1A patients (0.30 ± 0.09, 0.29 ± 0.06, 0.35 ± 0.08, and 0.29 ± 0.09). The FA values of the L5 nerve root, FN, and SN were significantly higher in controls (0.46 ± 0.08, 0.45 ± 0.07, and 0.48 ± 0.08) than in CMT2 patients (0.36 ± 0.06, 0.34 ± 0.07, and 0.34 ± 0.10). The MD and RD values of the L5 nerve root in CMT1A patients (1.59 ± 0.21 and 1.37 ± 0.21) were higher than those in CMT2 patients (1.31 ± 0.17 and 1.05 ± 0.14). The AUCs of the above parameters ranged from 0.780 to 1.000. For the measurements of nerve diameters, the ICC ranged from 0.91 to 0.97. For the measurements of DTI metrics, the ICC ranged from 0.87 to 0.97., Conclusions: MR neurography with DTI is able to differentiate CMT1A patients, CMT2 patients, and healthy controls., Key Points: • MR neurography with diffusion tensor imaging of the L4-5 nerve roots, proximal femoral nerve, and proximal sciatic nerve is able to discriminate CMT1A, CMT2, and healthy controls. • This method provides an alternative for the diagnosis and discrimination of CMT1A and CMT2, which is crucial for clinical management., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: The cavovarus deformity of Charcot-Marie-Tooth (CMT) disease is often characterized by a paradoxical relationship of hindfoot varus and forefoot valgus. The configuration of the midfoot, which links these deformities, is poorly understood. Accurate assessment of 3-dimensional alignment under physiologic loadbearing conditions is possible using weightbearing computed tomography (WBCT). This is the first study to examine the rotational deformity in the midfoot of CMT patients and, thus, provide key insights to successful correction of CMT cavovarus foot., Methods: A total of 27 WBCT scans from 21 CMT patients were compared to control WBCTs from 20 healthy unmatched adults. CMT patients with a history of bony surgery, severe degenerative joint disease, or open physes in the foot were excluded. Scans were analyzed using 3-dimensional software. Anatomic alignment of the tarsal bones was calculated relative to the anterior-posterior axis of the tibial plafond in the axial plane, and weightbearing surface in the coronal plane., Results: Maximal rotational deformity in CMT patients occurred at the transverse tarsal joints, averaging 61 degrees of external rotation (supination), compared to 34 degrees among controls ( P < .01). The talonavicular joint was also the site of peak adduction deformity in the midfoot, with an average talonavicular coverage angle measuring 12 degrees compared with -11 degrees in controls ( P < .01)., Conclusion: This 3-dimensional WBCT analysis is the first to isolate and quantify the multiplanar rotational deformity in the midfoot of CMT patients. Compared with healthy unmatched control cases, CMT patients demonstrated increased axial plane adduction and coronal plane rotation at the talonavicular (TN) joint. These findings support performing soft tissue release at the TN joint to abduct and derotate the midfoot as a first step for targeted deformity correction., Level of Evidence: Level III, retrospective case-control study.

