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.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neuropathies. The disease is generally characterized by sensory loss most prominent in distal extremities, muscle weakness, and muscle wasting. There is still no effective therapy for Charcot-Marie-Tooth disease.
METHODS: The patient is a 6-year-old Iranian girl, of Fars ethnicity, who was admitted with a chief complaint of hoarseness and an impression of Charcot-Marie-Tooth disease type 4B. She was initially treated with noninvasive ventilation and, after a year, electively underwent cordotomy as a novel therapeutic approach.
CONCLUSIONS: Charcot-Marie-Tooth disease type 4B is a less common but important cause of stridor. Noninvasive ventilation treatment and unilateral posterior cordotomy can be utilized for hereditary neuropathies.

Charcot-Marie-Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims.

OBJECTIVE: Inherited peripheral neuropathies can be divided into those diseases in which peripheral neuropathy is the sole or main feature of the disease (Charcot-Marie-Tooth disease) and those in which peripheral neuropathy is just one feature of a more complex syndrome. In recent years there has been a substantial expansion in the number of genes associated with complex neuropathy syndromes.
RESULTS: This review will focus on emerging themes in this group of diseases, namely the increasing number of diseases due to repeat expansions; the emergence of both recessive and dominant negative alleles in the same gene producing a common phenotype and diseases in which there is selective loss of the allele from haematopoietic stem cells making genetic diagnosis on blood derived DNA problematic.
CONCLUSIONS: In this review we provide a practical approach to investigating and diagnosing patients with peripheral neuropathy as part of a complex syndrome and provide an updated table of the genes associated with this group of diseases.

We report two cases wherein rotating hinge knee (RHK) arthroplasty was performed for Charcot joints that developed secondary to Charcot-Marie-Tooth disease (CMT).  Case 1 was of a 74-year-old woman with CMT. She presented with muscle weakness and sensory disturbances of the distal lower limbs, deformity, and significant medial instability of the bilateral knees. She was then diagnosed with Charcot joints of the knees secondary to CMT, which were treated with RHK arthroplasty. Five years postoperatively, there was no instability, and she was able to stand unassisted without pain. Case 2 was a 90-year-old woman with CMT who presented with muscle weakness and sensory disturbances of the distal lower limbs, deformity, and significant medial instability of the bilateral knees. She was then diagnosed with Charcot joints of the knees secondary to CMT, which were also treated with RHK arthroplasty. One year postoperatively, there was no instability, and she was able to walk smoothly using a walker. These clinical cases indicate that RHK arthroplasty can be a good therapeutic option for Charcot joints of the knees in patients with CMT.

Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity.

UNASSIGNED: Walking is a vital activity often compromised in individuals with neuropathic conditions. Charcot-Marie-Tooth (CMT) disease and Cerebral Palsy (CP) are two common neurodevelopmental disabilities affecting gait, predisposing to the risk of falls. With guiding scientific evidence limited, there is a critical need to better understand how surgical correction affects mobility, balance confidence, and gait compared to ankle foot orthosis (AFO) bracing. A systematic approach will enable rigorous collaborative research to advance clinical care.
UNASSIGNED: Key elements of this vision include 1) prospective studies in select patient cohorts to systematically compare conservative vs. surgical management, 2) objective laboratory-based evaluation of patient mobility, balance, and gait using reliable methods, and 3) use of patient-centric outcome measures related to health and mobility.
UNASSIGNED: Valid and reliable standardized tests of physical mobility and balance confidence have been described in the literature. They include 1) the four-square step test, a widely used test of balance and agility that predicts fall risk, 2) the self-selected walking velocity, a measure of general mobility able to detect function change with orthosis use, and 3) the activity specific balance confidence scale, a survey instrument that assesses an individual\'s level of balance confidence during activity. Additionally, motion capture and ground reaction force data can be used to evaluate whole-body motion and loading, with discriminative biomechanical measures including toe clearance during the swing phase of gait, plantarflexion at 50% of swing, peak ankle plantarflexor moment, and peak ankle push-off power.
UNASSIGNED: The tools needed to support evidence-based practice and inform clinical decision making in these challenging patient populations are all available. Research must now be conducted to better understand the potential benefits and limitations of AFO use in the context of mobility and balance during gait for individuals with neuropathic conditions, particularly relative to those offered by surgical correction.
UNASSIGNED: Following this path of research will provide comparative baseline data on mobility, balance confidence, and gait that can be used to inform an objective criterion-based approach to AFO prescription and the impact of surgical intervention.

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)-a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression.

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.

BACKGROUND: Charcot Marie tooth disease (CMTD) is also known as Hereditary sensory motor neuropathy. It poses difficulties in attaining intra-operative neuromonitoring signals for deformity correction surgery. In this case report, we intent to mention key points for obtaining good neuromonitoring signals in these cases which increases the safety in scoliosis surgery.
METHODS: We present a 14-year-old boy, known case of CMTD, presented with progressive deformity of the back. The child was wheelchair-bound and could walk only a few steps with support. He was unable to maintain a sitting balance without using upper limbs making him functionally quadriparatic. The radiographs showed a double scoliotic curve with costo-pelvic impingement. At the onset, no signals were obtained with routine intra-operative neuromonitoring settings.
CONCLUSIONS: Increasing the sweep length and voltage in our neuro-monitors helped in acquiring the baseline signals and we went ahead to proceed the deformity correction.