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Introduction Charcot-Marie-Tooth (CMT) disease is a progressively disabling syndrome phenotypically comprising distal muscle weakness and atrophy, foot deformities, sensory loss, and reduced or absent tendon reflexes. In spastic paraplegia (SPG), a hereditary disorder affecting the upper motor neuron only, pareses are spastic, and deep tendon reflexes increased. Mixed forms between both diseases have been previously described ( Liu et al., 2014 ). By multiple gene panel based analysis using next-generation-sequencing (NGS), we herein identified the novel variant c.785T>C; p.Leu262Pro in KIF5A as the putative cause of a mixed CMT and SPG phenotype. Methods The patient’s examination took place in the neuromuscular outpatient clinic of the RWTH Aachen University hospital. After obtaining the patient’s informed consent, the molecular genetic analysis of an NGS-based panel comprising 84 genes in total was performed following the commercialized standard procedures established by CeGaT GmbH. The pathogenicity of each variant was evaluated according to the international ACMG criteria ( Richards et al., 2015 ). Case report At the age of 44 years, the now 48-year-old male patient with a negative family history noticed the first signs of gait unsteadiness. In the course, he developed profound symmetric calf atrophies, high arched feet, claw toes, and steppage gait. Except for the absent ankle jerk reflex, the deep tendon reflexes where surprisingly brisk. Sensory loss turned out comparably mild. Nerve conduction studies showed an axonal motor neuropathy in the legs, but were normal in the arms. The molecular genetic analysis revealed the heterozygous variant c.785T>C; p.Leu262Pro in the KIF5A gene, which has been described in association to SPG10 and/or an axonal CMT subtype following an autosomal dominant inheritance. The variant c.785T>C; p.Leu262Pro affects a highly conserved amino acid position within a functionally relevant domain. A change of secondary protein structure is conceivable as the linear leucine is replaced by proline, a cyclic amino acid. Several other missense mutations are described in the very close vicinity. The variant is predicted to be pathogenic by all available prediction programs. Its allele frequency in the healthy reference population is unknown. Unfortunately, co-segregation analyses could be performed since further family members were not available. For further evaluation, functional tests would be required. Discussion On the current state of knowledge, the novel variant c.785T>C; p.Leu262Pro in KIF5A is evaluated as being a variant of uncertain significance. Due to the well matching phenotype ( Liu et al., 2014 ), however, we consider it to be putatively pathogenic. This example underlines the necessity of precise phenotyping in the context of NGS-based multigene panels. [ABSTRACT FROM AUTHOR]

Endovascular thrombectomy (EVT) is the most effective treatment for acute ischemic stroke caused by large vessel occlusion (LVO). Yet, long-term outcome (LTO) and health-related quality of life (HRQoL) in these patients have rarely been addressed, as opposed to modified Rankin scale (mRS) recordings. We analysed demographic data, treatment and neuroimaging parameters in 694 consecutive stroke patients in a maximum care hospital. In 138 of these patients with respect on receipt of written informed consent, LTO and HRQoL were collected over a period of 48 months after EVT using a standardised telephone survey (median 2.1 years after EVT). Age < 70 years (OR 4.82), lower NIHSS on admission (OR 1.11), NIHSS ≤ 10 after 24 h (OR 11.23) and complete recanalisation (mTICI3) (OR 7.79) were identified as independent predictors of favourable LTO. Occurrence of an infection requiring treatment within the first 72 h was recognised as a negative predictor for good long-term outcome (OR 0.22). Patients with mRS > 2 according to the telephone survey more often had complaints regarding mobility, self-care, and usual activity domains of the HRQoL. Our results underline a sustainable positive effect of effective EVT on the quality of life in LVO stroke. Additionally, predictive parameters of outcome were identified, that may support clinical decision making in LVO stroke., (© 2024. The Author(s).)

