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Objective Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) is caused by a heterozygous deletion of peripheral myelin protein‐22 (PMP22) gene resulting in focal sensorimotor deficits. Our lab has identified a disruption of myelin junctions in excessively permeable myelin that impairs action potential propagation. This mechanism is expected to cause fatigue in patients with HNPP. Therefore, the objective was to characterize fatigue in patients with HNPP and determine the relationship of fatigue to nerve pathology, disability, and quality of life. Methods Nine females with HNPP participated in a single visit that included genotyping, nerve conduction studies, neurological exam, quantitative magnetic resonance imaging, and a physical therapy exam incorporating upper and lower extremity function and survey measures of fatigue. This visit was followed by 2 weeks of ecological momentary assessment (wrist‐worn device) that captured fatigue ratings five times per day. Results Participants demonstrated mild neurological impairment (CMTNS: 5.7 ± 2.8), yet reported high fatigue levels (average fatigue intensity over 2 weeks: 5.9 out of 10). Higher fatigue levels were associated with poorer quality of life and more pain. Higher fatigue was associated with significantly greater distal nerve proton density changes on peripheral nerve MRI, which is in line with hyper‐permeable myelin in HNPP. Interpretation Fatigue is common and severe among patients with HNPP whose disabilities are minimal by conventional outcome measures. Therapeutic interventions targeting fatigue have the potential to improve quality of life and may serve as a robust outcome measure to show longitudinal changes for patients with HNPP.

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in individual nerves starting in adolescence or young adulthood, focal conduction abnormalities at entrapment sites on nerve conduction studies, and sausage-like swellings (tomacula) of the myelin sheaths by nerve biopsy. It is characterized genetically by the deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein-22 gene in the overwhelming majority of cases. HNPP may be frequently underdiagnosed or misdiagnosed owing to the heterogeneity of clinical and electrophysiological appearance. The main objective of this review is to describe clinical manifestations, paraclinical features such as electrodiagnostic, pathological, radiological and genetics findings, and possible treatments.

According to the definition of neurovascular compression syndromes (NVCS), a vascular structure in direct contact with a cranial nerve is causing mechanical irritation of the neural tissue producing correlating symptoms. Vestibular paroxysmia is an example of a neurovascular compression which is caused by neurovascular contact between the eighth cranial nerve and a vessel. It is crucial to understand the unique anatomy of the vestibulocochlear nerve in order to study the syndrome which is the result of its compression. More specifically, the long transitional zone between central and peripheral myelin plays a central role in clinical significance, as the transitional zone is the structure most prone to mechanical injury. Imaging techniques of the eighth cranial nerve and the surrounding structures are substantial for the demonstration of clinically significant cases and potential surgical decompression. The goal of the current review is to present and study the existing literature on vestibular paroxysmia and to search for the most appropriate imaging technique for the syndrome. An extensive literature search of PubMed database was performed, and the studies were ranked based on evidence-based criteria, followed by descriptive statistics of the data. The present analysis indicates that 3D CISS MRI sequence is superior to any other sequence, in the most studies reviewed, regarding the imaging of neurovascular compression of the eighth cranial nerve.

Introduction Many researchers have assumed that neurovascular compression of the facial nerve at the site covered by central myelin sheath causes hemifacial spasm. However, some cases do not correspond to this hypothesis. The aim of this study was to clarify the myelin histology in the facial nerve. Materials and methods Histological analyses were conducted on 134 facial nerves from 67 cadavers. Three dimensions were measured in these sections: the length from the upper border of the medullopontine sulcus to the boundary between the central and peripheral myelin sheath along the anterior side; the length from the detachment point of the brain stem to the boundary along the posterior side; and the length of the transitional zone (TZ), known as the Obersteiner-Redlich zone. Results Of the 134 facial nerves, 41 were available for study. The length of the central myelin segment ranged from 4.62 to 12.6 mm (mean 8.06 mm; median 7.98 mm) along the anterior side and from 0.00 to 4.58 mm (mean 1.68 mm; median 1.42 mm) along the posterior side of the facial nerve, and the length of the TZ ranged from 0.00 to 2.76 mm (mean 1.51 mm; median 1.42 mm). Conclusions In this study, the length of the central myelin segment in the facial nerve was found to be longer than that previously reported.

