Tumor microenvironment (Part I): Tissue integrity in a rat model of peripheral neural cancer.

ICAM-1 (intercellular adhesion molecule 1) and MPZ (myelin protein zero) are thought to be a factor in the integrity of nerve tissues. In this report, we attempted to trace the expression of ICAM-1, responsible for cell-to-cell adhesion, and of MPZ, the main constituent of myelin sheath, in malignant tissues of the sciatic nerve (SN) in inbred male Copenhagen rats. AT-1 Cells (anaplastic tumor 1) were injected in the perineurial sheath, and tissues of the SNs were collected after 7, 14 and 21 days and compared to a sham-operated group of rats (n = 6 each). Tissues were sectioned and histologically examined, under light microscope, and stained for measuring the immunoreactivity of ICAM-1 and MPZ under laser scanning microscope. The cancer model was established, and the tumor growth was confirmed. ICAM-1 showed severe decreases, proportional to the growing anaplastic cells, as compared to the sham group. MPZ revealed, however, a distinct defensive pattern before substantially decreasing in a comparison with sham. These results support the notion that malignancies damage peripheral nerves and cause severe axonal injury and loss of neuronal integrity, and clearly define the role of ICAM-1 and MPZ in safeguarding the nerve tissues.

Myelin protein zero mutation-related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort.

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.

Transcriptomic alterations in the olfactory bulb induced by exposure to air pollution: Identification of potential biomarkers and insights into olfactory system function.

This study evaluated how exposure to the ubiquitous air pollution component, ultrafine particles (UFPs), alters the olfactory bulb (OB) transcriptome. The study utilised a whole-body inhalation chamber to simulate real-life conditions and focused on UFPs due to their high translocation and deposition ability in OBs as well as their prevalence in ambient air. Female C57BL/6J mice were exposed to clean air or to freshly generated combustion derived UFPs for two weeks, after which OBs were dissected and mRNA transcripts were investigated using RNA sequencing analysis. For the first time, transcriptomics was applied to determine changes in mRNA expression levels occurring after subacute exposure to UFPs in the OBs. We found forty-five newly described mRNAs to be involved in air pollution-induced responses, including genes involved in odorant binding, synaptic regulation, and myelination signalling pathway, providing new gene candidates for future research. This study provides new insights for the environmental science and neuroscience fields and nominates future research directions.

Hereditary neuropathy.

The hereditary neuropathies, collectively referred as Charcot-Marie-Tooth disease (CMT) and related disorders, are heterogeneous genetic peripheral nerve disorders that collectively comprise the commonest inherited neurological disease with an estimated prevalence of 1:2500 individuals. The field of hereditary neuropathies has made significant progress in recent years with respect to both gene discovery and treatment as a result of next-generation sequencing (NGS) approach. These investigations which have identified over 100 causative genes and new mutations have made the classification of CMT even more challenging. Despite so many different mutated genes, the majority of CMT forms share a similar clinical phenotype, and due to this phenotypic homogeneity, genetic testing in CMT is increasingly being performed through the use of NGS panels. The majority of patients still have a mutation in one the four most common genes (PMP22 duplication-CMT1A, MPZ-CMT1B, GJB1-CMTX1, and MFN2-CMT2A). This chapter focuses primarily on these four forms and their potential therapeutic approaches.

Transcriptome Profiling of miRNA-mRNA Interactions and Associated Mechanisms in Chemotherapy-Induced Neuropathic Pain.

