Which peripheral nerves are myelinated

By imposing saltatory conduction on the nervous impulse, the principal role of the myelin sheath is to allow the faster propagation of action potentials along the axons which it surrounds. Peripheral nervous system PNS myelin is formed by the differentiation of the plasma membrane of Schwann cells. One of the biochemical characteristics that distinguishes myelin from other biological membranes is its high lipid-to-protein ratio. All the major lipid classes are represented in the myelin membrane, while several myelin-specific proteins have been identified.

Efficient debris removal constitutes a prerequisite for subsequent regeneration in both the PNS and CNS and the failure of axonal regeneration after injury in the CNS has been linked to the presence of myelin-associated inhibitors of axonal regrowth at the injury site reviewed in Vargas and Barres, WD involves the remarkable process of active subcellular self-destruction.

It is tightly regulated; involving a first latent phase around 1. This second step is accompanied by reactive glial changes and immune cell activation Beuche and Friede, ; Scheidt and Friede, In the PNS, these changes, especially the injury-response of Schwann cells, are the prerequisite of successful repair Arthur-Farraj et al.

The Wlds mutation comprises a tandem triplication resulting in the fusion of two genes Coleman et al. NMNAT2 traffics anterogradely from the cell body into the distal axon, thus its depletion after injury being unable to reach the axon distal to the injury and having a short half-life is thought to initiate axonal self-destruction Gilley and Coleman, Of note, a genetic knockout of Nmnat2 is embryonic lethal, however, the phenotype is rescued in vivo upon generation of a double knockout of Nmnat2 and Sarm1 Gilley et al.

A complex interplay with other signaling cascades such as MAPK and JNK also contribute to the initiation phase for more extensive reviews, see Conforti et al. It is now established that increased intra-axonal calcium together with calpain a calcium-dependent protease activation is crucial in the execution phase, leading to, amongst other things, neurofilament proteolysis and destabilization of microtubules Zhai et al.

Notably, other mechanisms and organelles are likely to be involved. Dying back axonopathy is a neuropathological feature of a heterogenous group of toxic injuries and genetic defects, and generally involves long axons of the peripheral nerves and spinal cord. The last three have not been extensively reviewed elsewhere and are described briefly in Box 1 — 3.

The geometry of the susceptible axonal populations and the limitations of histological evaluation probably contributed to the misconception that, in contrast to WD, degeneration in the dying back disorders progresses retrogradely from the axonal terminus.

Rather, it is likely that degeneration appears retrogradely progressing because at the level of the whole tract comprising many axons , it is most prevalent distally see Figure 1 of Coleman, Indeed, early ultrastructural studies on hexacarbone induced neurotoxicity in rats, demonstrated that although a retrograde temporal spread of axonal swellings occurred, axonal degeneration was not initiated at the axon terminal nor spread centripetally along individual fibers Spencer and Schaumberg, a , b.

Nevertheless, axonal degeneration in these diseases seems length-dependent, pointing to a particular vulnerability of the long axons, possibly related to metabolic dysfunction or transport defects.

Box 1. Organophosphorus OP compound-induced delayed neurotoxicity. OPIDN is an example of a pure axonal dying back neuropathy with a chemically induced degeneration of long, large-diameter sensorimotor axons in spinal cord and peripheral nerves, resulting in sensory loss and paralysis.

In humans and susceptible animals, causes include occupational and accidental exposures to OP compounds Smith and Spalding, Mechanistically, OP compounds inhibit serine esterases, including neuropathy target esterase NTE , by organophosphorylation of the active site Makhaeva et al.

Nonetheless, the mechanisms linking exposure to a neuropathic OP compound and the onset of OPIDN shortly after, are still poorly understood. GAN is characterized histologically by large axonal swellings filled with axonal intermediate filament IF. Using dorsal root ganglia cultures, Israeli et al.

Symptom onset usually occurs in childhood and most patients die in the second or third decade reviewed in Kang et al. Symptom onset usually occurs in the 3rd decade and can present with or without cerebral involvement see below.