In the peripheral nervous system (PNS) myelinating Schwann cells synthesize large amounts of myelin protein zero (P0) glycoprotein, an abundant component of peripheral nerve myelin. In humans, mutations in P0 cause the demyelinating Charcot-Marie-Tooth 1B (CMT1B) neuropathy, one of the most diffused genetic disorders of the PNS. We previously showed that several mutations, such as the deletion of serine 63 (P0-S63del), result in misfolding and accumulation of P0 in the endoplasmic reticulum (ER), with activation of the unfolded protein response (UPR). In addition, we observed that S63del mouse nerves display the upregulation of many ER-associated degradation (ERAD) genes, suggesting a possible involvement of this pathway in the clearance of the mutant P0. In ERAD in fact, misfolded proteins are dislocated from the ER and targeted for proteasomal degradation. Taking advantage of inducible cells that express the ER retained P0, here we show that the P0-S63del glycoprotein is degraded via ERAD. Moreover, we provide strong evidence that the Schwann cell-specific ablation of the ERAD factor Derlin-2 in S63del nerves exacerbates both the myelin defects and the UPR in vivo, unveiling a protective role for ERAD in CMT1B neuropathy. We also found that lack of Derlin-2 affects adult myelin maintenance in normal nerves, without compromising their development, pinpointing ERAD as a previously unrecognized player in preserving Schwann cells homeostasis in adulthood. Finally, we provide evidence that treatment of S63del peripheral nerve cultures with N-Acetyl-D-Glucosamine (GlcNAc), known to enhance protein quality control pathways in C.elegans, ameliorates S63del nerve myelination ex vivo. Overall, our study suggests that potentiating adaptive ER quality control pathways might represent an appealing strategy to treat both conformational and age-related PNS disorders., PLoS Genetics, 15 (4), ISSN:1553-7390, ISSN:1553-7404

Neddylation is a reversible post-translational modification in which a small ubiquitin-like molecule called NEDD8 covalently binds to substrate proteins. Although a recent study suggests that neddylation is essential for formation and maintenance of dendritic spines in the brain, the role of this protein modification in the peripheral nerves is wholly unknown. In this study, we demonstrate that neddylation-related molecules, NEDD8 and DCUN1D2 (defective in cullin neddylation 1, domain containing 2), were concentrated at the paranode of peripheral myelin, in addition to the myelinated and unmyelinated Schwann cell bodies. These proteins were localized mainly within larger fibers, but not in fibers with small diameters. Developmental analyses showed that these molecules first appeared at the paranode during later stages of myelination, and this characteristic distribution disappeared in sulfatide-deficient mice in which paranodal axo-glial junctions were disrupted. These results suggest that the myelin paranode may be one of the regions where neddylation occurs within the peripheral nerves.

Several studies have suggested that vascular compression of more distal portions of the trigeminal nerve (Vth cranial nerve: VN) may cause trigeminal neuralgia (TN). However, neurosurgeons performing microvascular decompression intraoperatively cannot identify which type of myelin is being compressed by blood vessels. The aim of this study was to clarify the histological anatomy of central and peripheral myelin in the human VN. Histological analyses were conducted using photomicrographs from 134 cisternal segments of the VN from the brains of 67 cadavers. The three dimensions of the VN were measured in these sections: distance from the point at which the lateral-most pontine VN merges with the boundary between central and peripheral myelin (line-a), distance along the medial aspect (line-b), and the length of the transitional zone (TZ), known as the Obersteiner-Redlich zone. Twenty-nine of 134 VNs were available for study. The length of central myelin ranged from 0.69 to 8.66 mm (mean, 3.56 mm; median, 3.10 mm) along the lateral aspect and from 0.36 to 5 mm (mean, 1.81 mm; median, 1.40 mm) along the medial aspect of the VN. The length of the TZ ranged from 0.31 to 3.37 mm (mean, 1.75 mm; median, 1.63 mm). We report here, for the first time, that some individuals had much longer spans of central myelin than those reported previously. Some cases of TN may thus be caused by vascular compression of VN peripheral myelin, especially in cases where central myelin is extended to an unprecedented degree. Clin. Anat. 32:541-545, 2019. © 2019 Wiley Periodicals, Inc.

Sulfatides have immunomodulatory functions, and play protective roles in multiple autoimmune diseases. In the present study, we showed that sulfatides ameliorated experimental autoimmune neuritis in Lewis rats induced with bovine peripheral myelin, which was associated with decreased proportions of Th1 and Th17 cells. Furthermore, compared control group, cells from sulfatide-treated rats exhibited lower potential in proliferation and IL-17 secretion in the presence of BPM or ConA in vitro. Moreover, sulfatides also reduced the proportions of NK and NKT cells. In summary, our study indicated that sulfatides might become a new therapeutic agent in Guillain-Barre syndrome in the future.