Purpose: Brain involvement in X-linked Charcot-Marie-Tooth disease (CMTX) has been previously reported. We studied the brain structural and functional integrity using a multimodal neuroimaging approach in patients with no current central nervous system (CNS) symptoms, in order to further delineate the disease's phenotype., Methods: Seventeen CMTX patients with no current CNS symptoms and 24 matched healthy controls underwent brain magnetic resonance imaging (MRI). Structural integrity was evaluated performing Gray matter analysis with voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI). Functional integrity was evaluated with resting-state functional MRI (rs-fMRI)., Results: Decreased gray matter density was detected in CMTX patients compared to healthy controls in bilateral hippocampus, left thalamus, left postcentral gyrus, left superior parietal lobule, left cerebellum crus I and II, and vermis VI. DTI analysis showed increased fractional anisotropy and radial diffusivity in the right anterior insula and increased axial diffusivity in right cerebellum crus I in CMTX patients. rs-fMRI revealed decreased spontaneous neural activity on left precentral gyrus in patients compared to healthy controls., Conclusion: Advanced magnetic resonance (MR) neuroimaging techniques in CMTX patients revealed structural and functional involvement of multiple motor and extra-motor brain areas. MR neuroimaging techniques have the potential to delineate the CNS phenotype of a peripheral neuropathy like CMTX., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive inherited demyelinating neuropathy caused by an FYVE, RhoGEF, and a PH domain-containing protein 4 (FGD4) gene mutation. CMT4H is characterized by an early onset, slow progression, scoliosis, distal muscle atrophy, and foot deformities. We herein present sibling cases of CMT4H with a homozygous mutation in the FGD4 gene. Both patients exhibited cauda equina thickening on magnetic resonance imaging, which had not been reported among the previous CMT4H cases. This is the first report of CMT4H with a homozygous FGD4 c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Hereditary neuropathies are of variable genotype and phenotype. With upcoming therapies, there is urgent need for early disease recognition and outcome measures. High-resolution nerve and muscle ultrasound is a dynamic, non-invasive, well-established tool in the field of inflammatory and traumatic neuropathies. In this study, we defined nerve and muscle ultrasound parameters as recognition and progression markers in 150 patients with genetically confirmed hereditary neuropathies, including Charcot-Marie-Tooth (CMT) disease (CMT1A, n = 55; other CMT1/4, n = 28; axonal CMT, n = 15; CMTX, n = 15), hereditary neuropathy with liability to pressure palsies (HNPP, n = 16), hereditary transthyretin-amyloidosis (ATTRv, n = 14), and Fabry's disease (n = 7). The CMT1A, followed by the CMT1/4 group, had the most homogeneous enlargement of the nerve cross-sectional areas (CSA) in the ultrasound pattern sum (UPSS) and homogeneity score. Entrapment scores were highest in HNPP, ATTRv amyloidosis, and Fabry's disease patients. In demyelinating neuropathies, the CSA correlated inversely with nerve conduction studies. The muscle echo intensity was significantly highest in the clinically most affected muscles, which was independent from the underlying disease cause and correlated with muscle strength and disease duration. Further correlations were seen with combined clinical (CMTES-2) and electrophysiological (CMTNS-2) scores of disease severity. We conclude that nerve ultrasound is a helpful tool to distinguish different types of hereditary neuropathies by pattern recognition, whereas muscle ultrasound is an objective parameter for disease severity. The implementation of neuromuscular ultrasound might enrich diagnostic procedures both in clinical routines and research., (© 2021. The Author(s).)

Objectives: To explore whether texture features using T1-weighted images correlate with fat fraction, and whether they differ between Charcot-Marie-Tooth (CMT) disease patients and volunteers., Methods: The institutional review board approved this retrospective study, and the requirement for informed consent was waived; data of eighteen CMT patients and eighteen healthy volunteers from a previous study was used. Texture features of the muscles including mean, standard deviation (SD), skewness, kurtosis, and entropy of the signal intensity were derived from T1-weighted images. Spearman's correlation analysis was used to assess the relationship between texture features and fat fraction measured by 3D multiple gradient echo Dixon-based sequence. Mann-Whitney U test was used to compare the texture features between CMT patients and volunteers. Intraobserver and interobserver agreements for the texture features were assessed using the intraclass correlation coefficient., Results: The SD (ρ = 0.256, p < 0.001) and entropy (ρ = 0.263, p < 0.001) were significantly and positively correlated with fat fraction; skewness (ρ = - 0.110, p = 0.027) and kurtosis (ρ = - 0.149, p = 0.003) were significantly and inversely correlated with fat fraction. The CMT patients showed a significantly higher SD (63.45 vs. 49.26; p < 0.001), skewness (1.06 vs. 0.56; p < 0.001), kurtosis (4.00 vs. 1.81; p < 0.001), and entropy (3.20 vs. 3.02; p < 0.001) than did the volunteers. Intraobserver and interobserver agreements were almost perfect for mean, SD, and entropy., Conclusions: Texture features using T1-weighted images correlated with fat fraction and differed between CMT patients and volunteers., Key Points: • Standard deviation and entropy of muscles derived from T1-weighted images were significantly and positively correlated with the muscle fat fraction. • Mean, standard deviation, and entropy were considered highly reliable in muscle analyses. • Texture features may have the potential to diagnose early stage of intramuscular fatty infiltration.