Chemotherapy-induced neuropathic pain (CINP) is a dose-limiting adverse event affecting 40% of chemotherapy patients. MiRNA-mRNA interaction plays an important role in various processes. However, detailed profiling of miRNA-mRNA interactions in CINP remains unclear. Here, a rat-based CINP model was established using paclitaxel, followed by nociceptive behavioral tests related to mechanical allodynia, thermal hyperalgesia, and cold allodynia. The landscape of miRNA-mRNA interaction in the spinal dorsal horn was investigated through mRNA transcriptomics and small RNA sequencing. Under CINP condition, 86 differentially expressed mRNAs and 56 miRNAs were identified. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated the activity of Odorant binding, postsynaptic specialization and synaptic density, extracellular matrix, mitochondrial matrix, retrograde endocannabinoid signaling, and GTPase activity. Protein-protein interaction (PPI), networks of circRNA-miRNA-mRNA, lncRNA-miRNA-mRNA, and TF-genes were demonstrated. We next explored the immune infiltration microenvironment and found a higher infiltration abundance of Th17 and a lower abundance of MDSC in CINP. RT-qPCR and dual-luciferase assays were used to verify the sequencing results, and single-cell analysis based on the SekSeeq database was conducted. Combined with bioinformatics analyses and experimental validations, Mpz, a protein-coding gene specifically expressed in Schwann cells, was found critical in maintaining CINP under miRNA regulation. Therefore, these data highlight the expression patterns of miRNA-mRNA, and the underlying mechanism in the spinal dorsal horn under CINP condition, and Mpz may serve as a promising therapeutic target for patients with CINP.

Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy.

The implementation of NGS methods into clinical practice allowed researchers effectively to establish the molecular cause of a disorder in cases of a genetically heterogeneous pathology. In cases of several potentially causative variants, we need additional analysis that can help in choosing a proper causative variant. In the current study, we described a family case of hereditary motor and sensory neuropathy (HMSN) type 1 (Charcot-Marie-Tooth disease). DNA analysis revealed two variants in the SH3TC2 gene (c.279G>A and c.1177+5G>A), as well as a previously described variant c.449-9C>T in the MPZ gene, in a heterozygous state. This family segregation study was incomplete because of the proband's father's unavailability. To evaluate the variants' pathogenicity, minigene splicing assay was carried out. This study showed no effect of the MPZ variant on splicing, but the c.1177+5G>A variant in the SH3TC2 gene leads to the retention of 122 nucleotides from intron 10 in the RNA sequence, causing a frameshift and an occurrence of a premature stop codon (NP_078853.2:p.Ala393GlyfsTer2).

Intravenous immunoglobulin preparations attenuate lysolecithin-induced peripheral demyelination in mice and comprise anti-large myelin protein zero antibody.

Intravenous immunoglobulin (IVIg) has been used to treat inflammatory demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, and multifocal motor neuropathy. Despite studies demonstrating the clinical effectiveness of IVIg, the mechanisms underlying its effects remain to be elucidated in detail. Herein, we examined the effects of IVIg on lysolecithin-induced demyelination of the sciatic nerve in a mouse model. Mice -administered with IVIg 1 and 3 days post-injection (dpi) of lysolecithin -exhibited a significantly decreased demyelination area at 7 dpi. Immunoblotting analysis using two different preparations revealed that IVIg reacted with a 36-kDa membrane glycoprotein in the sciatic nerve. Subsequent analyses of peptide absorption identified the protein as a myelin protein in the peripheral nervous system (PNS) known as large myelin protein zero (L-MPZ). Moreover, injected IVIg penetrated the demyelinating lesion, leading to deposition on L-MPZ in the myelin debris. These results indicate that IVIg may modulate PNS demyelination, possibly by binding to L-MPZ on myelin debris.

Genotype-phenotype characteristics and baseline natural history of Chinese myelin protein zero gene related neuropathy patients.

BACKGROUND AND PURPOSE: The aim was to characterize the phenotypic and genotypic features of myelin protein zero (MPZ) related neuropathy and provide baseline data for longitudinal natural history studies or drug clinical trials. METHOD: Clinical, neurophysiological and genetic data of 37 neuropathy patients with MPZ mutations were retrospectively collected. RESULTS: Nineteen different MPZ mutations in 23 unrelated neuropathy families were detected, and the frequency of MPZ mutations was 5.84% in total. Mutations c.103_104InsTGGTTTACACCG, c.513dupG, c.521_557del and c.696_699delCAGT had not been reported previously. Hot spot mutation p.Thr124Met was detected in four unrelated families, and seven patients carried de novo mutations. The onset age indicated a bimodal distribution: prominent clustering in the first and fourth decades. The infantile-onset group included 12 families, the childhood-onset group consisted of two families and the adult-onset group included nine families. The Charcot-Marie-Tooth Disease Neuropathy Score ranged from 3 to 25 with a mean value of 15.85 ± 5.88. Mutations that changed the cysteine residue (p.Arg98Cys, p.Cys127Trp, p.Ser140Cys and p.Cys127Arg) in the extracellular region were more likely to cause severe early-onset Charcot-Marie-Tooth disease type 1B (CMT1B) or Dejerine-Sottas syndrome. Nonsense-mediated mRNA decay mutations p.Asp35delInsVVYTD, p.Leu174Argfs*66 and p.Leu172Alafs*63 were related to severe infantile-onset CMT1B or Dejerine-Sottas syndrome; however, mutation p.Val232Valfs*19 was associated with a relatively milder childhood-onset CMT1 phenotype. CONCLUSION: Four novel MPZ mutations are reported that expand the genetic spectrum. De novo mutations accounted for 30.4% and were most related to a severe infantile-onset phenotype. Genetic and clinical data from this cohort will provide the baseline data necessary for clinical trials and natural history studies.