Transmission electron microscopy (TEM) can provide excellent high-resolution images of cellular structures. A critical step with this technique is sample preparation. Here we describe our protocol for the preparation of semithin and ultrathin sections of mouse peripheral nerves in order to visualize the structure and pathological features of peripheral myelin with TEM.

Peripheral neuropathy in patients with merosin-negative congenital muscular dystrophy (MN-CMD) has been sporadically investigated and has been considered to be motor and demyelinating in nature on the basis of nerve conduction studies. We performed neurophysiologic studies in 12 children with MN-CMD to establish the spectrum and evolution of peripheral nervous system involvement. In our patients, nerve conduction studies for both motor and sensory nerves were near normal in the children younger than six months and abnormal in the older children. The older children had the relatively slowest nerve conduction velocities suggesting a progressive, age-related dysmyelinating neuropathy. We hypothesize that the findings are due to a myelination arrest as a result of insufficient synthesis and maintenance of the peripheral myelin sheath. (J Pediatr Neurol 2004; 2(4): 213–218).

Hereditary sensorimotor neuropathies form a heterogeneous group of genetically determined diseases, of which Charcot-Marie-Tooth (CMT) disease is the most common. In order to establish relations between genotype and the expression of peripheral myelin proteins, we carried out a quantitative study by ultrastructural immunocytochemistry of several myelin proteins (PMP22, P0, MBP) on sural nerve biopsy samples from 12 unrelated CMT patients. The diagnosis of CMT was based on the clinical, electrophysiological, and histological findings along with those of molecular biological studies. CMT X diagnoses were not included in this study. The expression of myelin proteins was well correlated with the molecular biological findings in these patients. The results also provided evidence for interference between different myelin proteins. Our findings are in line with the results from animal studies (trembler and knock-out mice), which may provide insights into the pathogenesis of these human conditions.

Besides its involvement in peripheral myelin maintenance, the physiologic function of the ubiquitously expressed cellular prion protein PrPC remains enigmatic. Phenotypic studies on previously avai...

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype-phenotype correlations in Charcot-Marie-Tooth diseases.

The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability.

[Purpose] The purpose of this study was to analyze and compare electrophysiological characteristics observed in nerve conduction studies (NCS) of chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth disease type 1 (CMT 1). [Subjects] A differential diagnosis of acquired and congenital demyelinating neuropathies was based on a study of 35 patients with NCS-confirmed CIDP and 30 patients with CMT 1 genetically proven by peripheral myelin protein-22 (PMP-22) gene analysis, pulsed-field gel electrophoresis (PFGE), and Southern blot analysis. [Methods] We analyzed values collected in motor nerve conduction studies. We conducted dispersion analysis of the amplitudes of the compound muscle action potential (CMAP) of various nerve types and correlation coefficient analysis of the motor nerve conduction velocity (MNCV). [Results] We found that CIDP and CMT 1 were clearly attributable to severe polyneuropathy. In dispersion analysis, CIDP showed greater differences in proximal-to-distal amplitude ratios. Moreover, CMT 1 showed relatively high correlations compared to CIDP based on correlation coefficient analysis of MNCV. [Conclusion] The results of this study suggest that CIDP showed greater asymmetry than CMT 1 in MNCV and CMAP amplitudes.

It has been postulated that the emergence of vertebrates was made possible by the acquisition of neural crest cells, which then led to the development of evolutionarily advantageous complex head structures (Gans and Northcutt, 1983). In this regard the contribution of one important neural crest derivative-the peripheral myelin sheath-to the success of the vertebrates has to be pointed out. Without this structure, the vertebrates, as we know them, simply could not exist. After briefly reviewing the major functions of the myelin sheath we will ask and provide tentative answers to the following three questions: when during evolution has myelin first appeared? Where has myelin initially appeared: in the CNS or in the PNS? Was it necessary to acquire a new cell type to form a myelin sheath? Careful examination of fossils lead us to conclude that myelin was acquired 425 MY ago by placoderms, the earliest hinge-jaw fishes. I argue that the acquisition of myelin during evolution has been a necessary prerequisite to permit gigantism of gnathostome species, including the sauropods. I propose that this acquisition occurred simultaneously in the PNS and CNS and that myelin forming cells are the descendants of ensheathing glia, already present in invertebrates, that have adapted their potential to synthesize large amount of membrane in response to axonal requirements. This article is part of a Special Issue entitled SI: Myelin Evolution.

