Glutathione Consumptive Dual-Sensitive Lipid-Composite Nanoparticles Induce Immunogenic Cell Death for Enhanced Breast Tumor Therapy.

Although chemotherapy remains the standard therapy for tumor treatment, serious side effects can occur because of nontargeted distribution and damage to healthy tissues. Hollow mesoporous silica nanoparticles (HMSNs) modified with lipids offer potential as delivery systems to improve therapeutic outcomes and reduce adverse effects. Herein, we synthesized HMSNs with integrated disulfide bonds (HMSN) for loading with the chemotherapeutic agent oxaliplatin (OXP) which were then covered with the synthesized hypoxia-sensitive lipid (Lip) on the surface to prepare the dual-sensitive lipid-composite nanoparticles (HMSN-OXP-Lip). The empty lipid-composite nanoparticles (HMSN-Lip) would consume glutathione (GSH) in cells because of the reduction of disulfide bonds in HMSN and would also inhibit GSH production because of NADPH depletion driven by Lip cleavage. These actions contribute to increased levels of ROS that induce the immunogenic cell death (ICD) effect. Simultaneously, HMSN-Lip would disintegrate in the presence of high concentrations of GSH. The lipid in HMSN-OXP-Lip could evade payload leakage during blood circulation and accelerate the release of the OXP in the tumor region in the hypoxic microenvironment, which could significantly induce the ICD effect to activate an immune response for an enhanced therapeutic effect. The tumor inhibitory rate of HMSN-OXP-Lip was almost twice that of free OXP, and no apparent side effects were observed. This design provides a dual-sensitive and efficient strategy for tumor therapy by using lipid-composite nanoparticles that can undergo sensitive drug release and biodegradation.

Sporadic hereditary neuropathies misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: Pitfalls and red flags.

Hereditary neuropathies may be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). A correct diagnosis is crucial for avoiding unnecessary therapies and access genetic counseling. We report on nine patients (seven men, mean age 49.2 ± 16.1) diagnosed with and treated as CIDP, in whom mutations or variants of unknown significance (VUS) in genes associated with hereditary neuropathies were reported. All underwent neurological and neurophysiological examination, eight also cerebrospinal fluid (CSF) analysis. In 4/9, nerve ultrasound and/or MR-neurography were performed. All the patients complained of progressive upper or lower limbs sensory-motor symptoms, with heterogeneous disease duration (1-34 years, mean 8.6 ± 10.8). Neurophysiology showed demyelinating signs in seven patients, mixed findings with predominant axonal damage in two patients. Neuroimaging disclosed diffuse abnormalities at proximal and distal segments. Molecular screening showed PMP22 duplication in two patients, mutations in the MPZ, EGR2, and GJB1 genes were reported in each of the remaining patients. The two patients with mixed neurophysiological findings had p.Val30Met mutation in the transthyretin gene. Two patients had VUS in the MARS and HSPB1 genes. Four patients had partial response to immunomodulant therapies, and CSF and neurophysiological features suggesting an inflammatory condition concomitant with the hereditary neuropathy. Hereditary neuropathy may be misdiagnosed with CIDP. The most common pitfalls are CSF (high protein levels and oligoclonal bands), incorrect interpretation of neurophysiology, and transient benefit from therapies. Neuroimaging may be helpful in cases with atypical presentations or when severe axonal damage complicate the neurophysiological interpretation.

Towards a functional pathology of hereditary neuropathies.

A growing number of hereditary neuropathies have been assigned to causative gene defects in recent years. The study of human nerve biopsy samples has contributed substantially to the discovery of many of these neuropathy genes. Genotype-phenotype correlations based on peripheral nerve pathology have provided a comprehensive picture of the consequences of these mutations. Intriguingly, several gene defects lead to distinguishable lesion patterns that can be studied in nerve biopsies. These characteristic features include the loss of certain nerve fiber populations and a large spectrum of distinct structural changes of axons, Schwann cells and other components of peripheral nerves. In several instances the lesion patterns are directly or indirectly linked to the known functions of the mutated gene. The present review is designed to provide an overview on these characteristic patterns. It also considers other aspects important for the manifestation and pathology of hereditary neuropathies including the role of inflammation, effects of chemotherapeutic agents and alterations detectable in skin biopsies.