Clinical identification of expressed proteins in adrenal medullary hyperplasia detected with hypertension.

Background: Hypertension remains a challenging public health problem worldwide, and adrenal gland-related diseases are one class of the major causes for secondary hypertension. Among them, one relatively rare pattern is adrenal hyperplastic hypertension caused by adrenal medullary hyperplasia (AMH), leading to excessive secretion of autonomic catecholamine. Given that the pathological changes of adrenal medulla are not well correlated to the onset and even severity of secondary hypertension, the molecular basis why some AMH patients are accompanied with hypertension remains unclear and is worth exploring. Aims: For this reason, this study aims at investigating differentially expressed proteins in clinical AMH tissue, with special focus on the potential contribution of these differentially expressed proteins to AMH development, in order to have a better understanding of mechanisms how AMH leads to secondary hypertension to some extent. Methods and results: To this end, AMH specimens were successfully obtained and verified through computed tomography (CT) and haematoxylin-eosin (HE) staining. Proteomic analyses of AMH and control tissues revealed 782 kinds of differentially expressed proteins. Compared with the control tissue, there were 357 types of upregulated proteins and 425 types of downregulated proteins detected in AMH tissue. Of interest, these differentially expressed proteins were significantly enriched in 60 gene ontology terms (P < 0.05), including 28 biological process terms, 14 molecular function terms, and 18 cellular component terms. Pathway analysis further indicated that 306 proteins exert their functions in at least one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Western blotting showed enhanced expression of phenylethanolamine N- methyltransferase (PNMT), myelin protein zero (MPZ), and Ras-related protein Rab-3C (RAB3C), and reduced expression of cluster of differentiation 36 (CD36) observed in AMH tissue in comparison with controls. Conclusions: Clinical AMH specimens display a different proteomic profile compared to control tissue. Of note, PNMT, MPZ, RAB3C, and CD36 are found to differentially expressed and can be potential targets for AMH, providing a theoretical basis for mechanistic exploration of AMH along with hypertension.

Effect of sesamol on damaged peripheral nerves: Evaluation of functional, histological, molecular, and oxidative stress parameters.

Objective: Peripheral nerve injury is a clinical problem that may cause sensory and motor inabilities. Sesamol is an antioxidant that can help in repairing damaged central nervous system (CNS) and other organs. The present study aimed to investigate whether the antioxidant effects of sesamol could improve the function, structure, and myelination in rats' damaged peripheral nervous system (PNS). Materials and Methods: In this study, 28 adult male Wistar rats were randomly divided into four groups. In the sham group, the sciatic nerve was exposed and restored to its place without inducing crush injury. The control received DMSO (solvent) and the two experimental groups received 50 or 100 mg/kg sesamol intraperitoneally for 28 days after sciatic nerve crush injury, respectively. Next, sciatic function index (SFI), superoxide dismutase (SOD) activity, malondialdehyde (MDA) level, expression of nerve growth factor (NGF) and myelin protein zero (MPZ) proteins in the sciatic nerve, and histological indices of the sciatic nerve and gastrocnemius muscle were evaluated. Results: The results showed that sesamol reduced oxidative stress parameters, increased expression of NGF and MPZ proteins, and improved function and regeneration of the damaged sciatic nerve. Furthermore, a significant regeneration was observed in the gastrocnemius muscle after treatment with sesamol. Although administration of both doses of sesamol was useful, the 100 mg/kg dose was more effective than the 50 mg/kg one. Conclusion: The results suggest that sesamol may be effective in improving damaged peripheral nerves in rats by reducing oxidative stress and increasing the expression of NGF and MPZ proteins.