The integrity of peripheral nerves relies on communication between axons and Schwann cells. The axonal signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown. Here we show that ablation of the prion protein PrP(C) triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. Ablation of the neighboring Prnd locus, or inbreeding to four distinct mouse strains, did not modulate the CDP. CDP was triggered by depletion of PrP(C) specifically in neurons, but not in Schwann cells, and was suppressed by PrP(C) expression restricted to neurons but not to Schwann cells. CDP was prevented by PrP(C) variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrP(C) lacking its glycolipid membrane anchor. These results indicate that neuronal expression and regulated proteolysis of PrP(C) are essential for myelin maintenance.

Charcot-Marie-Tooth disease (CMT) and related inherited peripheral neuropathies, including Dejerine-Sottas syndrome, congenital hypomyelination, and hereditary neuropathy with liability to pressure palsies (HNPP), are caused by mutations in three myelin genes: PMP22, MPZ and Cx32 (GJB1). The most common mutations are the 1.5 Mb CMT1A tandem duplication on chromosome 17p11.2-p12 in CMT1 patients and the reciprocal 1.5 Mb deletion in HNPP patients. We performed a mutation screening in 174 unrelated CMT patients and three HNPP families of Russian origin. The unrelated CMT patients included 108 clinically and electrophysiologically diagnosed CMT1 cases, 32 CMT2 cases, and 34 cases with unspecified CMT. Fifty-nine CMT1A duplications were found, of which 58 belonged to the CMT1 patient group. We found twelve distinct mutations in Cx32, six mutations in MPZ, and two mutations in PMP22. Of these respectively, eight, five, and two lead to a CMT1 phenotype. Eight mutations (Cx32: Ile20Asn/Gly21Ser, Met34Lys, Leu90Val, and Phe193Leu; MPZ: Asp134Gly, Lys138Asn, and Thr139Asn; PMP22: ValSer25-26del) were not reported previously. Phenotype-genotype correlations were based on nerve conduction velocity studies and mutation type.

Morphological modifications were investigated in the peripheral nerve of three unrelated patients with CMT1B. In two patients, molecular genetic analysis showed an Arg98His mutation in the extracellular domain of MPZ, associated with irregularly uncompacted lamellae. This observation confirms previous studies of a well-defined correlation between mutations and morphological phenotypes. In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations associated with this morphological phenotype.

Plasma samples from 35 individuals with HIV infection but without clinical peripheral neuropathy were screened by ELISA for IgM and IgG antibodies against peripheral myelin. Eighteen of the 35 samples (51%) showed IgM reactivity and 11 (31%) showed IgG reactivity. By comparison, none of 48 samples from healthy blood donors showed IgM or IgG reactivity. Epitopes reacting with these antibodies were identified by TLC immunostaining as sulphatide (GalS) and the gangliosides GM1, GD1a and GD1b. Plasma samples from four people with HIV infection and neuropathy (HIV+PN), six HIV-seronegative individuals with IgM paraproteinaemic demyelinating neuropathy (IgMPDN) and 12 HIV-seronegative individuals with a variety of other neurological disorders (HIV-OND) were also investigated. Two of the four HIV+PN samples showed IgM reactivity with GalS; and two showed IgG reactivity against GalS. Of the six IgMPDN samples, three showed IgM reactivity with GalS. These data indicate that antibodies against peripheral myelin glycolipids, in particular GalS, occur more frequently in HIV infection than in HIV-seronegative individuals with and without neurological disease, and may contribute to subclinical neuropathy in HIV infection.

It is widely thought that mammalian Schwann cells do not express P 0 , the major glycoprotein in peripheral myelin, unless they are induced to do so by axonal signals that can be mimicked by agents that trigger cAMP signaling pathways. In contrast, we find that cultured Schwann cells make large amounts of P 0 without the addition of any axonal-like signal, provided they have not been exposed to serum during the culture process. We also report that glial growth factor/neuregulin inhibits this constitutive P 0 expression. Myelin basic protein is regulated in a similar way. We suggest that expression of P 0 by Schwann cells before the onset of myelination may be prevented by inhibitory signals within the nerve, rather than by the absence of a positive signal from axons.