Neurological symptoms include a progressive ataxic gait and spastic paraparesis and most probably reflect the degeneration of long spinal cord axons Pujol et al. A role of lipid-derived inflammatory mediators has been proposed Kassmann and Nave, ; Ruiz et al.

Recent work suggests that the acute peripheral neuropathy triggered by Zika virus infection Cao-Lormeau et al. MS, which is the best known inflammatory demyelinating disorder of the CNS, involves progressive axonal degeneration. Zika virus is a neurotropic arbovirus of the family Flaviviridae that recently received considerable attention due to its links to microcephaly and, less sensationally, to GBS Cao-Lormeau et al. In Ifnar1 knockout mouse spinal cord and dorsal root ganglia-derived cultures Cumberworth et al.

However, infection of dorsal root ganglia neurons in Ifnar1 knockout mice in vivo was reported recently Oh et al. Differences in the experimental studies may be due to viral strain-specific effects, although dissimilarity in glycosylation of the viral coat protein, related to the cell type in which the virus was propagated pre-administration, is an another confounding factor Alain Kohl, personal communication. In contrast, CNS glia are highly susceptible in vitro, consistent with white matter pathology in pre-term and newborn infants with congenital Zika virus infection Chimelli et al.

Using live imaging in vivo , they showed that FAD, which begins with focal axonal swelling, either progressed to axonal fragmentation or resolved. Similarly, in a mouse model of Pelizaeus Merzbacher disease PMD , defined by a primary oligodendropathy, focal axonal swellings can occur on otherwise intact non-transected myelinated axons Edgar et al. FAD can be initiated by high levels of reactive oxygen and reactive nitrogen species ROS and RNS alone, implicating macrophages in its evolution in EAE, and likely also in MS, where morphologically similar changes can be observed in acute lesions Nikic et al.

This raises the question whether axons undergoing the early pre-fragmentation stage of FAD can support electrical conduction. Certainly, nitric oxide can block neural conduction in rat spinal roots Redford et al.

Mechanistically, this is likely related to axonal energy deficits, as nitric oxide and reactive oxygen species can damage mitochondrial respiratory chain complexes reviewed in Smith and Lassmann, Indeed, a deficiency in complex IV function in axons Mahad et al. Evidence for a role for the adaptive immune system in axonal injury originated from the analysis of mouse models of genetically determined CNS and PNS disorders with secondary immune reactions.

Here, a role for T-lymphocytes in secondary axonal injury was demonstrated. Similar observations were made in heterozygous myelin protein zero Mpz knockout and homozygous gap junction protein b Gjb1 knockout mice; models of progressive demyelinating forms of the inherited peripheral neuropathies, Charcot Marie Tooth disease CMT; Kobsar et al. Nonetheless, immune cells protect myelin and axons in Mpz deficient mice, a genetic model of a severe dysmyelinating peripheral neuropathy, Dejerine—Sottas syndrome DSS; Berghoff et al.

Hence, the role of the adaptive immune system seems to be dependent on disease-specific mechanisms, probably including myelin integrity and the response of the innate immune system Berghoff et al. All of these diseases were first identified by and later successfully modelled in Plp1 mutant and Plp1 overexpressing mice Nave and Griffiths, ; Gruenenfelder et al. PLP and its isoform DM20 are expressed in oligodendrocytes and located in the compact myelin. The view that the survival of myelinated CNS axons is linked to the performance of surrounding glial cells initially emerged from studies of Plp1 knockout mouse models Griffiths et al.

However, defects in myelin biosynthesis and maintenance do not inevitably lead to axonal degeneration. For example, in the spontaneously occurring Long-Evans shaker les rat and the shiverer mouse, which both lack a functional myelin basic protein Mbp gene Roach et al. Thus, shiverer elucidates the profound influence the myelinating oligodendrocyte exerts on the axonal cytoskeleton and on radial axonal growth see Cell autonomous and bi-directional signalling regulate axonal and glial dimensions.

Of note, the PNS of shiverer mice is fully myelinated Privat et al. Figure 5. Oligodendrocytes support axons. A In the CNS, oligodendrocytes green provide axons with the insulating myelin sheath green: myelinated internodes.