Novel mutation in the MPZ gene causes early-onset but slow-progressive Charcot-Marie-Tooth disease in a Russian family: a case report.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of peripheral neuropathies most of which are associated with mutations in four genes including peripheral myelin protein-22 (PMP22), myelin protein zero (MPZ), gap junction protein beta1 (GJB1) and mitofusin2 (MFN2). This current case report describes the clinical and genetic characteristics of a 6-year-old male proband. A physical examination revealed muscular hypotonia. He started walking on his own at 18 months. A nerve conduction study with needle electromyography revealed conduction block. A novel MPZ mutation (c.398C > T, p.Pro133Leu) was revealed in the proband. This mutation was also found in the 32-year-old father of the proband. The father had had deformity of the feet and distal muscle weakness since childhood. The novel p.Pro133Leu pathogenic mutation was responsible for early onset but slowly progressive CMT1B. We assume that this site is an intolerant to change region in the MPZ gene. This variant in the MPZ gene is an important contributor to hereditary neuropathy with reduced nerve conduction velocity in the Russian population. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of CMT associated with a mutation in the MPZ gene.

A Rare Phenotype of Uncommon Charcot-Marie-Tooth Genotypes Complicated With Inflammation Evaluated by Genetics and Magnetic Resonance Neurography.

The pathogenesis of Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is associated with more than 60 nuclear genes. We reported a rare phenotype of the uncommon CMT genotype complicated with neuroinflammation, that is, an MPZ mutation, NC_000001.11 (NM_000530.6): c.308G > C detected by next-generation sequencing. Moreover, we present a case of the CMT type 1B, with atypical presentation as two patterns of hypertrophy in the brachial and lumbosacral plexus, as well as enhancement in the cauda equina and nerve roots on multimodal magnetic resonance neurography (MRN). MRN assessment facilitated the identification of coexisting neuroinflammation and provided more evidence, especially for patients with atypical symptoms in hereditary sensory and motor neuropathy, who could benefit from immunotherapy.

Influence of novel readthrough agents on myelin protein zero translation in the peripheral nervous system.

Translational readthrough-inducing agents have been developed for the treatment of nonsense mutations in hereditary diseases. The clinical effectiveness of readthrough agents has been reported, although newly developed agents are still desired because of their toxicities or limited clinical effectiveness. Recently, novel negamycin-derived readthrough agents without antimicrobial activity have been developed. Our aim was to evaluate the activities of these readthrough agents by monitoring the production of large myelin protein zero (L-MPZ), the programmed translational readthrough isoform of myelin protein zero (P0, MPZ) mRNA, and to clarify the influence of these agents on the sciatic nerve in vivo. First, we examined the readthrough activities of novel negamycin-derived agents using cell-free and cell culture systems using plasmids encoding human MPZ (hP0) cDNA. Three of the negamycin derivatives, TCP-112, TCP-169, and TCP-1109, suppressed the canonical stop codon to induce readthrough. Direct injection of TCP-1109, which showed higher readthrough activity for Mpz in mouse sciatic nerves, exhibited a 1.3-fold increase in the L-MPZ/P0 ratio compared to that with the vehicle control on western blotting. The nerve conduction velocity and beam walk test showed abnormalities in the classical readthrough agent G418-treated group, but not in the TCP-1109-treated group. Immunofluorescence analysis showed that TCP-1109 caused less damage to the sciatic nerve than G418. In the semi-thin sections, a lower g-ratio and more tomacula-like structures were observed in TCP-1109-treated nerves. Thus, the present results indicate that negamycin-derived readthrough agents enhance programmed translational readthrough, and the management of readthrough activities using canonical stop codons may be important.

Identification and characterization of Crumbs polarity complex proteins in Caenorhabditis elegans.