Microneedle-assisted percutaneous delivery of methotrexate-loaded nanoparticles enabling sustained anti-inflammatory effects in psoriasis therapy.

Methotrexate (MTX) is one of the first-line drugs used for the treatment of moderate to severe psoriasis. However, low bioavailability and systemic side effects of traditional oral and injectable MTX greatly limit its clinical application. Delivering MTX using dissolving microneedles (MNs) into psoriasis-like skin lesion could improve the in situ therapeutic effects with higher bioavailability and less side effects. Here, we propose a novel therapeutic approach for psoriasis involving MN-assisted percutaneous delivery of chitosan-coated hollow mesoporous silica nanoparticles containing MTX (MTX@HMSN/CS). The MTX@HMSN/CS-loaded MNs were strong enough to successfully penetrate the psoriasiform thickened epidermis, allowing MTX@HMSN/CS to be accurately delivered to the site of skin lesion following the rapid dissolution of MNs. MTX was then released continuously from HMSN/CS for at least one week to maintain effective therapeutic drug concentration for skin lesion with long-term anti-proliferative and anti-inflammatory effects. Incubation with MTX@HMSN/CS not only inhibited the proliferation of human immortalized keratinocytes (HaCaT cells), but also significantly reduced the expression of proinflammatory cytokines and chemokines. In addition, MTX@HMSN/CS-loaded MNs showed better efficacy in alleviating psoriasis-like skin inflammation than MTX-loaded MNs at the same dose. Compared to psoriasiform mice treated with 15.8 µg MTX-loaded MNs every day, 47.4 µg MTX@HMSN/CS-loaded MNs reduce the frequency of treatment to once every 3 days and achieve comparable amelioration. Therefore, MTX@HMSN/CS loaded MNs are a promising treatment strategy for psoriasis due to their durability, efficacy, convenience, and safety in relieving psoriasis-like skin inflammation.

Nanocatalytic theranostics with intracellular mutual promotion for ferroptosis and chemo-photothermal therapy.

The reactive oxygen species (ROS) produced through the Fenton reaction, induces lipid peroxide (LPO), causing cellular structural damage and ultimately triggering ferroptosis. However, the generation of ROS in the tumor microenvironment (TME) is limited by the catalytic efficiency of the Fenton reaction. Herein, a novel hollow mesoporous silica nanoparticle (HMSN) combined with multi-metal sulfide-doped mesoporous silica nanocatalyzers (NCs) was developed, namely MxSy-HMSN NCs (M represents Cu Mn and Fe, S denotes sulfur). The MxSy-HMSN can dramatically enhanced the ferroptosis by: (1) facilitating the conversion of H2O2 to ·OH through Fenton or Fenton-like reactions through co-catalysis; (2) weakening ROS scavenging systems by depleting the over expressed glutathione (GSH) in TME; (3) providing exceptional photothermal therapy to augment ferroptosis. The MxSy-HMSN can also act as smart cargos for anticancer drug-doxorubicin (DOX). The release of DOX is responsive to GSH/pH/Near-infrared Light (NIR) irradiation at the tumor lesion, significantly improving therapeutic outcomes while minimizing side effects. Additionally, the MxSy-HMSN has demonstrated excellent magnetic resonance imaging (MRI) potential. This smart MxSy-HMSN offer a synergetic approach combining ferroptosis with chemo-photothermal therapy and magnetic resonance imaging (MRI) diagnose, which could be an informative guideline for the design of future NCs.

[Monoclonal antibodies in inflammatory disease of the muscle and peripheral nervous system]. / Anticuerpos monoclonales en patología inflamatoria del sistema nervioso periférico y músculo.

INTRODUCTION: A significant group of neuromuscular diseases are of autoimmune origin, but the classic immunomodulatory drugs are not often effective. For this reason, there is a need to find new more effective treatments that will lead to better control of these conditions, particularly those that are usually more resistant. In the last few years, the use of monoclonal antibodies against specific antigens of lymphocyte populations or against pro-inflammatory molecules has seen a great expansion, and has been demonstrated to be a useful alternative in autoimmune diseases. An intensive search was made in Medline using the Keywords neuromuscular, myopathy, neuropathy, myasthenia, Lambert-Eaton, monoclonal antibody, rituximab, alemtuzumab, and anti-TNF-α. DEVELOPMENT: Clinical trials performed to evaluate the efficacy of monoclonal antibodies in neuromuscular disease are very limited and of reduced size. Thus, the experience in this field is basically limited to anecdotal cases or short series of patients on open-label treatment. The published data are encouraging, with favourable responses having been observed in patients resistant to classic treatments and in diseases that do not normally respond to the usual immunosuppressant drugs. On the other hand, it has been observed that anti-TNF-α antibodies may trigger the appearance of autoimmune neuromuscular diseases. CONCLUSIONS: Monoclonal antibodies could be an effective alternative treatment in autoimmune neuromuscular diseases, but the favourable responses observed need to be confirmed by means of controlled clinical trials with a sufficient number of patients.