Moreover, oligodendrocytes support axonal integrity and function independent of myelination per se for details see main text. Astrocytes blue not only contact blood vessels but additionally interact with axons and oligodendrocytes and contribute to brain homeostasis. Oligodendrocyte precursor cells not illustrated are also present in the mature CNS and are the main cellular source for new oligodendrocytes after injury and in remyelination.

B Oligodendrocyte dysfunction leads to a perturbed axon-glia interaction which ultimately impairs axonal health. As the myelinic channel system is likely acting as a route by which oligodendrocytes supply metabolites to the myelinated axons, any perturbation of this system could potentially impact axonal integrity, resulting for example in focal axonal swelling and distal axonal degeneration.

De- and dysmyelination are associated with the re distribution of sodium channels along the axolemma, thus maintaining axonal conduction Utzschneider et al. However, the resultant non-saltatory action potential propagation increases energy consumption, and accordingly, increased numbers of mitochondria have been observed in shiverer axons Andrews et al. Taking advantage of the X-linked nature of the Plp1 gene and female heterozygotes harbouring a mosaic of wild type and PLP-deficient myelin the latter with subtle defects in compaction , we demonstrated that secondary axonal changes, such as organelle-filled focal swellings, are localised to the internodes formed by the PLP-deficient myelin Edgar et al.

This demonstrates that oligodendroglial support of axonal integrity is a very local function. Late onset length-dependent axonal degeneration in this mutant is likely a consequence of these early focal changes and organelle transport stasis Edgar et al. That the axonal changes are secondary to the glial-cell defect was confirmed by cell transplantation experiments Edgar et al. Similarly, Cnp1 knockout mice Lappe-Siefke et al. Thus, abnormal MBP-dependent closures of the myelinic channels likely result in the observed swellings at the inner tongue, that are predicted to perturb axon-glia communication Lappe-Siefke et al.

These and other observations have led us to hypothesise that the myelinic channel system is crucial to the function of the oligodendrocyte in axonal support, likely acting as the route through which the oligodendrocyte supplies metabolites to the myelinated axon and delivers membrane proteins to the adaxonal myelin surface Figure 5. In the Plp1 transgenic line 72 Readhead et al. This supports our suggestion that axons shielded from nutrients in the extracellular milieu, are susceptible to injury if even minor damage to myelinic channels leaves oligodendrocytes unable to fuel the axon's energy requirements.

Further evidence for a role of oligodendrocytes in axonal support comes from mice lacking the Pex5 gene encoding the peroxisomal biogenesis factor and targeting signal type-I receptor in myelinating glia.

In this model, the absence of oligodendroglial peroxisomes does not interfere with myelination but underlies a progressive clinical phenotype caused by subcortical demyelination, inflammation and widespread axonal degeneration Kassmann et al. Primary oligodendrocyte death also elicits axonal changes. The diphtheria-toxin mediated ablation of oligodendrocytes in mice leads to secondary focal axonal changes and a reduction in axonal densities Ghosh et al. The significant temporal delay between oligodendrocyte cell death and axonal demise can probably be explained by the initial preservation of myelin sheaths, including their content of glycolytic enzymes and metabolite transporters Saab et al.

Axonal changes in this model are independent of the adaptive immune system, as evidenced by crossbreeding to Rag1 deficient mice Pohl et al. Peripheral neuropathies are a heterogeneous group of diseases and result from inflammatory, toxic and metabolic conditions in addition to genetic defects.

Evidence for axonal support by Schwann cells emerged from murine mutants and transgenics for the peripheral myelin protein Pmp22 gene encoding the peripheral myelin protein of 22kDA; PMP22 , which model CMT1A. A Pmp22 point mutation defines the Trembler mouse Suter et al.

Schwann cell—axon interactions are perturbed at paranodal glial-axonal junctions in Trembler Robertson et al. Transgenic overexpression of Pmp22 also induces dys- and demyelination and, in this case, a slowly progressive, distally pronounced, axonal loss Sereda et al. HNPP is characterized by focal hypermyelination of peripheral nerves, and the application of mechanical compression induces a conduction block in affected patients as well as in respective animal models Adlkofer et al.