We report the first case of a missense mutation in MPZ causing a gain of glycosylation in myelin protein zero, the main protein of peripheral nervous system myelin. The patient was affected by a severe demyelinating neuropathy caused by a missense mutation, D32N, that created a new glycosylation sequence. We confirmed that the mutant protein is hyperglycosylated, is partially retained into the Golgi apparatus in vitro, and disrupts intercellular adhesion. By sequential experiments, we demonstrated that hyperglycosylation is the main mechanism of this mutation. Gain of glycosylation is a new mechanism in Charcot-Marie-Tooth type 1B.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and loss of neurological function, local macrophage infiltrate and neuroantigen-specific CD4(+)T cells. MS arises from complex interactions between genetic, immunological, infective and biochemical mechanisms. Although the circumstances of MS etiology remain hypothetical, one persistent theme involves immune system recognition of myelin-specific antigens derived from myelin basic protein, the most abundant extrinsic myelin membrane protein, and/or another equally suitable myelin protein or lipid. Knowledge of the biochemical and physico-chemical properties of myelin proteins and lipids, particularly their composition, organization, structure and accessibility with respect to the compacted myelin multilayers, becomes central to understanding how and why myelin-specific antigens become selected during the development of MS. This review focuses on the current understanding of the molecular basis of MS with emphasis: (i) on the physical-chemical properties, organization, morphology, and accessibility of the proteins and lipids within the myelin multilayers; (ii) on the structure-function relationships and characterization of the myelin proteins relevant to the manifestation and evolution of MS; (iii) on conformational relationships between myelin epitopes which might become selected during the development of MS; (iv) on the structure of MHC/HLA in complex with MBP peptides as well as with TCR, which is crucial to the understanding of the pathogenesis of MS with the ultimate goal of designed antigen-specific treatments. Curr Med Chem

The peripheral myelin proteins P0 and PMP22 are associated in preparations of compact myelin and in cell cultures coexpressing both molecules. The mechanism of this interaction, however, still needs to be unravelled. We have established three different (cell-cell, cell-protein, protein-protein based) assay systems using retrovirally transduced HeLa cells that overexpressed either PMP22 or P0 and purified GST fusion oligopeptides of PMP22 and P0 to detect domain-specific interactions between these proteins. The results revealed that PMP22 and P0 are involved in both trans-homophilic and trans-heterophilic interactions. Moreover, the data clearly indicate that the heterophilic trans-interaction is mediated through the second loop of PMP22, while the first loop is involved in homophilic trans-interaction of PMP22 proteins. Both modes of interaction are due to direct protein-protein binding. In addition, we demonstrate that disease-related point mutations of P0 resulted in a decreased adhesion capability correlating with the severity of the respective disease phenotype.

Glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22) are two proteins playing a crucial physiological role in the maintenance of the multilamellar structure of peripheral myelin. We here demonstrate that the removal of circulating androgens by orchidectomy induces a significant decrease of the synthesis of Po and PMP22 in the rat sciatic nerve. In case of Po, this effect may be counteracted by the subsequent treatment with testosterone metabolites, dihydrotestosterone or 5alpha-androstan-3alpha,17beta-diol (3alpha-diol). Experiments have been consequently performed in order to evaluate the role of androgen receptor (AR) in the control of Po synthesis. In vivo treatment with flutamide (i.e., an antagonist of AR) induces a decrease of the synthesis of this myelin protein in the sciatic nerve of intact male rats confirming a role for this steroid receptor. On the contrary, PMP22 seems not to be under the control of AR, but a role for GABAA receptor may be proposed. This concept is based on the findings that: (a) only 3alpha-diol, which is able to interact with GABAA receptor, is effective in stimulating the synthesis of PMP22 in the sciatic nerve of castrated male rats, and (b) flutamide treatment is ineffective in decreasing the protein levels in intact male rats. The observations here reported clearly show similarities and dissimilarities with the effects exerted by other members of neuroactive steroid family, like for instance progesterone derivatives, which will be discussed in text.