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification of these cases. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor-stroma ratio (as a quantitative description of stromal desmoplasia), tumor-infiltrating lymphocytes (TIL), "microcystic, elongated, fragmented" (MELF) pattern) were analyzed in resection specimens of the TCGA-UCEC cohort ( n = 228). For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. Associations with survival outcomes were calculated in univariate and multivariate analysis and validated in two independent cohorts. In MSI tumors, only TB remained an independent prognostic factor. TB (≥3 buds/high-power field) was associated with inferior outcomes and with lymph node metastases. The prognostic significance of TB was confirmed in two validation cohorts. For CN-low tumors, established grading defined by the WHO was independently prognostic with inferior outcomes for high-grade tumors. The evaluation of TB might help in identifying MSI-patients with unfavorable prognosis who, e.g., could benefit from lymphadenectomy. WHO-based grading facilitates independent prognostic stratification of CN-low endometrioid adenocarcinomas. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management.

Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2 -/- mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2 -/- mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2 -/- mice). Comparing the apparent affinities (IC 50 ) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC 50 : 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP.

Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subjective treatment response, side effects, and reasons for carbamazepine discontinuation. The underlying diagnoses leading to muscle pain were diverse, ranging from metabolic (n = 5) and other hereditary (n = 9) to acquired (n = 2) myopathies and myotonia syndromes (n = 22). Under carbamazepine (daily dose 254 ± 138 mg), patients reported a significant reduction of pain, quantified by an 11-point numeric rating scale (−1.9 ± 1.8, p < 0.001). Compared to age- and sex-matched controls, our sensory assessment revealed a significant dysfunction of Aδ-nerve fibers in patients with chronic muscle pain. Neuropathic pain components identified by the painDETECT questionnaire or quantitative sensory testing did not seem to influence the reported treatment response. Side effects (n = 18) such as fatigue, elevated liver enzymes, and diarrhea, as well as lack of pain improvement (n = 6), led to carbamazepine discontinuation in 44.4% (24/54). Mediated by dysfunctional Aδ-nerve fibers, muscle pain is common in a variety of myopathies. Carbamazepine may reduce pain levels, but comes with therapy-limiting side effects.

Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. Selected proteins and additional potential biomarkers, such as growth differentiation factor 15 (GDF15) and cell free mitochondrial DNA, were validated by ELISA and quantitative PCR, respectively. We propose that neural cell adhesion molecule 1 (NCAM1) is a candidate biomarker for CMT, as it was elevated in Gjb1-null, Hspb8K141N, GarsC201R and GarsP278KY mice as well as in patients with both demyelinating (CMT1A) and axonal (CMT2D, CMT2N) forms of CMT. We show that NCAM1 may reflect disease severity, demonstrated by a progressive increase in mouse models with time and a significant positive correlation with CMTES neuropathy severity in patients. The increase in NCAM1 may reflect muscle regeneration triggered by denervation, which could potentially track disease progression or the effect of treatments. We found that member proteins of the complement system were elevated in Gjb1-null and Hspb8K141N mouse models as well as in patients with both demyelinating and axonal CMT, indicating possible complement activation at the impaired nerve terminals. However, complement proteins did not correlate with the severity of neuropathy measured on the CMTES scale. Although the complement system does not seem to be a prognostic biomarker, we do show complement elevation to be a common disease feature of CMT, which may be of interest as a therapeutic target. We also identify serum GDF15 as a highly sensitive diagnostic biomarker, which was elevated in all CMT genotypes as well as in Hspb8K141N, Gjb1-null, GarsC201R and GarsP278KY mouse models. Although we cannot fully explain its origin, it may reflect increased stress response or metabolic disturbances in CMT. Further large and longitudinal patient studies should be performed to establish the value of these proteins as diagnostic and prognostic molecular biomarkers for CMT., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Abstract: Defined by dysfunction or degeneration of Aδ and C fibers, small fiber neuropathies (SFNs) entail a relevant health burden. In 50% of cases, the underlying cause cannot be identified or treated. In 100 individuals (70% female individuals; mean age: 44.8 years) with an idiopathic, skin biopsy-confirmed SFN, we characterized the symptomatic spectrum and measured markers of oxidative stress (vitamin C, selenium, and glutathione) and inflammation (transforming growth factor beta, tumor necrosis factor alpha), as well as neurotoxic 1-deoxy-sphingolipids. Neuropathic pain was the most abundant symptom (95%) and cause of daily life impairment (72%). Despite the common use of pain killers (64%), the painDETECT questionnaire revealed scores above 13 points in 80% of patients. In the quantitative sensory testing (QST), a dysfunction of Aδ fibers was observed in 70% and of C fibers in 44%, affecting the face, hands, or feet. Despite normal nerve conduction studies, QST revealed Aβ fiber involvement in 46% of patients' test areas. Despite absence of diabetes mellitus or mutations in SPTLC1 or SPTLC2 , plasma 1-deoxy-sphingolipids were significantly higher in the sensory loss patient cluster when compared with those in patients with thermal hyperalgesia ( P < 0.01) or those in the healthy category ( P < 0.1), correlating inversely with the intraepidermal nerve fiber density (1-deoxy-SA: P < 0.05, 1-deoxy-SO: P < 0.01). Patients with arterial hypertension, overweight (body mass index > 25 kg/m 2 ), or hyperlipidemia showed significantly lower L-serine (arterial hypertension: P < 0.01) and higher 1-deoxy-sphingolipid levels (arterial hypertension: P < 0.001, overweight: P < 0.001, hyperlipidemia: P < 0.01). Lower vitamin C levels correlated with functional Aβ involvement ( P < 0.05). Reduced glutathione was lower in patients with Aδ dysfunction ( P < 0.05). Idiopathic SFNs are heterogeneous. As a new pathomechanism, plasma 1-deoxy-sphingolipids might link the metabolic syndrome with small fiber degeneration., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

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).)

Progressive multifocal leukoencephalopathy (PML) is a subacute brain infection by the opportunistic John Cunningham (JC) virus. Herein, we describe seven patients with PML, lymphopenia, and sarcoidosis, in three of whom PML was the first manifestation of sarcoidosis. At onset, the clinical picture comprised rapidly progressive spastic hemi- or limb pareses as well as disturbances of vision, speech, and orientation. Cerebral magnetic resonance imaging showed T2-hyperintense, confluent, mainly supratentorial lesions. Four patients developed punctate contrast enhancement as a radiological sign of an immune reconstitution inflammatory syndrome (IRIS), three of them having a fatal course. In the cerebrospinal fluid, the initial JC virus load (8-25,787 copies/ml) did not correlate with interindividual severity; however, virus load corresponded to clinical dynamics. Brain biopsies ( n  = 2), performed 2 months after symptom onset, showed spotted demyelination and microglial activation. All patients had lymphopenia in the range of 270-1150/µl. To control JC virus, three patients received a combination of mirtazapine and mefloquine, another two patients additionally took cidofovir. One patient was treated with cidofovir only, and one patient had a combined regimen with mirtazapine, mefloquine, cidofovir, intravenous interleukin 2, and JC capsid vaccination. To treat sarcoidosis, the four previously untreated patients received prednisolone. Three patients had taken immunosuppressants prior to PML onset, which were subsequently stopped as a potential accelerator of opportunistic infections. After 6-54 months of follow up, three patients reached an incomplete recovery, one patient progressed, but survived so far, and two patients died. One further patient was additionally diagnosed with lung cancer, which he died from after 24 months. We conclude that the combination of PML and sarcoidosis is a diagnostic and therapeutic challenge. PML can occur as the first sign of sarcoidosis without preceding immunosuppressive treatment. The development of IRIS might be an indicator of poor outcome., Competing Interests: Conflict of interest statement: Ralf Gold is the editor-in-chief of Therapeutic Advances in Neurological Disorders. The remaining authors declare that they have no conflicts of interest relevant for this work., (© The Author(s), 2021.)

