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Mutations in MTMR2, the myotubularin-related 2 gene, cause autosomal recessive Charcot-Marie-Tooth type 4B1 (CMT4B1). This disorder is characterized by childhood onset of weakness and sensory loss, severely decreased nerve conduction velocity, demyelination in the nerve with myelin outfoldings, and severe functional impairment of affected patients, mainly resulting from loss of myelinated fibers in the nerve. We recently generated Mtmr2-nullneo mice, which show a dysmyelinating neuropathy with myelin outfoldings, thus reproducing human CMT4B1. Mtmr2 is detected in both Schwann cells and neurons, in which it interacts with discs large 1/synapse associated protein 97 and neurofilament light chain, respectively. Here, we specifically ablated Mtmr2 in either Schwann cells or motor neurons. Disruption of Mtmr2 in Schwann cells produced a dysmyelinating phenotype very similar to that of the Mtmr2-nullneo mouse. Disruption of Mtmr2 in motor neurons does not provoke myelin outfoldings nor axonal defects. We propose that loss of Mtmr2 in Schwann cells, but not in motor neurons, is both sufficient and necessary to cause CMT4B1 neuropathy. Thus, therapeutical approaches might be designed in the future to specifically deliver the Mtmr2 phospholipid phosphatase to Schwann cells in affected nerves. [ABSTRACT FROM AUTHOR]

Introduction. Selective serotonin reuptake inhibitors are the most widely used agents for delaying ejaculation in patients with premature ejaculation (PE). Aim. The aim of this study was to assess the acceptance of and the discontinuation rate from paroxetine treatment in patients with lifelong PE. Methods. We analyzed the acceptance of and discontinuation rates of 93 consecutive potent patients (mean age, 37.6 years) seeking medical treatment for lifelong PE. The patients were assessed with detailed medical and sexual history, self-reported intravaginal ejaculatory latency time, self-administered International Index of Erectile Function, complete physical examination, and the Meares–Stamey test. The patients received a paroxetine prescription (10 mg daily for 21 days and then 20 mg as needed) for the first 3 months. Thereafter, the patients could either stay with the same on-demand treatment or take paroxetine 10 mg daily for 3 months. The patients were evaluated at 3 and 6 months, and requested to complete multiple-choice global assessment questions regarding specific reasons for eventual therapy discontinuation. Main Outcome Measures. The primary end point was acceptance and discontinuation rates for paroxetine treatment in patients seeking medical treatment for lifelong PE. The secondary end point was the reasons for nonacceptance of treatment or discontinuation. Results. Twenty-eight (30.10%) patients decided not to start paroxetine. Fear of using an “antidepressant drug” was the main reason (42.9%) for treatment nonacceptance. Twenty (30.8%) patients who initiated therapy eventually discontinued it. Treatment effect below expectations was the main reason of treatment dropout (75%) during the first 3 months, followed by temporary loss of interest in sex because of relationship issues (15%) and side effects (10%). Of the patients who continued treatment, 77.8% preferred daily paroxetine, while 22.2% continued as-needed therapy. Conclusions. Thirty percent of lifelong PE patients seeking medical treatment for complaints of early ejaculation freely decided not to start any paroxetine treatment, and roughly 30% of patients who started therapy eventually discontinued it. Salonia A, Rocchini L, Sacca A, Pellucchi F, Ferrari M, Del Carro U, Ribotto P, Gallina A, Zanni G, Deho' F, Rigatti P, and Montorsi F. Acceptance of and discontinuation rate from paroxetine treatment in patients with lifelong premature ejaculation. J Sex Med 2009;6:2868–2877. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a demyelinating lysosomal storage disorder for which new treatments are urgently needed. We previously showed that transplantation of gene-corrected hematopoietic stem progenitor cells (HSPCs) in presymptomatic myeloablated MLD mice prevented disease manifestations. Here we show that HSC gene therapy can reverse neurological deficits and neuropathological damage in affected mice, thus correcting an overt neurological disease. The efficacy of gene therapy was dependent on and proportional to arylsulfatase A (ARSA) overexpression in the microglia progeny of transplanted HSPCs. We demonstrate a widespread enzyme distribution from these cells through the CNS and a robust cross-correction of neurons and glia in vivo. Conversely, a peripheral source of enzyme, established by transplanting ARSA-overexpressing hepatocytes from transgenic donors, failed to effectively deliver the enzyme to the CNS. These results indicate that the recruitment of gene-modified, enzyme-overexpressing microglia makes the enzyme bioavailable to the brain and makes therapeutic efficacy and disease correction attainable. Overall, our data provide a strong rationale for implementing HSPC gene therapy in MLD patients. [ABSTRACT FROM AUTHOR]