We aimed to establish the cross-sectional area (CSA) reference values for peripheral nerves of lower extremities in a healthy Chinese population, and to determine their diagnostic values for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth disease type1A (CMT1A). One hundred eleven healthy subjects, 15-70 years of age, as well as 104 CIDP patients and 26 CMT1A patients were recruited. CSA at predetermined sites of the tibial, fibular, sciatic and sural nerves was measured. The CSA of the tibial nerve ranged from 10.2 ± 1.9 to 20.7 ± 3.6 mm 2 , and for fibular nerve from 8.4 ± 1.8 to 9.5 ± 1.9 mm 2 . 86% CIDP patients had upper limb nerve enlargement, while only 67% had lower limb nerve enlargement. In CIDP patients with normal upper limb ultrasound, 56% (5/9) would have lower limb nerve enlargement. All CMT1A patients had both upper and lower limb nerve enlargement. Addition of lower limb nerve ultrasound showed no added value in diagnosis of CMT1A, but could be supplementary for CIDP when upper limb ultrasound is normal., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Pes cavovarus is a foot deformity that can be idiopathic (I-PC) or acquired secondary to other pathology. Charcot-Marie-Tooth disease (CMT) is the most common adult cause for acquired pes cavovarus deformity (CMT-PC). The foot morphology of these distinct patient groups has not been previously investigated. The aim of this study was to assess if morphological differences exist between CMT-PC, I-PC and normal feet (controls) using weightbearing computed tomography (WBCT)., Methods: A retrospective analysis of WBCT scans performed between May 2013 and June 2017 was undertaken. WBCT scans from 17 CMT-PC, 17 I-PC and 17 healthy normally-aligned control feet (age-, side-, sex- and body mass index-matched) identified from a prospectively collected database, were analysed. Eight 2-dimensional (2D) and three 3-dimensional (3D) measurements were undertaken for each foot and mean values in the three groups were compared using one-way ANOVA with the Bonferroni correction., Results: Significant differences were observed between CMT-PC or I-PC and controls (p<0.05). Two-dimensional measurements were similar in CMT-PC and I-PC, except for forefoot arch angle (p=0.04). 3D measurements (foot and ankle offset, calcaneal offset and hindfoot alignment angle) demonstrated that CMT-PC exhibited more severe hindfoot varus malalignment than I-PC (p=0.03, 0.04 and 0.02 respectively)., Conclusions: CMT-related cavovarus and idiopathic cavovarus feet are morphologically different from healthy feet, and CMT feet exhibit increased forefoot supination and hindfoot malalignment compared to idiopathic forms. The use of novel three-dimensional analysis may help highlight subtle structural differences in patients with similar foot morphology but aetiologically different pathology., Level of Evidence: Level III, retrospective comparative study., (Copyright © 2020 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: Charcot-Marie-Tooth (CMT) disease is diagnosed through clinical findings and genetic testing. While there are neurophysiological tools and clinical functional scales in CMT, objective disease biomarkers that can facilitate in monitoring disease progression are limited., Purpose: To investigate the utility of diffusion tensor imaging (DTI) in determining the microstructural integrity of sciatic and peroneal nerves and its correlation with the MRI grading of muscle atrophy severity and clinical function in CMT as determined by the CMT neuropathy score (CMTNS)., Study Type: Prospective case-control., Subjects: Nine CMT patients and nine age-matched controls., Field Strength/sequence: 3 T T 1 -weighted in-/out-of phase spoiled gradient recalled echo (SPGR) and DTI sequences., Assessment: Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values for sciatic and peroneal nerves were obtained from DTI. Muscle atrophy was graded according to the Goutallier classification using in-/out-of phase SPGRs. DTI parameters and muscle atrophy grades were compared between CMT and controls, and the relationship between DTI parameters, muscle atrophy grades, and CMTNS were assessed., Statistical Tests: The Wilcoxon Signed Ranks test was used to compare DTI parameters between CMT and controls. The relationship between DTI parameters, muscle atrophy grades, and CMTNS were analyzed using the Spearman correlation. Receiver operating characteristic (ROC) analyses of DTI parameters that can differentiate CMT from healthy controls were done., Results: There was a significant reduction in FA and increase in RD of both nerves (P < 0.05) in CMT, with significant correlations between FA (negative; P < 0.05) and RD (positive; P < 0.05) with muscle atrophy grade. In the sciatic nerve, there was significant correlation between FA and CMTNS (r = -0.795; P < 0.05). FA and RD could discriminate CMT from controls with high sensitivity (77.8-100%) and specificity (88.9-100%)., Data Conclusion: There were significant differences of DTI parameters between CMT and controls, with significant correlations between DTI parameters, muscle atrophy grade, and CMTNS. Level of Evidence 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:437-444., (© 2020 International Society for Magnetic Resonance in Medicine.)