Consistent with this, other CMT forms with increased myelin outfoldings, such as CMT4B, demonstrate a reduced nerve conduction velocity as well as a decreased compound muscle action potential Previtali et al.

However, the precise molecular mechanisms of disease progression and functional failure in CMT diseases remain only partially understood, and it is most likely that all human dysmyelinating neuropathies share a defect of Schwann cell-axon communication that is ultimately responsible for axonal conduction blocks, degeneration and a progressive clinical phenotype Nave et al. Rather, it was the observation that axonal changes occur on axons with relatively Mag and Plp1 knockout mice or completely Cnp1 knockout mice normal-appearing compact myelin that provided evidence that glial cells, independent of myelin, support axonal health Nave, a ; and see Mechanisms of injury: axonal pathology caused by oligodenroglial defects.

Mice lacking the myelin-associated glycoprotein Mag gene, assemble CNS and PNS myelin that harbours very minor morphological changes at the inner wrap, but have reduced axon calibre associated with altered neurofilament spacing and phosphorylation in the PNS Yin et al. A progressive degenerative response including paranodal myelin tomaculi and axonal loss subsequently ensues Yin et al. Just as oligodendrocytes likely provide metabolic support for axons see Energy supply and use , so there is evidence that Schwann cells play a similar role in the PNS.

Beirowski et al. LKB1 is a key regulator of energy homeostasis, suggesting axonal degeneration in this model could pertain to axonal energy insufficiency; however the phenotype is complex and its interpretation is not straightforward. More recently, using mice lacking the nutrient sensing protein O-GlcNAc transferase OGT in Schwann cells, the same group demonstrated that Schwann cell OGT is required for the maintenance of normal myelin and to prevent axonal loss Kim et al.

Recently, using the compound action potential as a readout of ex-vivo sciatic nerve function, Rich and Brown provided evidence that non-myelinated C fibres and myelinated A fibres in the same sciatic nerve preparation, have distinct metabolic profiles.

The authors showed that when fructose is supplied as the sole energy source, C fibres can utilise it directly whereas A fibres benefit through receipt of lactate from Schwann cells. Together, these data are compatible with the hypothesis that myelinating cells provide metabolic support to axons encased in compact myelin, to abrogate the consequences of their being sequestered from extracellular glucose Nave, b.

In summary, we have provided an overview of the unique physical and functional properties of myelinated axons, with an emphasis on how these might contribute to the axon's vulnerability to injury in a variety of diseases and traumas. In some cases, such as SPG10, which is due to a mutation in KIF5A encoding a motor protein of axonal transport , the reason why axons are vulnerable seems evident.

However, the particular susceptibility of motor neuron axons in some complex disorders such as familial amyotrophic lateral sclerosis fALS , in which the mutated gene SOD1 ; superoxide dismutase 1 is expressed in all neural cell types, remains an enigma; although multiple mechanisms have been implicated. In classical axonal and demyelinating GBS, which also fall into this category, antibody-mediated complement activation and downstream calpain-dependent proteolysis is now generally considered the most likely effector of axonal demise Willison et al.

Insight into the effectors of this and other genetically-determined length-dependent axonopathies might come from understanding how axons are injured in the neurotoxic disorders like OPIDN Box 1. Indeed axonal energy insufficiency might represent a common pathway in multiple neurodegenerative disorders; either due to failure of metabolic support from neighbouring glia; to ischemia as in stroke; or as a consequence of failure of OXPHOS due to nitric oxide and potentially other factors mediated injury to axonal mitochondria summarised in Figure 5B.

Thus, actual physical length is not the defining factor. Recently, we and others demonstrated reduced axonal calibre in mouse models of two complex neuropsychological disorders Rett and Angelman syndromes; Box 5 , which could potentially contribute to symptoms. Thus a variety of axonal changes, from reduced calibre, through mitochondrial dysfunction and focal swelling to transection, can probably all contribute to neurological symptoms in neurodegenerative diseases or injuries with primary or secondary involvement of axons.

Rett and Angelman syndromes comprise part of the spectrum of neurologic disorders previously considered associated with autism Jedele, Both present, after a short period of normal development, with global developmental delay, severe speech and communication deficits, progressive microcephaly, seizures, autistic behavior and a characteristic movement disorder.