Crumbs proteins are evolutionarily conserved transmembrane proteins with essential roles in promoting the formation of the apical domain in epithelial cells. The short intracellular tail of Crumbs proteins are known to interact with several proteins, including the scaffolding protein PALS1 (protein associated with LIN7, Stardust in Drosophila). PALS1 in turn binds to a second scaffolding protein PATJ (PALS1-associated tight junction protein) to form the core Crumbs/PALS1/PATJ complex. While essential roles in epithelial organization have been shown for Crumbs proteins in Drosophila and mammalian systems, the three Caenorhabditis elegans crumbs genes are dispensable for epithelial polarization and development. Here, we investigated the presence and function of PALS1 and PATJ orthologs in C. elegans. We identified MAGU-2 as the C. elegans ortholog of PALS1 and show that MAGU-2 interacts with all three Crumbs proteins and localizes to the apical membrane domain of intestinal epithelial cells in a Crumbs-dependent fashion. Similar to crumbs mutants, magu-2 deletion showed no epithelial polarity defects. We also identified MPZ-1 as a candidate ortholog of PATJ based on the physical interaction with MAGU-2 and sequence similarity with PATJ proteins. However, MPZ-1 is not broadly expressed in epithelial tissues and, therefore, not likely a core component of the C. elegans Crumbs complex. Finally, we show overexpression of the Crumbs proteins EAT-20 or CRB-3 can lead to apical membrane expansion in the intestine. Our results shed light on the composition of the C. elegans Crumbs complex and indicate that the role of Crumbs proteins in promoting apical domain formation is conserved.

MPZ gene variant site in Chinese patients with Charcot-Marie-Tooth disease.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a hereditary monogenic peripheral nerve disease. Variants in the gene encoding myelin protein zero (MPZ) lead to CMT, and different variants have different clinical phenotypes. A variant site, namely, c.389A > G (p.Lys130Arg), in the MPZ gene has been found in Chinese people. The pathogenicity of this variant has been clarified through pedigrees, and peripheral blood-related functional studies have been conducted. METHOD: Whole-exome sequencing and Sanger sequencing were used to detect the c.389A > G (p.Lys130Arg) variant in the MPZ gene in family members of the proband. Physical examination was performed in the case group to assess the clinical characteristics of MPZ site variants. The expression of MPZ and phosphorylated MPZ in the blood of 12 cases and 12 randomly selected controls was compared by RT-qPCR, Western blotting, and ELISA. RESULTS: The proband and 12 of her family members presented the AG genotype with different clinical manifestations. The expression of MPZ mRNA in the case group was increased compared with that in the control group, and the levels of MPZ and phosphorylated MPZ in peripheral blood were higher than those in normal controls. CONCLUSION: The heterozygous genotype of the c.389A > G (p.Lys130Arg) variant in the MPZ gene mediated the increase in MPZ and phosphorylated MPZ levels in peripheral blood and was found to be involved with CMT.

Thr124Met myelin protein zero mutation mimicking motor neuron disease.

Mutations in myelin protein zero (MPZ) are associated with heterogeneous manifestations. In this study, we report clinical, electrophysiological, pathological, and muscle MRI findings from two relatives with MPZ Thr124Met variants, disclosing different phenotypes. The proband was a 73-year-old female with a 12-year-story of atrophy, weakness, and fasciculations in her proximal and distal lower limbs. EMG examination showed neurogenic signs with active denervation together with reduced sensory action potentials, without sensory symptoms. The initial diagnosis was of a slowly progressive lower motor neuron disease (MND) with subclinical sensory axonal neuropathy. Two years later, the observation of her 60-year-old nephew, who had a distal sensory-motor neuropathy, prompted the analysis of inherited neuropathies-related genes and revealed a MPZ Thr124Met mutation in both cases. Our findings expand the clinical spectrum of MPZ-related neuropathy and highlight that Thr124Met mutation may cause a syndrome mimicking MND. The challenging issue to detect sensory features in the diagnostic MND work up is discussed.

Proteome Profile of Myelin in the Zebrafish Brain.