Astaxanthin Activated the Nrf2/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP)-induced liver injury (AILI) is a common liver disease in clinical practice. Only one clinically approved drug, N-acetylcysteine (NAC), for the treatment of AILI is available in clinics, but novel treatment strategies are still needed due to the complicated pathological changes of AILI and the side effects of NAC. Here, we found that astaxanthin (ASX) can prevent AILI through the Nrf2/HO-1 pathway. After treatment with ASX, there was a positive activation of the Nrf2/HO-1 pathway in AILI models both in vivo and in vitro accompanied by enhanced autophagy and reduced ferroptosis. In APAP-challenged L02 liver cells, ASX reduced autophagy and enhanced apoptosis of the cells. Furthermore, we developed ASX-loaded hollow mesoporous silica nanoparticles (HMSN@ASX) to improve the aqueous solubility of ASX and targeted delivery of ASX to the liver and then significantly improve the therapeutic effects. Taken together, we found that ASX can protect against AILI by activating the Nrf2/HO-1 pathway, which mainly affects oxidative stress, autophagy, and ferroptosis processes, and the HMSN@ASX nanosystem can target the liver to enhance the treatment efficiency of AILI.

Targeted Therapies for Hereditary Peripheral Neuropathies: Systematic Review and Steps Towards a 'treatabolome'.

BACKGROUND: Hereditary peripheral neuropathies are inherited disorders affecting the peripheral nervous system, including Charcot-Marie-Tooth disease, familial amyloid polyneuropathy and hereditary sensory and motor neuropathies. While the molecular basis of hereditary peripheral neuropathies has been extensively researched, interventional trials of pharmacological therapies are lacking. OBJECTIVE: We collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies. METHODS: We searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale. RESULTS: Of the 2046 studies initially identified, 119 trials met our inclusion criteria, of which only 34 were carried over into our final analysis. Ascorbic acid was shown to have no therapeutic benefit in CMT1A, while a combination of baclofen, naltrexone and sorbitol (PXT3003) demonstrated some efficacy, but phase III data are incomplete. In TTR-related amyloid polyneuropathy tafamidis, patisiran, inotersen and revusiran showed significant benefit in high quality RCTs. Smaller studies showed the efficacy of L-serine for SPTLC1-related hereditary sensory neuropathy, riboflavin for Brown-Vialetto-Van Laere syndrome (SLC52A2/3) and phytanic acid-poor diet in Refsum disease (PHYH). CONCLUSIONS: The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies.

Clemastine improves electrophysiologic and histomorphometric changes through promoting myelin repair in a murine model of compression neuropathy.

Compression neuropathies are common and debilitating conditions that result in variable functional recovery after surgical decompression. Recent drug repurposing studies have verified that clemastine promotes functional recovery through enhancement of myelin repair in demyelinating disease. We investigated the utility of clemastine as a treatment for compression neuropathy using a validated murine model of compression neuropathy encircling the compression tube around the sciatic nerve. Mice received PBS or clemastine solution for 6 weeks of compression phase. Mice taken surgical decompression received PBS or clemastine solution for 2 weeks of decompression phase. Electrodiagnostic, histomorphometric, and Western immunoblotting analyses were performed to verify the effects of clemastine. During the compression phase, mice treated with clemastine had significantly decreased latency and increased amplitude compared to untreated mice that received PBS. Histomorphometric analyses revealed that mice treated with clemastine had significantly higher proportions of myelinated axons, thicker myelin, and a lower G-ratio. The expression levels of myelin proteins, including myelin protein zero and myelin associated glycoprotein, were higher in mice treated with clemastine. However, the electrophysiologic and histomorphometric improvements were observed regardless of clemastine treatment in mice taken surgical decompression. Mice treated with clemastine during compression of the sciatic nerve demonstrated that clemastine treatment attenuated electrophysiologic and histomorphometric changes caused by compression through promoting myelin repair.