Deep neural networks recently showed high performance and gained popularity in the field of radiology. However, the fact that large amounts of labeled data are required for training these architectures inhibits practical applications. We take advantage of an unpaired image-to-image translation approach in combination with a novel domain specific loss formulation to create an "easier-to-segment" intermediate image representation without requiring any label data. The requirement here is that the task can be translated from a hard to a related but simplified task for which unlabeled data are available. In the experimental evaluation, we investigate fully automated approaches for segmentation of pathological muscle tissue in T1-weighted magnetic resonance (MR) images of human thighs. The results show clearly improved performance in case of supervised segmentation techniques. Even more impressively, we obtain similar results with a basic completely unsupervised segmentation approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gadermayr, Heckmann, Li, Bähr, Müller, Truhn, Merhof and Gess.)

With emerging treatment approaches, it is crucial to correctly diagnose and monitor hereditary and acquired polyneuropathies. This study aimed to assess the validity and accuracy of magnet resonance imaging (MRI)-based muscle volumetry.Using semi-automatic segmentations of upper- and lower leg muscles based on whole-body MRI and axial T1-weighted turbo spin-echo sequences, we compared and correlated muscle volumes, and clinical and neurophysiological parameters in demyelinating Charcot-Marie-Tooth disease (CMT) ( n = 13), chronic inflammatory demyelinating polyneuropathy (CIDP) ( n = 27), and other neuropathy ( n = 17) patients.The muscle volumes of lower legs correlated with foot dorsiflexion strength ( p < 0.0001), CMT Neuropathy Score 2 ( p < 0.0001), early gait disorders ( p = 0.0486), and in CIDP patients with tibial nerve conduction velocities ( p = 0.0092). Lower ( p = 0.0218) and upper ( p = 0.0342) leg muscles were significantly larger in CIDP compared to CMT patients. At one-year follow-up ( n = 15), leg muscle volumes showed no significant decrease.MRI muscle volumetry is a promising method to differentiate and characterize neuropathies in clinical practice.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare, autoimmune or paraneoplastic condition characterized by muscle weakness and fatigability. In cancer therapy, immune checkpoint inhibitors (ICI) sensitize the immune system for tumor antigens. We report a 62-year-old, female patient with paraneoplastic LEMS as first manifestation of Merkel cell carcinoma. Under avelumab, the LEMS exacerbated with worsening of limb weakness and a severely reduced vital capacity (< 1 l). To treat this immunological side effect, we added a regimen with intravenous immunoglobulins. Hereby, the LEMS improved significantly. As we were able to continue the cancer treatment, the Merkel cell carcinoma has been in remission so far. This is the first description of paraneoplastic LEMS, avelumab, and Merkel cell carcinoma. We conclude that immunoglobulins are an option to control an ICI-associated deterioration of paraneoplastic symptoms., Competing Interests: Competing interestsMaike F. Dohrn has received scientific funding from Pfizer (ASPIRE 2018), has served as a paid consultant for Amicus, Akcea, Alnylam, and Pfizer, and is currently receiving a scholarship for a research fellowship by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). Jörg B. Schulz serves at advisory boards for Biogen and Roche. Burkhard Gess received financial support from Pfizer, Grifols, and Bayer for conference contributions. Simone Tauber has participated in paid scientific advisory boards by Roche and received financial travelling support and consultant honoraries by Novartis, Tena, Merck, Roche, and Biogen. All of the aforementioned conflicts are not related to the content of the manuscript. US, CK, and DC have no conflicts to disclose. All authors read and approved the manuscript., (© The Author(s) 2020.)