Objective The aim of this study was to evaluate the microanatomy and histological features of the central myelin in the root exit zone of facial nerve. Methods Forty facial nerves with brain stem were obtained from 20 formalin fixed cadavers. Among them 17 facial nerves were ruined during preparation and 23 root entry zone (REZ) of facial nerves could be examined. The length of medial REZ, from detach point of facial nerve at the brain stem to transitional area, and the thickness of glial membrane of central myelin was measured. We cut brain stem along the facial nerve and made a tissue block of facial nerve REZ. Each tissue block was embedded with paraffin and serially sectioned. Slices were stained with hematoxylin and eosin (H&E), periodic acid-Schiff, and glial fibrillary acid protein. Microscopy was used to measure the extent of central myelin and thickness of outer glial membrane of central myelin. Thickness of glial membrane was examined at two different points, the thickest area of proximal and distal REZ. Results Special stain with PAS and GFAP could be differentiated the central and peripheral myelin of facial nerve. The length of medial REZ was mean 2.6 mm (1.6-3.5 mm). The glial limiting membrane of brain stem is continued to the end of central myelin. We called it glial sheath of REZ. The thickness of glial sheath was mean 66.5 µm (40-110 µm) at proximal REZ and 7.4 µm (5-10 µm) at distal REZ. Conclusion Medial REZ of facial nerve is mean 2.6 mm in length and covered by glial sheath continued from glial limiting membrane of brain stem. Glial sheath of central myelin tends to become thin toward transitional zone.

The inherited neuropathies of the peripheral nervous system are clinically and genetically a heterogeneous group of disorders. Molecular genetic studies have made major breakthroughs in unraveling the underlying gene defects, and DNA diagnosis can now be offered to a large number of families with distinct forms of hereditary peripheral neuropathies. With the currently available technology, however, molecular genetic diagnosis still remains a labor-intensive and costly procedure. We have developed an algorithm for mutation screening based on clinical phenotype, electrophysiological findings, and the relative frequencies of mutations in the distinct peripheral myelin genes.

Recent molecular models and crystallographic analysis of the major protein of peripheral myelin have provided new insights into the molecular basis of membrane adhesion in myelin. These studies have proved useful in understanding the molecular basis of clinical phenotypes in certain demyelinating neuropathies.

The News Focus article “In search of vertebrate origins: Beyond brain and bone” by Carl Zimmer (3 Mar., p. [1576][1]) highlights recent findings of the progressive acquisition of bone and brain structures. These findings support Gans and Northcutt's theory ([1][2]), which postulates that the emergence of vertebrates was made possible by the invention of neural crest cells (embryonic cells that give rise to many peripheral tissues including the eyes, nerves, and skull), and specifically, this then led to the development of evolutionarily advantageous complex head structures. We agree with the importance of the neural crest in this regard, but wish to point out the contribution of one important neural crest derivative—the peripheral myelin sheath—to the success of the vertebrates. Without this structure, the vertebrates as we know them simply could not exist ([2][3]). Invertebrate axons are ensheathed by supporting cells but do not have a compact myelin sheath. As a consequence, action potentials (electrical pulses) that propagate along invertebrate axons are generally conducted at a speed of about 1 meter per second or less, fast enough for animals of small size to survive. However, as body size increases, a proportionate increase in action potential velocity down very long nerves is required. Rapid nerve conduction is critical for escape maneuvers as well as for effective predation. In cephalopods, the conduction problem has been solved by vastly increasing the diameter of those axons for which fast conduction is essential. Certain of these single axons can be as thick as a few millimeters in diameter. In contrast, vertebrates have developed a much more efficient system that creates a thin, compact membrane sheath around their axons—myelin—allowing them to conduct action potentials with speeds of 50 to 100 meters per second along an axon with a diameter of only 1 to 40 micrometers (see the figure). The myelin sheath is synthesized by oligodendrocytes in the central nervous system and by neural crest-derived Schwann cells in the peripheral nervous system. With respect to Gans and Northcutt's theory, it is interesting that protovertebrates (lancelets, hagfishes, and lampreys) are not myelinated. The presence of the myelin sheath exactly parallels the development of the jaw. The oldest contemporary vertebrates that are myelinated are the jawed cartilaginous fishes (sharks and rays), consistent with the concept that a large-bodied, fast-reacting predator requires myelin-mediated, highly rapid conduction of the action potential. One might retrodict that the jawless ostracoderms and conodonts were not myelinated, and so would not have been successful competitors with other fish (for example, placoderms) that had developed neural crest-derived myelin, and jaws. 1. [↵][4]1. C. Gans, 2. R. G. Northcutt , Science 220, 268 (1983). [OpenUrl][5][Abstract/FREE Full Text][6] 2. [↵][7]1. K. R. Jessen, 2. W. D. Richardson 1. D. R. Colman 2. et al. , in Glial Cell Development, K. R. Jessen, W. D. Richardson, Eds. (Bios Scientific, Oxford, UK, 1996), p. 85, 98. [1]: /lookup/doi/10.1126/science.287.5458.1576 [2]: #ref-1 [3]: #ref-2 [4]: #xref-ref-1-1 "View reference 1 in text" [5]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.issn%253D0036-8075%26rft.aulast%253DGans%26rft.auinit1%253DC.%26rft.volume%253D220%26rft.issue%253D4594%26rft.spage%253D268%26rft.epage%253D273%26rft.atitle%253DNeural%2BCrest%2Band%2Bthe%2BOrigin%2Bof%2BVertebrates%253A%2BA%2BNew%2BHead%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.220.4594.268%26rft_id%253Dinfo%253Apmid%252F17732898%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIyMjAvNDU5NC8yNjgiO3M6NDoiYXRvbSI7czoyNDoiL3NjaS8yODgvNTQ2NC8yNzEuMy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [7]: #xref-ref-2-1 "View reference 2 in text"