Angelman syndrome is due to loss of function of the maternally inherited ubiquitin protein ligase E3A UBE3A allele, while Rett syndrome is due in the majority of cases to loss of function mutation in the X-linked methyl-CpG- binding protein 2 MECP2 gene. Remarkably, clinical features occur in the absence of evident neurodegeneration, and activation of a silenced Mecp2 allele, even with a radically truncated MeCP2 protein, in adult mice reverses neurological and morphological changes, suggesting MeCP2 might be required for maintenance of neuronal function, rather than for normal development Guy et al.

Female mice heterozygous for a Mecp2 null allele develop normally but subsequently exhibit a stiff, uncoordinated gait, tremor, breathing difficulties and hindlimb clasping. Similarly, in a mouse model of Angelman syndrome, reduced axonal diameter and white matter abnormalities underlie impaired brain growth and microcephaly Judson et al.

Similar subtle morphological changes could, in principle, contribute to the neurological signs in Rett and Angelman syndromes. JE and RS wrote the review and provided images. JE planned and edited the review. K-AN was involved in planning, writing and finally edited the manuscript. WM contributed electron micrographs and figure legends. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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It has also been found that patients treated with gangliosides for pain and neuropathy in the early s later developed GBS Gangliosides, axo-glial junctional proteins, neurofascin and gliomedin at nodes of Ranvier could contribute toward the autoimmunity seen in GBS Figure 1. The clinical manifestations of GBS include acute ascending fairly symmetric paralysis and paresthesia, choking and difficulty in breathing over the course of hours to several days 2. Involvement of the respiratory muscles in GBS may require the need for artificial ventilation Some patients also experienced autonomic dysfunctions such as cardiac arrhythmia, arterial hypotension, gastrointestinal dysmotility, urinary retention, and abnormal sweating Management of GBS is mostly supportive Affected patients would require comprehensive assisted respiratory ventilation with monitoring for cardiac arrhythmia and bed-bound complications such as ventilator-associated pneumonia, thromboembolism and infections Plasma exchange and intravenous immunoglobulin IVIG have been shown in large randomized trials to be beneficial Overall, most cases of GBS have good prognosis with functional recovery within 12 months after disease onset However, some patients do suffer from residual deficits Chronic inflammatory demyelinating polyradiculoneuropathy CIDP is an acquired immune mediated demyelinating disease of the PNS characterized by progressive loss of motor and sensory functions The onset is insidious and occurs more commonly in older age individuals 38 , The immune system primarily attacks and damages the myelin sheath of the PNS followed by segmental demyelination and axonal degeneration 6.

Histological findings of CIDP demonstrate thin myelin sheath with short internodes described as onion bulbs. Demyelination is indicated by the slow nerve conduction velocity suggestive of conduction block 6. Recently evidence of autoimmunity toward neurofascin NF and contactin-1 CNTN1 in some patients have been reported. NF is an adhesion molecule that is expressed at paranodes of glial side which interacts with CNTN1, a key axonal adhesion molecule This interaction is essential for the formation of paranodal septate-like junction and loss of this junction is associated with slow conduction Symptoms of CIDP develop slowly but progressive and neurological deficits peak after 8 weeks of disease onset Treatment with oral glucocorticoids usually produce a favorable response Apart from that, plasmapheresis and IVIG are also effective MAG is a type I transmembrane glycoprotein l presents in peri-axonal SC and oligodendroglial membranes of myelin sheaths that central in glial-axon interaction and maintenance of axonal function Loss of MAG compromises the myelin sheath integrity and axonal function.

MAG contains a carbohydrate epitope shared with other glycoconjugates that serve as primary antigenic targets for IgM paraproteins Injection of serum containing IgM anti-MAG paraproteins into chickens causes segmental demyelination and conduction block The disease is also described as progressive mild to moderate distal muscle weakness; along with progressive sensory ataxia and frequent tremors The clinical course is generally benign, with minimal functional deterioration manifested over time As the symptoms of anti-MAG neuropathy usually are minimal and do not interfere with the patient's daily activities initially; management at this stage comprises of supportive care such as exercise and balance training.