The velocity of nerve conduction along vertebrate axons depends on their ensheathment with myelin. Myelin membranes comprise specialized proteins well characterized in mice. Much less is known about the protein composition of myelin in non-mammalian species. Here, we assess the proteome of myelin biochemically purified from the brains of adult zebrafish (Danio rerio), considering its increasing popularity as model organism for myelin biology. Combining gel-based and gel-free proteomic approaches, we identified > 1,000 proteins in purified zebrafish myelin, including all known constituents. By mass spectrometric quantification, the predominant Ig-CAM myelin protein zero (MPZ/P0), myelin basic protein (MBP), and the short-chain dehydrogenase 36K constitute 12%, 8%, and 6% of the total myelin protein, respectively. Comparison with previously established mRNA-abundance profiles shows that expression of many myelin-related transcripts coincides with the maturation of zebrafish oligodendrocytes. Zebrafish myelin comprises several proteins that are not present in mice, including 36K, CLDNK, and ZWI. However, a surprisingly large number of ortholog proteins is present in myelin of both species, indicating partial evolutionary preservation of its constituents. Yet, the relative abundance of CNS myelin proteins can differ markedly as exemplified by the complement inhibitor CD59 that constitutes 5% of the total zebrafish myelin protein but is a low-abundant myelin component in mice. Using novel transgenic reporter constructs and cryo-immuno electron microscopy, we confirm the incorporation of CD59 into myelin sheaths. These data provide the first proteome resource of zebrafish CNS myelin and demonstrate both similarities and heterogeneity of myelin composition between teleost fish and rodents.

Genetic and clinical spectrums in Korean Charcot-Marie-Tooth disease patients with myelin protein zero mutations.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common disorder of inherited peripheral neuropathies characterized by distal muscle weakness and sensory loss. CMT is usually classified into three types, demyelinating, axonal, and intermediate neuropathies. Mutations in myelin protein zero (MPZ) gene which encodes a transmembrane protein of the Schwann cells as a major component of peripheral myelin have been reported to cause various type of CMT. METHODS: This study screened MPZ mutations in Korean CMT patients (1,121 families) by whole exome sequencing and targeted sequencing. RESULTS: We identified 22 pathogenic or likely pathogenic MPZ mutations in 36 families as the underlying cause of the CMT1B, CMTDID, or CMT2I subtypes. Among them, five mutations were novel. The frequency of CMT patients with the MPZ mutations was similar or slightly lower compared to other ethnic groups. CONCLUSIONS: We showed that the median onset ages and clinical phenotypes varied by subtypes: the most severe in the CMT1B group, and the mildest in the CMT2I group. This study also observed a clear correlation that earlier onsets cause more severe symptoms. We believe that this study will provide useful reference data for genetic and clinical information on CMT patients with MPZ mutations in Korea.

CIDP, CMT1B, or CMT1B plus CIDP?

Charcot-Marie-Tooth disease type 1 (CMT1) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have distinct clinical and neurophysiological features that result from dysmyelination in CMT1 and macrophage-mediated segmental demyelination in CIDP. CMT1 may occur in genetically isolated cases with atypical presentations that converge phenotypically with CIDP; in rare cases, however, CMT1 may be complicated by superimposed CIDP. We report the case of a patient harboring a de novo heterozygous null mutation of the myelin protein zero (MPZ) gene and affected by subclinical CMT1B who became symptomatic due to superimposed CIDP. Peripheral nerve high-resolution ultrasound (HRUS) aided in establishing the coexistence of CMT1B and CIDP; the diagnosis was further supported by favorable clinical, neurophysiological, and ultrasound responses to immunoglobulin therapy.

New evidence for secondary axonal degeneration in demyelinating neuropathies.

Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. The intermediate steps between the loss of these functions and the initiation of axon degeneration are unknown but the importance of these processes provides insightful clues. Prevalent demyelinating diseases of the PNS include the inherited neuropathies Charcot-Marie-Tooth Disease, Type 1 (CMT1) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and the inflammatory diseases Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Secondary axon degeneration is a common feature of demyelinating neuropathies and this process is often correlated with clinical deficits and long-lasting disability in patients. There is abundant electrophysiological and histological evidence for secondary axon degeneration in patients and rodent models of PNS demyelinating diseases. Fully understanding the involvement of secondary axon degeneration in these diseases is essential for expanding our knowledge of disease pathogenesis and prognosis, which will be essential for developing novel therapeutic strategies.