Charcot­Marie­Tooth type 1A drug therapies: role of adenylyl cyclase activity and G­protein coupled receptors in disease pathomechanism.

Charcot­Marie­Tooth type 1A (CMT1A) is a dysmyelinating disease of the peripheral nervous system that results in a slow progressive weakening and wasting of the distal muscles of the upper and lower limbs. Despite extensive research and clinical trials there is still no treatment for CMT1A that results in complete neurological improvement. Recent studies investigating various pharmacological modulators of adenylyl cyclase activity, including ascorbic acid and ligands of G protein­coupled receptors (GPCRs), provide hope for future treatments of this type of hereditary motor and sensory neuropathy. A review of mechanisms of action of several compounds tested for CMT1A in pre­clinical and clinical studies ascorbic acid, onapristone, PXT3003 (baclofen, naltrexone, and sorbitol), and ADX71441, very clearly indicates an important role for adenylyl cyclase activity and GPCRs in the pathomechanism of the disease. Metabotropic γ­aminobutyric acid receptors (GABABR), subtype mu (µ) opioid receptors (MOR), and muscarinic acetylcholine receptors (mACh) appear to be particularly significant in both pathogenesis and treatment, and their activation may exert a similar and synergistic effect on the physiology of Schwann cells as well as neurons. These receptors participate in proliferation and differentiation of Schwann cells and influence excitatory transmission in neurons. We also hypothesize that onapristone might act through a non­classical mechanism via membrane progesterone receptor (mPR) and cAMP signaling. This review endeavors to outline a pathway leading inversely from therapy to an indispensable role for adenylyl cyclase activity and GPCRs in the modulation of dosage sensitive peripheral myelin protein (PMP22) gene expression.

[Treatment of multifocal motor neuropathies with conduction block in France in 2005. Results of a national opinion survey]. / Prise en charge des neuropathies motrices multifocales avec blocs de conduction en France en 2005. Résultats d'une enquête nationale d'opinion.

INTRODUCTION: The epidemiology of multifocal motor neuropathies (MMNs) is unknown. Prevalence is estimated at 1-2/100,000 population. METHODS: The objective of this study was to gain knowledge on MMN diagnosis and treatment in metropolitan France. An opinion survey was conducted by SOFRES from November 2004 to March 2005 on 4,040 hospital and private practice physicians (215 interviewed directly and 3,825 contacted only by mail) using two questionnaires (one for hospital physicians [HPs] and the other for physicians working for the most part in private practice [PPPs]). SOFRES received 424 questionnaires, 392 of which were included in the study, 32 having been excluded for incomplete responses, giving a high response rate for this type of survey. RESULTS: The 392 responses were made up of 296 for the HPs and 96 for the PPPs. The HPs were neurologists (56 percent), followed by internists (23 percent), and rheumatologists (13 percent), while the PPPs were nearly all neurologists (96 percent). One of the most interesting results was the number of patients seen during a physician's career: 1,964, comprising 1,557 for the HPs, and 407 for the PPPs. The responses describing care in terms of diagnosis and treatment generally complied with good practices as well as the recommendations and guidelines published in the field of MMN. CONCLUSION: MMN is a rare disorder whose prevalence in France, estimated by this survey, comes close to that published in the literature; diagnosis and treatment seem globally satisfactory.

[Multifocal motor neuropathies with conduction block: long-term follow-up of ten patients treated with IVIg]. / Neuropathie motrice multifocale avec blocs de conduction: suivi à long terme de 10 patients traités par IgIV.