The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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: Several independent prognostic factors, such as age of onset, type of onset, body mass index (BMI), and progression rate have been identified for amyotrophic lateral sclerosis (ALS) in Caucasians. The aim of this study was to identify such factors in Chinese patients and to compare their impact with German patients., Methods: Comparison of prognostic factors was based on two hospital-based registries. The registry of the German Network for Motor Neuron Diseases contains 3100 patients with ALS. The Chinese registry comprises 2101 patients who were collected between 2003 and 2015 in the metropolitan area of Beijing., Results: Disease progression was slower in China [median loss of 0.50 points (IQR 0.26-0.87 points) versus 0.55 points (IQR 0.28-1.00 points) of ALS functional rating scale revised (ALS-FRS-R) score per month; p < 0.0001]. Survival of patients with ALS was similar in Germany and China (p > 0.05). We found that younger age of onset (p < 0.0001), spinal onset (p < 0.0001), high BMI (p < 0.0001) and low progression rate (p < 0.0001) were positive prognostic factors in China as well as in Germany., Interpretation: Prognostic factors, which are known to modify the course of disease in Caucasians, apply to Chinese patients as well. The results indicate that despite the apparent differences regarding genotype and clinical phenotype, findings from interventional studies in Caucasians aiming at disease-modifying prognostic factors (such as body weight) may be transferred to Chinese patients.

Background: Fat-fraction has been established as a relevant marker for the assessment and diagnosis of neuromuscular diseases. For computing this metric, segmentation of muscle tissue in MR images is a first crucial step., Purpose: To tackle the high degree of variability in combination with the high annotation effort for training supervised segmentation models (such as fully convolutional neural networks)., Study Type: Prospective., Subjects: In all, 41 patients consisting of 20 patients showing fatty infiltration and 21 healthy subjects. Field Strength/Sequence: The T 1 -weighted MR-pulse sequences were acquired on a 1.5T scanner., Assessment: To increase performance with limited training data, we propose a domain-specific technique for simulating fatty infiltrations (i.e., texture augmentation) in nonaffected subjects' MR images in combination with shape augmentation. For simulating the fatty infiltrations, we make use of an architecture comprising several competing networks (generative adversarial networks) that facilitate a realistic artificial conversion between healthy and infiltrated MR images. Finally, we assess the segmentation accuracy (Dice similarity coefficient)., Statistical Tests: A Wilcoxon signed rank test was performed to assess whether differences in segmentation accuracy are significant., Results: The mean Dice similarity coefficients significantly increase from 0.84-0.88 (P < 0.01) using data augmentation if training is performed with mixed data and from 0.59-0.87 (P < 0.001) if training is conducted with healthy subjects only., Data Conclusion: Domain-specific data adaptation is highly suitable for facilitating neural network-based segmentation of thighs with feasible manual effort for creating training data. The results even suggest an approach completely bypassing manual annotations., Level of Evidence: 4 Technical Efficacy: Stage 3., (© 2019 International Society for Magnetic Resonance in Medicine.)

Schwann cells (SCs) are essential in the production of the axon-wrapping myelin sheath and provide trophic function and repair mechanisms in the peripheral nerves. Consequently, well-characterized SC in vitro models are needed to perform preclinical studies including the investigation of the complex biochemical adaptations occurring in the peripheral nervous system (PNS) under different (patho)physiological conditions. MSC80 cells represent a murine SC line used as an in vitro system for neuropathological studies. Here, we introduce the most abundant 9532 proteins identified via mass spectrometry-based protein analytics, and thus provide the most comprehensive SC protein catalogue published thus far. We cover proteins causative for inherited neuropathies and demonstrate that in addition to cytoplasmic, nuclear and mitochondrial proteins and others belonging to the protein processing machinery are very well covered. Moreover, we address the suitability of MSC80 to examine the molecular effect of a drug-treatment by analyzing the proteomic signature of Vitamin C-treated cells. Proteomic findings, immunocytochemistry, immunoblotting and functional experiments support the concept of a beneficial role of Vitamin C on oxidative stress and identified TMX1 as an oxidative stress protective factor, which might represent a promising avenue for therapeutic intervention of PNS-disorders with oxidative stress burden such as diabetic neuropathy.