Background and Purpose: Changes of brain structure and function have been described in peripheral neuropathies. The aim of our study was to systematically investigate possible modifications of major large-scale brain networks using resting-state functional magnetic resonance imaging (RS-fMRI) in Charcot-Marie-Tooth disease type 1A (CMT1A) patients., Methods: In this cross-sectional study, 3-T MRI brain scans were acquired of right-handed genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing neurological impairment. RS-fMRI data were analysed using a seed-based approach, with 32 different seeds sampling the main hubs of default mode, sensorimotor, visual, salience (SN), dorsal attention, frontoparietal, language and cerebellar networks. Between-group differences in terms of functional connectivity (FC) with the explored seeds were tested voxelwise, correcting for local grey matter density to account for possible structural abnormalities, whilst the relationship between FC modifications and neurological impairment was investigated using robust correlation analyses., Results: Eighteen CMT1A patients (34.0 ± 11.4 years; M/F 11/7) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F 11/9). In the CMT group compared to controls, clusters of increased FC with the visual cortex (P = 0.001), SN (P < 6 × 10 -4 ), dorsal attention network (P < 8 × 10 -5 ) and language network (P < 7 × 10 -4 ) were found, along with a single cluster of reduced FC with the visual cortex in the left lentiform nucleus (P = 10 -6 ). A significant correlation emerged between neurophysiological impairment and increased FC with right temporal language areas (r = 0.655, P = 0.006), along with an association between walking ability and increased FC with the left supramarginal gyrus (SN) (r = 0.620, P = 0.006)., Conclusions: Our data show evidence of diffuse functional reorganization involving multiple large-scale networks in the CMT1A brain, independent of structural modifications and partially correlating with peripheral nerve damage and functional impairment., (© 2020 European Academy of Neurology.)

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., (© 2020 Wiley Periodicals LLC.)

Background and Purpose: Both clinical autonomic dysfunction and involvement of autonomic nerves have been reported in a range of peripheral nerve disorders. We employed nerve ultrasound to assess the size of the vagus nerve in a serial study of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth type 1B (CMT1B) as compared to healthy controls (HCs). We correlated these findings with involvement of the median and ulnar nerves., Methods: Forty-three patients with CIDP, 8 with CMT1A, and 105 HC were prospectively recruited. The cross-sectional areas (CSAs) of the vagus, median, and ulnar nerves were measured bilaterally. The alteration of CSA of those nerves was followed longitudinally in CIDP., Results: The median (range) CSA of the vagus nerve was 2 (1-28) mm 2 in CIDP, 3 (2-6) mm 2 in CMT1A, and 1 (1-2) mm 2 in HC. The vagus nerve CSA was positively correlated with the maximum CSA of median/ulnar nerve in CIDP and CMT1A. The alteration in vagus nerve CSA was positively correlated with the alteration in mean median/ulnar nerve CSA in CIDP during follow-up., Conclusions: The vagus nerve was involved to a similar extent as the median and ulnar nerves in CIDP and CMT1A, although no symptoms or signs of vagus nerve involvement were found. Further study should be performed to explore the clinical relevance of vagus nerve enlargement in these disorders., (© 2020 American Society of Neuroimaging.)