This article presents a study which shows that disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis. Although MTMRS share extensive homology with PTP/DSP phosphatases, they preferentially dephosphorylate phosphoinositides. The likely physiological substrate of both MTM1 and MTMR2 is phosphatidylinositol biphosphate, a key regulator of vacuolar homeostasis and vesicle transport at the level of multivesicular bodies/late endosomes. In neurons, MTMR2 may interact with NF-L, a nervous system-specific protein mutated in axonal CMT2E.

An abstract of the article "HSC-Based Ex Vivo Gene Therapy Prolongs Survival and Improves the Phenotype of Globoid Cell Leukodystrophy Mice," by Alessandra Biffi and colleagues is presented.

An abstract of the article "Cure of Established Disease and Direct Evidence of Cellular Cross-Correction in the Nervous System of Metachromatic Leukodystrophy Mice after HSC-Based Gene Therapy," by Alessandra Biffi, Alessia Capotondo, Angelo Quattrini and colleagues is presented.

Charcot-Marie-Tooth (CMT) neuropathies represent a broad and very heterogeneous group of disorders for which no therapies are yet available. Due to the huge genetic heterogeneity, therapeutical approaches that can benefit several forms independently of the unique pathogenetic mechanism have been sought. Niacin, nicotinic acid, is a vitamin used for many decades as anti-dyslipidaemic and anti-cholesterol drug product under the commercial name of Niaspan ® , the extended-release formulation of niacin. Of note, niacin can have other effects depending on the dose, formulation and physiology and it has been used to reduce inflammation, to promote angiogenesis and to protect neurons, muscle and axons by boosting nicotinamide adenine dinucleotide (NAD + ) levels. Niacin also activates TNF-alpha convertase enzyme (TACE) secretase, which negatively regulates Neuregulin type I-mediated signalling in the peripheral nervous system and myelination. We previously postulated that niacin-mediated TACE activation can be effective in reducing aberrant excessive myelin associated with different CMT forms. Here, we explored efficacy of this strategy by performing a long-term preclinical trial and we provided evidence that a novel niacin-based long-lasting formulation ameliorates neurophysiology and reduces fibre degeneration in a model of Charcot-Marie-Tooth type 4B1 (CMT4B1) neuropathy, characterized by aberrant myelin. We also sought to determine whether this strategy might interfere with nerve regeneration, which is dependent on Neuregulin type I signalling. Surprisingly, we found that the Mtmr2 knockout mice, a model of CMT4B1, have a defect in nerve regeneration and that niacin-based treatment is not detrimental to nerve regeneration., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 ( Xbp1s ). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation., Competing Interests: Competing interests JWK and RLW are shareholders and scientific advisory board members for Protego Biopharma who have licensed IRE1/XBP1s activators including IXA4 for therapeutic development.