UNLABELLED: Multifocal motor neuropathy (MMN) with conduction block responds to high-dose i.v. polyvalent immunoglobulins (IVIg) over the short term, but several studies have demonstrated a long-term increase in the degree of axonal degeneration and the number of conduction blocks, factors indicating a poor prognosis. The objective of this study was to evaluate the long-term effect of IVIg on clinical and neurophysiological parameters. METHODS: We reviewed the records of ten patients who had initially responded well to IVIg and received regular, long-term treatment. The parameters studied were muscular strength, motor function status (modified Rankin scale), as well as the number and progression of conduction blocks and the degree of axonal degeneration. Patients were followed up for a mean of 7.25 years (range, 3.5-12). They were all initially treated with 2 g IgIV/kg in 5 days every 4 weeks for 3 months. Maintenance therapy was administered every 4 weeks with dose adjustment to prevent muscular strength deterioration. RESULTS: We noted a significant and persistent improvement in muscular strength and in the Rankin motor function score over the long term, with no escape phenomenon. The number of conduction blocks and the degree of axonal degeneration decreased markedly. CONCLUSION: IVIg treatment remains effective over the long term in MMN. These conclusions differ from those of other authors in earlier studies, but our patients were treated with significantly higher doses of IVIg. These results have important implications for long-term treatment of patients with MMN.

Compression of lateral antebrachial cutaneous nerve in waitresses.

OBJECTIVE: In a retrospective survey of our electrophysiology laboratory, we encountered 3 cases of lateral antebrachial cutaneous nerve (LACN) compression in waitresses and propose direct compression of LACN by carrying heavy trays on the lateral bicipital tendon. LACN, a branch of musculocutaneous nerve, provides sensory innervations to lateral forearm. Causes of LACN involvement include venipuncture, elbow surgery, and trauma. METHODS: We encountered 6 cases of LACN neuropathy, 3 cases that were in slim waitresses carrying heavy trays. History and physical examination and forearm electrophysiologic studies (EPS) were performed in 3 waitresses at initial and follow-up visits. Antidromic stimulation of LACN was undertaken by Spindler and Felsenthals technique. Latency, amplitude, and conduction velocity were measured and compared with contralateral limb. RESULTS: All 3 patients were female waitresses aged 35-42 years, presented with few months of painful paresthesias of distal forearm, worse during working hours. Tinel sign at lateral cubital fossa was positive in all. EPS confirmed delayed latency, low amplitude, and slow conduction velocity of LACN on symptomatic side compared with normal. All 3 patients revealed electrophysiologic abnormalities consistent with LACN compression due to heavy trays in slim waitresses and considered occupational hazard. Treatment included nortriptyline or gabapentin and avoidance of heavy trays. Clinical and EPS findings improved over 8 months. CONCLUSIONS: We described 3 cases of LACN compression in waitresses from edges of heavy trays with typical symptoms and abnormal electrophysiological studies and improvement by avoiding compression and with analgesics. We propose inadequate fatty tissue in antecubital fossa contributed to compression of LACN.

Hereditary motor and sensory neuropathy with treatable extrapyramidal features.

Seven patients with a sensorimotor peripheral neuropathy followed years later by extrapyramidal manifestations are presented. This appears to be a separate genetic disorder(s) from that described as Machado-Joseph disease. In five subjects, other relatives had similar multisystem involvement. None was of known Portuguese ancestry. The extrapyramidal syndrome was mainly parkinsonian. Pain was prominent in five subjects. In all cases, low or moderate doses of levodopa/carbidopa ameliorated both the pain and the parkinsonian features. In one patient, a randomized placebo-controlled trial of levodopa/carbidopa was found to significantly improve most symptoms and neurologic dysfunction scores related to the extrapyramidal syndrome.

Corticosteroid- responsive asymmetric neuropathy with a myelin protein zero gene mutation.

A patient with hereditary neuropathy presented with asymmetric distal weakness. On nerve biopsy, there was demyelination and onion-bulb formation, and molecular analysis revealed that the patient was heterozygous for an MPZ mutation. The patient improved with corticosteroid treatment.

Leber's hereditary optic atrophy: an atypical case with response to hydroxycobalamine therapy.

A 15-year old Chinese boy was diagnosed to have Leber's hereditary optic neuropathy (LHOA), having manifested with typical findings of bilateral severe visual loss and telangiectasia at the optic disc. However, no family history was elicited and an interval of more than 5 years separated visual loss in the two eyes. The latter is an extremely uncommon finding. Visual improvement was rapid and marked after instituting intramuscular hydroxycobalamine 5 mg weekly. Bilateral improvement of Snellen acuity to 6/9 was achieved within 6 months. This is also unusual in that visual prognosis is generally poor in LHOA, although spontaneous remissions have occasionally been recorded. In addition, the eye with a longer history of poor vision responded to therapy first.