Diseases related to peripheral myelin protein 22 (PMP22) have been implicated to involve the central nervous system (CNS). This study aimed to detect central nerve impairment using somatosensory evoked potentials (SSEPs) in patients with Charcot-Marie-Tooth disease (CMT) 1A. A total of 30 CMT1A patients and 26 healthy volunteers were included. Baseline characteristics, brain MRI and segmental SSEPs were collected from the participants. The peak latencies of N9, N13 and N20 were recorded, and central conduction velocity (CCT) was calculated and compared between groups. Significant differences were found in the peak latencies and amplitudes of N9, N13 and N20 between the two groups. CCT was significantly prolonged in the CMT group (7.05 ± 2.09 ms) compared to the control group (5.40 ± 1.79 ms) (p = 0.003). Six of 30 CMT patients had abnormal MRI signals, but no correlation with CCT was found. The central somatosensory pathway that carries SSEPs was impaired in CMT1A patients, which implies an important underlying role of PMP22 in the CNS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Purpose: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMNs). A series of BSCL2 patients is presented and clinical, neurophysiological and muscle magnetic resonance imaging (MRI) findings are correlated., Methods: Twenty-six patients from five families carrying the p.N88S mutation were identified. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth, spastic paraplegia), physical examination, disability measured as a modified Rankin Scale score and neurophysiological findings were collected. A whole body muscle MRI had been performed in 18 patients. The pattern of muscle involvement on T1-weighted and short time inversion recovery sequences was analysed. Hierarchical analysis using heatmaps and an MRI Composite Score were generated. Statistical analysis was carried out with STATA SE v.15 (TX, USA)., Results: The mean age was 51.54 ± 19.94 years and 14 patients were men. dHMN was the most common phenotype (50%) and five patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (modified Rankin Scale score 1.34 ± 1.13) although median time since onset of disease was 32 years (range 10-47). Charcot-Marie-Tooth-like patients were more disabled and disability correlated with age. On muscle MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI Composite Score was strongly correlated with disability., Conclusion: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials., (© 2020 European Academy of Neurology.)

Background and Purpose: Nerve tissue alterations have rarely been quantified in Charcot-Marie-Tooth type 1A (CMT1A) patients. The aim of the present study was to quantitatively assess the magnetic resonance imaging (MRI) anomalies of the sciatic and tibial nerves in CMT1A disease using quantitative neurography MRI. It was also intended to seek for correlations with clinical variables., Methods: Quantitative neurography MRI was used in order to assess differences in nerve volume, proton density and magnetization transfer ratio in the lower limbs of CMT1A patients and healthy controls. Disease severity was evaluated using the Charcot-Marie-Tooth Neuropathy Score version 2, Charcot-Marie-Tooth examination scores and Overall Neuropathy Limitations Scale scores. Electrophysiological measurements were performed in order to assess the compound motor action potential and the Motor Unit Number Index. Clinical impairment was evaluated using muscle strength measurements and Charcot-Marie-Tooth examination scores., Results: A total of 32 CMT1A patients were enrolled and compared to 13 healthy subjects. The 3D nerve volume, magnetization transfer ratio and proton density were significantly different in CMT1A patients for the whole sciatic and tibial nerve volume. The sciatic nerve volume was significantly correlated with the whole set of clinical scores whereas no correlation was found between the tibial nerve volume and the clinical scores., Conclusion: Nerve injury could be quantified in vivo using quantitative neurography MRI and the corresponding biomarkers were correlated with clinical disability in CMT1A patients. The sensitivity of the selected metrics will have to be assessed through repeated measurements over time during longitudinal studies to evaluate structural nerve changes under treatment., (© 2020 European Academy of Neurology.)

Background: Muscle MRI is of increasing importance for neuromuscular patients to detect changes in muscle volume, fat-infiltration, and edema. We developed a method for semi-automated segmentation of muscle MRI datasets., Methods: An active contour-evolution algorithm implemented within the ITK-SNAP software was used to segment T1-weighted MRI, and to quantify muscle volumes of neuromuscular patients (n = 65)., Results: Semi-automated compared with manual segmentation was shown to be accurate and time-efficient. Muscle volumes and ratios of thigh/lower leg volume were lower in myopathy patients than in controls (P < .0001; P < .05). We found a decrease of lower leg muscle volume in neuropathy patients compared with controls (P < .01), which correlated with clinical parameters. In myopathy patients, muscle volume showed a positive correlation with muscle strength (r left = 0.79, p left  < .0001). Muscle volumes were independent of body mass index and age., Conclusions: Our method allows for exact and time-efficient quantification of muscle volumes with possible use as a biomarker in neuromuscular patients., (© 2020 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