Peripheral myelin protein 22 (PMP22) plays a dual role in regulating cells growth and peripheral myelin compaction. Charcot-Marie-Tooth 1A neuropathy (CMT1A) and Hereditary Neuropathy with liability to Pressure Palsies (HNPP) are respectively due to a duplication and a deletion of the PMP22 gene, leading to over and underexpression of the protein. It is unknown how the altered PMP22 dosage impairs peripheral myelination. By means of transmission electron microscopy (TEM) morphometry we found that myelin periodicity is significantly increased in CMT1A patients (9.79 ± 0.9 nm) and compared to normal sural nerves (9.1 ± 0.7 nm). Conversely, myelin periodicity was slightly reduced in HNPP patients (8.9 ± 0.7 nm). Interestingly, the difference between CMT1A and HNPP patients was highly significant. Moreover, we found an increased myelin periodicity in sciatic nerves of a transgenic rat model of CMT1A (8.9 ± 0.08) and in organotypic dorsal root ganglia cultures (10.1 ± 0.1 nm) established from this rat line, compared to control animals (8.6 ± 0.1) and cultures (9.6 ± 0.1 nm). Since TEM studies suffer considerably from radiation damage, we also used small-angle X-ray scattering (SAXS) with a synchrotron radiation microbeam (5 m diameter) for in-situ experiments on single sural nerves of CMT 1A and HNPP patients and of normal controls. For comparison with the TEM-data, the periodicities were divided by two. Myelin periodicities ranged from 8.4 to 8.9 nm (mean: 8.7 ± 0.3) in CMT 1A nerves, from 8.0 to 8.4 nm (mean: 8.1 ± 0.3) in normal controls, and from 6.9 to 7.2 nm (mean 7.1 ± 0.3) in HNPP. In conclusion, altered PMP22 levels induce significant changes in myelin lamellae spacing, which may be recorded by appropriate morphometric techniques, and in particular by microbeam SAXS. Differences in term of myelin periodicity between TEM morphometry and x-ray microbeam analysis may be due to the higher resolution and accuracy of the latter technique to measure periodic structures. Having an altered myelin period could lead to demyelination and subsequent remyelination. Therefore, the pathomechanism of both CMT1A and HNPP may be also related to a dysfunction of PMP22 as a structural protein of peripheral myelin.

The authors wish to correct a mistake which occurred in the reporting of one of the mutations. The mutation in Cx32 Met34Lys is wrongly described as 100A>G. The correct description of the mutation should be 101T>A (Met34Lys).

To the Editor: In the February 1997 issue of Neurology , Young et al.1 described a novel 1-nucleotide insertion at codon 94 (insG94) of the gene encoding peripheral myelin protein-22 (PMP22) in a family with hereditary neuropathy with liability to pressure palsies (HNPP). In the majority of cases, HNPP is caused by a 1.5-megabase deletion on chromosome 17p11.2-12 encompassing the PMP22 gene. Among the rare HNPP patients not carrying the deletion, PMP22 micromutations have been thus far identified in only four cases.2 In three of them, frameshift or nonsense mutations were found at codon 7,3 124, and 145,2,4 which were predicted to cause synthesis of a truncated protein. All patients carrying these mutations showed classical …