However, patients with sensorimotor weakness should be treated. Steroids, IVIG and plasmapheresis are rarely effective. Rituximab, a monoclonal antibody against CD20 surface antigen is promising POEMS syndrome is a rare paraneoplastic syndrome with demyelinating neuropathy Emprical data on POEMS syndrome is deficient owing to the complexity and multisystemic nature of its clinical manifestations.

It is usually associated with an underlying plasma cell neoplasm POEMS syndrome commonly presents in the fifth to sixth decade The pathogenesis of POEMS syndrome is not well understood, but several hypotheses have been proposed. The pathological assessment does not reveal inflammatory infiltrates or immunoglobulin deposition within the nerves; instead, there is endothelial cell hypertrophy with extended process, reduced luminal diameter, and disrupted tight junction that could cause leakage Excessive VEGF secreted by plasma cells is thought to cause endothelial proliferation and subsequent leaky vessels that compromise blood flow The polyneuropathy involves both sensory and motor systems Patients usually begin to experience sensory abnormalities described as tingling, paresthesia and coldness in the feet, along with touch, pressure, and proprioception disturbances Motor symptoms then develop, including symmetrical severe weakness on extremities progressing distally with gradual spreading to proximal Nerve conduction studies, as well as nerve biopsies show evidence of demyelination and axonal loss Hepatomegaly is commonly reported, but splenomegaly and lymphadenopathy are not frequent.

Endocrinopathy, usually gonadal dysfunction is noted by testicular atrophy and gynecomastia and diabetes mellitus. Skin changes include hyperpigmentation and hypertrichosis. Other additional features that are not included in the acronym are sometimes present.

These include peripheral edema, effusion in body cavities such as ascites, sclerotic bone lesions, Castleman's disease, elevated intracranial pressure, papilledema, fatigue, renal failure and clubbing However, not all features are necessarily required for the diagnosis. Treatment with high dose chemotherapy and autologous peripheral blood stem cell transplant are the first line therapy. Alternative therapeutics are including corticosteroids, low-dose alkylator therapy and radiation therapy.

Mortality usually results from cardiorespiratory failure, infection and renal failure. Supportive care such as physical and occupational therapy should be in line with the treatment to improve outcome and quality of life. Some patients might even require assisted ventilation due to respiratory muscle weakness Charcot Marie Tooth disease CMT is a rare hereditary neurological disorder affecting the peripheral nerves 7.

Although CMT is rare, it is the most commonly inherited form of neuropathy affecting approximately 1 in 2, people The majority of CMT have an autosomal dominant inheritance but X-linked and autosomal recessive pattern also exist The gene abnormalities in CMT disrupt the structure and functions of Schwann cell and peripheral nerve axons. Several subtypes of CMT have been identified: mutations of genes encoding myelin-related proteins such as PMP22, P0, and connexin 32 are classified as demyelinating subtype 54 ; mutations of proteins involved in axonal transport such as mitofusin-2 MFN2 , ganglioside-induced differentiation- associated protein 1 GDAP1 , heat shock factor binding protein 1 are classified as axonal neuropathies subtype Next-generation gene sequencing involving 17, samples with neuropathy identified the prevalence of specific mutations as such: CMT1B on the other hand, involves mutations of P0 gene that result in misfolding and retention of a mutant P0 protein intracellularly This condition triggers the activation of unfolded protein response which later lead to cell apoptosis Typically, the progression of CMT is slow.

The neuropathy of CMT could affect both motor and sensory nerves. Patients may experience distal muscle weakness, foot drop that formed pes cavus, scoliosis and hammer toes. Respiratory insufficiency is rare, but possible. Neuropathic pain and fatigue have been reported in several cases. At present, the management of PDD is central upon synthetic drugs and natural products However, this disease remains underdiagnosed owing to lack of reliable biomarkers and a disease specific-diagnostic criteria.

Table 1 summarized the pathogenesis, clinical features and management of PDD. Table 1. Pathogenesis, clinical features and management of various types of Peripheral Demyelinating diseases. Biomarkers serve as an important clinical tool in disease diagnosis, therapeutic response and prognosis Only original articles and in the English language were selected to be included in the review Table 2.