Objective: To quantitatively describe the MRI fat infiltration pattern of muscle degeneration in Charcot-Marie-Tooth (CMT) type 1A (CMT1A) disease and to look for correlations with clinical variables., Methods: MRI fat fraction was assessed in lower-limb musculature of patients with CMT1A and healthy controls. More particularly, 14 muscle compartments were selected at leg and thigh levels and for proximal, distal, and medial slices. Muscle fat infiltration profile was determined quantitatively in each muscle compartment and along the entire volume of acquisition to determine a length-dependent gradient of fat infiltration. Clinical impairment was evaluated with muscle strength measurements and CMT Examination Scores (CMTESs)., Results: A total of 16 patients with CMT1A were enrolled and compared to 11 healthy controls. Patients with CMT1A showed a larger muscle fat fraction at leg and thigh levels with a proximal-to-distal gradient. At the leg level, the largest fat infiltration was quantified in the anterior and lateral compartments. CMTES was correlated with fat fraction, especially in the anterior compartment of leg muscles. Strength of plantar flexion was also correlated with fat fraction of the posterior compartments of leg muscles., Conclusion: On the basis of quantitative MRI measurements combined with a dedicated segmentation method, muscle fat infiltration quantified in patients with CMT1A disclosed a length-dependent peroneal-type pattern of fat infiltration and was correlated to main clinical variables. Quantification of fat fraction at different levels of the leg anterior compartment might be of interest in future clinical trials., (© 2020 American Academy of Neurology.)

Background: We present one patient with an initial diagnosis of Guillain-Barré syndrome (GBS) and one with Charcot-Marie-Tooth disease (CMT) type 1A., Methods: Both patients underwent ankle tibial nerve fusion-imaging of high-resolution ultrasound (HRUS) with 7T MR neurography (MRN)., Results: In GBS, the nerve was enlarged, T2-hyperintense, and showed increased vascularization 21 months after symptom onset. In CMT1A, the enlarged nerve was T2-isointense with normal endoneurial blood flow., Conclusions: We demonstrate the utility of 7T-MRN-HRUS-fusion-imaging. In GBS, there was evidence of ongoing inflammation resulting in a changed diagnosis to acute-onset chronic demyelinating polyradiculoneuropathy and maintenance of immunotherapy. By MRN-HRUS-fusion, patients with presumed peripheral axonal degeneration could be shown to display imaging markers associated with peripheral nervous system inflammation. Thus, more accurate identification of a treatable inflammatory component may become possible., (© 2020 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

Aims: Infected and deformed neuropathic feet and ankles are serious challenges for surgical management. In this study we present our experience in performing ankle arthrodesis in a closed manner, without surgical preparation of the joint surfaces by cartilaginous debridement, but instead using an Ilizarov ring fixator (IRF) for deformity correction and facilitating fusion, in arthritic neuropathic ankles with associated osteomyelitis., Methods: We retrospectively reviewed all the patients who underwent closed ankle arthrodesis (CAA) in Ilizarov Scientific Centre from 2013 to 2018 (Group A) and compared them with a similar group of patients (Group B) who underwent open ankle arthrodesis (OAA). We then divided the neuropathic patients into three arthritic subgroups: Charcot joint, Charcot-Maire-Tooth disease, and post-traumatic arthritis. All arthrodeses were performed by using an Ilizarov ring fixator. All patients were followed up clinically and radiologically for a minimum of 12 months to assess union and function., Results: The union rate for Group A was 81% (17/21) while it was 84.6% (33/39) for Group B. All the nonunions in Group A underwent revision with an open technique and achieved 100% union. Mean duration of IRF was 71.5 days (59 to 82) in Group A and 69 days (64.8 to 77.7) in Group B. The American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score was similar in both groups. The postoperative hospital stay was shorter in Group A (21 days (SD 8)) than Group B (28 days (SD 9)). In the latter Group there were more problems with wound healing and greater requirement for antibiotic treatment. The mean operating time was 40 minutes (SD 9) in Group A compared to 80 minutes (SD 13) in Group B. Recurrence of infection occurred in 19% (4/21) and 15.5% (6/39) for Group A and Group B respectively., Conclusion: We found CAA using an IRF to be an effective method for ankle arthrodesis in infected neuropathic foot and ankle cases and afforded comparable results to open methods. Due to its great advantages, Ilizarov method of CAA should always be considered for neuropathic ankles in suitable patients. Cite this article: Bone Joint J 2020;102-B(4):470-477.