Formation of the myelin sheath in peripheral nerve of the newborn rat is compared with its formation in postnatal cerebral white matter. The unmyelinated central axon is bare and myelination begins by the spiral wrapping of an oligodendrocytic process around the axon. The paired membranes of this process fuse on their inside surfaces, lengthen, and spiral around the axon to make a loose sheath of major dense lines. Compact myelin results after fusion of the outside surfaces to form the intraperiod line. Cytoplasm is sparse in developing central myelin, usually being restricted to inner and outer tongues. Unmyelinated peripheral axons are enclosed within a mesaxon formed by the invagination and fusion of the outside surfaces of the Schwann cell plasma membranes. Loose myelin is produced by lengthening and spiralling of the mesaxon (intraperiod line) around the axon. As Schwann cell cytoplasm is extruded from between the spirals, the major dense line forms and compact myelin results. Trapped cytoplasm, a characteristic of developing peripheral myelin, is found in the internodal compact myelin sheath as the inner and outer collars and the Schmidt-Lanterman clefts.

An investigation was made of ventral and dorsal spinal roots (L7 and S1) in the postnatal life of the rabbit. The development of the Schwann sheath of the nerve fibers was studied and correlated with the distribution and morphological characteristics of the desmosome-like structures connected with them. The association of these structures with constituents of the endoplasmic granular and smooth-surfaced reticulum of the Schwann cell is pointed out. The possibility is discussed of a direct relationship between the desmosome-like structures and the growth of the axon-Schwann sheaths at the outer and inner mesaxons, as well as along the length of the peripheral myelin lamellae. In addition, it is suggested that in some cases already existing membrane formations of the adjacent cytoplasm become attached to the developing Schwann sheaths, which results in branching mesaxons or “poli-mesaxonal” nerve fibers.

Biopsy specimens of sural nerve from 10 patients with multiple sclerosis (MS), of whom only 1 was severely disabled, were assessed by morphometric techniques and compared to nerves from age-matched controls. The frequency of abnormal teased fibers was increased in MS nerve, with many internodes showing at least a 50% reduction in myelin thickness. Myelinated nerve fiber densities were not significantly different in MS and control nerves. Regression analysis of axonal area on number of myelin lamellae indicated a generalized reduction of myelin lamellae in this disorder. It is suggested that peripheral myelin may be involved in multiple sclerosis.

To determine the morphologic effect of chronic hypoxia on peripheral nerve development, four-week-old rats were placed in a 10% O2 environment for ten weeks and compared with controls. Light microscopic morphometric analysis of hind limb nerves of hypoxic as compared to control nerves showed at statistically significant levels, a) smaller total fascicular areas, b) smaller median diameters, c) fiber spectra with peaks at smaller diameters, d) fewer large myelinated fibers per nerve, e) larger fiber density, f) smaller myelin areas. On average myelin areas, relative to axon size, were smaller in oxygen-deprived than in control rats. Also myelin spiral length and the number of myelin lamellae relative to axon area were smaller. These findings suggest that hypoxia retards myelinated fiber diameter and especially myelin development.

A patient with an acute inflammatory demyelinating disease and bilateral involvement of the peripheral (i.e. extracranial) portion of the VIII n. is described. The diagnosis of VIII n. involvement was made on the basis of grossly prolonged Auditory Brainstem Response (ABR) component P1 latencies which resolved to normal latencies in one year. It is suggested that involvement of the peripheral myelin is not uncommon in central demyelinating disease even in the absence of auditory system complaints.

The caudal half of the spinal cords of 3 day old Sprague-Dawley rats were subjected to 2000 R x-irradiation. Morphological studies revealed that a considerable number of oligodendroglia were destroyed in the irradiated animals by 5 days post-irradiation, and that the proliferation of the surviving glia as well as myelination were inhibited. By 35 days post-irradiation there appeared to be a cephalo-caudal progression of glial proliferation and myelination within the irradiated area, which by 50 days post-irradiation had progressed into the upper lumbar segments; little further progression was noted after GS days post-irradiation. Although the lower lumbarand sacral segments remained unmyelinated, the animals displayed no permanent neurological abnormalities. The appearance of Schwann-like cells within the irradiated spinal cord was first noted at the dorsal aspect of the cord 25 days after irradiation. In later periods the cellular invasion was found to be more extensive and accompanied by the deposition of peripheral myelin within the cord. Histochemical evidence also suggested that these cells were Schwann cells.