Traditionally, the diagnosis of GBS has relied on clinical features such as electrodiagnostic studies and CSF analysis. Testing for serum IgG antibodies to gangliosides Q1b GQ1b is available and useful for the diagnosis of GBS variants Miller Fisher syndrome with 85 to 90 percent sensitivity although it is not routinely indicated 1.

Furthermore, the laboratory measurement standard for these biomarkers also has not been established and studies using different methods have been plagued by inconsistent findings At present, novel biomarkers are being explored for better prognosis of GBS patients.

The likes of neutrophil-lymphocyte ratio NLR and platelet-lymphocyte ratio PLR has received much attention as novel prognostic biomarkers of inflammation.

On the other hand, Piccolo, a multidomain zinc finger protein that is involved in synaptic active zones and synaptic vesicle trafficking was shown to present in sera of GBS patients.

High serological levels of Piccolo were associated with better outcomes in GBS patients Ganglionic nicotinic acetylcholine receptors gAChR are nicotinic receptors that assist synaptic transmission in peripheral autonomic ganglia.

Over the last decades, the autoantibodies toward gAChR have been associated with autoimmune dysautonomia Several GBS patients experience autonomic dysfunctions such as cardiac arrhythmia and urinary retention Detection of autoantibodies against gAChR could measure the risk of developing debilitating autonomic dysfunction. Unfortunately, the disease specificity of the identified protein was low. The captured proteins include transferrin, proapolipoprotein, retinal binding protein and transthyretin Anti-MAG titers could also be correlated with prognosis of the neuropathy.

High baseline and increasing anti-MAG titer correlated with higher chances of recurrence Clinical improvement and prolonged relapse-free survival were reported among patients with normalized serum level of VEGF Diagnostic markers for CMT disease are usually determined through genetic testing. Once the suspicion of CMT disease is made through clinical judgement and electrophysiological studies. During demyelination, various components of myelin and axon are being released as a result of the damage toward the Schwann cells.

These components can be detected in CSF, serum and even peripheral nerve biopsies 71 , which can potentially indicate the degree of demyelination during the disease progress and also the efficacy of the treatment as reflected by the degree of remyelination.

Figure 2. Demyelination and released of myelin associated protein. Glycolipids such as gangliosides are one of the major lipid components of the myelin sheath. Situated in the plasma membrane with the hydrophilic carbohydrate moiety exposed extracellularly, gangliosides have a greater propensity for autoimmune reaction, especially in GBS, CIDP, and anti- MAG neuropathy Association of autoimmune diseases such as systematic lupus erythematosus, scleroderma with GBS 96 led researchers Nakos et al to ascertain the role of few antiphospholipid antibodies which include phosphatidic acid PA , cardiolipin, phosphatidylethanolamine PE , phosphatidylcholine PC , phosphatidylserine PS , phosphatidylinositol PI , phosphatidylglyecerol PG , and cardiolipin.

This indicates that serum levels of anti-PI and anti-cardiolipin antibodies may be useful to monitor the response of the patient toward treatment with IVIG in GBS patients The ability to distinguish between demyelinating variant from axonal variant supports the connotation that sphingomyelin is specific biomarker for peripheral myelin breakdown.

In addition, the techniques used to detect and quantify sphingomyelin were also reliable, cost-effective with good sensitivity and specificity Myelin sheath consists of two compartments, compact myelin dense area around axon and non-compact myelin Figure 3.

The compact myelin consists of intraperiod line and the major dense line MDL. Figure 3. A Structure of myelin sheath of Schwann cell around axon under electron microscope. B Compact myelin that consist of major dense line and intraperiod line. P0 is a transmembrane glycoprotein that stabilizes the intraperiod line through homophilic binding to another P0 protein Knockout P0 mice were shown to undergo severe hypomyelination and also demonstrated thin, non-compacted myelin sheath with axonal degeneration.

In addition, the mice also exhibited tremors, convulsion and deficits in motor coordination P2 protein, also participate in fusion of the MDL in compact myelin