Objective: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19., Methods: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered., Results: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002)., Conclusions: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The present study aimed to perform a comprehensive data analysis of 47 consecutive patients treated in 8 years and to observe how clinical, radiologic, and surgical factors affect early and long-term outcomes, recurrence rate, and survival., Methods: Clinical, radiologic, and surgical data were collected retrospectively from the review of a prospectively collected database. The neurologic disability was evaluated according to the modified Rankin Scale (mRS). Radiologic data were obtained by direct measurement performed on magnetic resonance imaging (MRI). Univariate and multivariate statistical analysis was performed., Results: From 2008 to 2016, 47 consecutive patients underwent microsurgical resection of intramedullary lesions (28 males and 19 females; mean age, 41.2 years). Ependymoma (53.2%), astrocytoma (14.9%), hemangioblastoma (14.9%), and cavernous angioma (6.4%) were the most frequent tumor histology. The mean follow-up duration was 69.3 months. Gross total tumor resection was performed in 80.8% of cases. Forty-two patients (89.4%) were alive at last follow-up. Five-year overall survival and recurrence-free survival were 92% and 82%, respectively., Conclusions: Among the examined variables, age seemed to strongly correlate with outcomes; better chances of recovery and a good postoperative outcome were observed in younger patients. Surfacing lesions had a better early functional outcome than did intramedullary located lesions. Patients' preoperative neurologic and functional status (mRS score ≤2) had a significant impact on late neurologic outcome. Progression-free survival correlated with the extent of tumor resection. Surgery should probably be performed before patients' neurologic decline, aiming to achieve maximal resection without compromising patients' quality of life., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Charcot-Marie-Tooth (CMT) neuropathies are a group of genetic disorders that affect the peripheral nervous system with heterogeneous pathogenesis and no available treatment. Axonal neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain-of-function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17), also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pain is a disabling symptom and is often the foremost symptom of conditions for which patients undergo neurorehabilitation. We systematically searched the PubMed and Embase electronic databases for current evidence on the frequency, evolution, predictors, assessment, and pharmacological and non-pharmacological treatment of pain in patients with headache, craniofacial pain, low back pain, failed back surgery syndrome, osteoarticular pain, myofascial pain syndrome, fibromyalgia, and chronic pelvic pain. Despite the heterogeneity of published data, consensus was reached on pain assessment and management of patients with these conditions and on the utility of a multidisciplinary approach to pain therapy that combines the benefits of pharmacological therapy, physiotherapy, neurorehabilitation, and psychotherapy. We of the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) suggest a need to conduct randomized controlled trials on the efficacy of pain treatments and their risk-benefit profile for the conditions we have reviewed.

Despite the improved understanding of spinal cord anatomy and spinal cord ischemia pathophysiology, the rate of debilitating postoperative paraparesis or paraplegia is still not negligible after procedures for thoracic or thoracoabdominal aortic disease. Single studies have demonstrated the role of different treatment modalities to prevent or treat spinal cord ischemia. A multimodal approach, however, is advocated by most authors. Even after the employment of endovascular techniques become routine, the rate of spinal cord ischemia after treatment of thoracoabdominal aortic pathology remained unchanged over time. Spinal cord ischemia is often treatable by different means that concur to improve indirect spinal perfusion through collateral circulation; it should, therefore, be managed promptly and aggressively due to its potential reversibility. Ongoing technical improvements of non-invasive diagnostic tools may allow a better preoperative assessment of the spinal vascular network and a better planning of both open and endovascular thoracic or thoracoabdominal repair.

P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation.

Background: The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS)., Methods: We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center., Results: We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later., Conclusions: The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability.

We report a patient who developed acute myelopathy after intranasal insufflation of amphetamines and heroin. The functional prognosis was very poor; after 4 months, she remained paraplegic. MRI imaging showed selective T2 hyperintensity and intense enhancement confined to the spinal anterior horns and lumbar nerve roots and plexus. This unique MRI pattern, together with neurophysiological data, suggests that the pathological process at the first primary affected spinal anterior horns (SAH), conditioning motoneuron cell death, and then nerve roots and lumbar plexus as a consequence of wallerian degeneration.

Objective: To compare the effects of sildenafil and sublingual (sl) apomorphine on nocturnal erections., Methods: In a prospective, single-blinded, placebo-controlled at-home study we compared the effect of apomorphine sl and sildenafil on sleep-related erectile activity in 30 healthy potent volunteers (mean age, 26.4 years; range, 23-35 years; Erectile Function domain of the International Index of Erectile Function > or =26), not reporting any subjective sleep abnormality during 4 consecutive nights with rigidity monitoring (NPTR) with the RigiScantrade mark device. After the first night of adaptation, they were randomized to receive placebo or apomorphine sl 2mg or sildenafil 50mg taken at bedtime during the following 3 consecutive nights., Results: Sildenafil increased the mean+/-SE number of erections, overall length of erectile events, and the time of erections with rigidity >60% at both tip and base, as compared to placebo. The same parameters were reduced after administration of apomorphine sl. Similar findings were observed with regards to Rigidity Activity Units and Tumescence Activity Units., Conclusions: Our results confirm that sildenafil taken at bedtime might increase nocturnal erectile activity also in young potent men as compared to placebo. Apomorphine sl taken at bedtime seems to have the opposite effect.