[Chronic peripheral neuropathies with corticosensitive heredodegenerative aspects: 2 cases]. / Neuropathies périphériques chroniques d'allure hérédodégénérative corticosensibles: deux cas.

Two cases of peripheral neuropathy beginning in childhood are reported. Both had features suggestive of HMSN with pes cavus and kyphoscoliosis. Familial history of HMSN type I was present in 9 members of the kinship in case 1. In case 2, a mild neuropathy without pes cavus was present in the father. Case 1 developed four relapses of ascending sensory-motor deficit with conduction blocks suggestive of a superimposed chronic inflammatory polyneuropathy (CIP) which improved under prednisone. In case 2, the course was progressive with a severe proximal and distal motor weakness and sensitive disturbances. CSF protein concentration was high. Nerve biopsy showed rare onion bulbs and intense demyelination. These results joint to the unspecificity of the father's neuropathy are consistent with a probable childhood. CIP which improved under prednisone. These two cases indicated that in some patients with unusual symptoms for HMSN, prednisone should be considered and that the physiopathology of these neuropathies is probably heterogeneous.

[A case of motor and sensory neuropathy with elevated serum lactate and pyruvate which responded to large dose of coenzyme Q10 therapy].

A 16-year-old high school male student was admitted to our hospital with complaints of difficulty in walking and muscle atrophy of the lower legs. He noticed his gait disturbance when he was about 12 years old and his symptoms had gradually increased. On examination, he was unable to walk on his heels and on his toes. He had mild pes cavus and marked muscle wastes of the lower legs. The weakness was limited to the feet, lower legs, and hands. Mild sensory losses were demonstrated inside of the feet. Autonomic dysfunction was not present. The deep tendon reflexes were diminished. Nerves were not enlarged or excessively firm. On laboratory examinations, pyruvate and lactate were elevated in both serum and cerebrospinal fluid. The serum level of coenzyme Q10 (CoQ10) was low (0.57 micrograms/ml). Nerve conduction velocities were normal or just below normal except sural nerves and amplitudes of M waves were decreased. The sural nerve finding revealed marked reduction in number of large myelinated fibers and no onion bulb formation. The teased myelinated fiber analysis suggested ongoing axonal degeneration. Electron microscopy showed no mitochondrial abnormalities in muscle and nerve. The therapeutic trial of large dose of CoQ10 (120 mg/day) was dramatically effective to muscle weakness and atrophy at about third week after therapy. His gait disturbance disappeared after about 16 months. These findings may indicate an alteration of mitochondrial function in this case.

TAR DNA-binding protein 43 pathology in a case clinically diagnosed with facial-onset sensory and motor neuronopathy syndrome: an autopsied case report and a review of the literature.

We report an autopsy case of a 48-year-old female clinically diagnosed with facial-onset sensory and motor neuronopathy (FOSMN) syndrome with TAR DNA-binding protein 43 (TDP-43) pathology. She developed paresthesia involving her whole face, right upper extremity and the right side of her upper trunk, followed by dysphagia, dysarthria, muscle atrophy and weakness with fasciculation in both upper extremities. Her symptoms showed a marked cranial and right-sided dominancy. She had anti-sulfoglucuronyl paragloboside (SGPG) IgG and anti-myelin-associated glycoprotein (MAG) IgG, and repeatedly showed limited response to immunotherapies. Her disease was essentially progressive, culminating in death due to respiratory failure three and a half years after onset. The autopsy revealed severe degeneration of the nuclei of the right trigeminal nerve and right facial nerve and widespread TDP-43-positive glial inclusions in the brainstem tegmentum. Neurons in the hypoglossal nerve nuclei were also shrunken and lost, with TDP-43-positive neuronal inclusions. Neuronal loss and gliosis in the anterior horn, predominantly in the cervical cord, were prominent with TDP-43-positive skein-like inclusions. Bilateral ventral roots were obviously atrophic. Spinal tract degeneration was also prominent in the ventral columns, essentially sparing the anterior corticospinal tracts at the cervical cord level. Additionally there was severe myelin pallor in the right spinal trigeminal tract and right fasciculus cuneatus of the cervical cord. The right spinal root ganglion showed numerous Nageotte's nodules and focal lymphocytic infiltration. The present case manifested FOSMN syndrome clinically, while the pathological findings suggested a motor neuron disease like TDP-43 proteinopathy and a possible involvement of immune-mediated neuropathy.