Demyelinating Peripheral Neuropathy Research Articles

PO32-FR-11 Peripheral demyelinating neuropathy (PN) in multiple sclerosis (MS)

PO32-FR-11 Peripheral demyelinating neuropathy (PN) in multiple sclerosis (MS)

Node of Ranvier formation on motoneurons in vitro

One of the most significant interactions between Schwann cells and neurons is myelin sheath formation. Myelination is a vertebrate adaptation that enables rapid conduction of action potentials without a commensurate increase in axon diameter. In vitro neuronal systems provide a unique modality to study both factors influencing myelination and diseases associated with myelination. Currently, no in vitro system for motoneuron myelination by Schwann cells has been demonstrated. This work details the myelination of motoneuron axons by Schwann cells, with complete Node of Ranvier formation, in a defined in vitro culture system. This defined system utilizes a novel serum-free medium in combination with the non-biological substrate, N-1[3 (trimethoxysilyl) propyl] diethylenetriamine (DETA). The myelinated segments and nodal proteins were visualized and quantified using confocal microscopy. This defined system provides a highly controlled, reproducible model for studying Schwann cell interactions with motoneurons as well as the myelination process and its effect on neuronal plasticity. Furthermore, an in vitro system that would allow studies of motoneuron myelination would be beneficial for understanding peripheral demyelinating neuropathies such as diabetes induced peripheral neuropathy and could lead to a better understanding of CNS demyelinating diseases like multiple sclerosis, as well as neuromuscular junction maturation and maintenance.

Cardiac myxoma presenting with sensory neuropathy

A 51-year-old man was admitted for burning dysesthesias over the soles. Neurologic examination showed a pansensory loss over both feet associated with weakness of toes dorsiflexion. Motor conduction study of the sural nerve showed a significant reduction of nerve conduction velocity (21.4 m/s) suggesting a demyelinating neuropathy. In the following days he was referred to the cardiologist because of the sudden onset of a rapid atrial tachycardia, which was terminated by adenosine. Echocardiography showed a left atrial mass arising from the atrial septum consistent with the diagnosis of cardiac myxoma. The patient underwent cardiac surgery to remove the tumor, which was confirmed a myxoma by pathology. In the days following cardiac mass removal, neurological symptoms progressively disappeared in the absence of anti-inflammatory and steroid therapy and control motor conduction study showed complete normalization of nerve conduction velocity (54.5 m/s). Peripheral demyelinating neuropathy represented the first clinical presentation of cardiac myxoma in our patient and should be included among the possible paraneoplastic manifestations of this cardiac tumor.

Selective Vulnerability of Peripheral Nerves in Avian Riboflavin Deficiency Demyelinating Polyneuropathy

Riboflavin (vitamin B2) deficiency in young chickens produces a demyelinating peripheral neuropathy. In this study, day-old broiler meat chickens were fed a riboflavin-deficient diet (1.8 mg/kg) and killed on posthatch days 6, 11, 16, 21, and 31, while control chickens were given a conventional diet containing 5.0 mg/kg riboflavin. Pathologic changes were found in sciatic, cervical, and lumbar spinal nerves of riboflavin-deficient chickens from day 11 onwards, characterized by endoneurial oedema, hypertrophic Schwann cells, tomacula (redundant myelin swellings), demyelination/remyelination, lipid deposition, and fibroblastic onion bulb formation. Similar changes were also found in large and medium intramuscular nerves, although they were less severe in the latter. However, by contrast, ventral and dorsal spinal nerve roots, distal intramuscular nerves, and subcutaneous nerves were normal at all time points examined. These findings demonstrate, for the first time, that riboflavin deficiency in young, rapidly growing chickens produces selective injury to peripheral nerve trunks, with relative sparing of spinal nerve roots and distal nerve branches to muscle and skin. These novel findings suggest that the response of Schwann cells in peripheral nerves with riboflavin deficiency differs because either there are subsets of these cells in, or there is variability in access of nutrients to, different sites within the nerves.

Demyelinating polyneuropathy with focally folded myelin sheaths in a family of Miniature Schnauzer dogs

A spontaneous demyelinating polyneuropathy in two young Miniature Schnauzer dogs was characterized clinically, electrophysiologically and histopathologically. Both dogs were related and a third dog, belonging to the same family, had similar clinical signs. On presentation, clinical signs were restricted to respiratory dysfunction. Electrophysiological tests showed a dramatic decrease in both motor and sensory nerve conduction velocities. Microscopic examination of peripheral nerve biopsies (light and electron microscopy, teased nerve fibers), showed that this neuropathy was characterized by segmental demyelination and focally folded myelin sheaths. Various clinical syndromes associated with tomacula or focal thickening of the myelin sheath of the peripheral nerves have been described in humans and shown to be caused by gene mutations affecting the myelin proteins, such as the hereditary neuropathy with liability to pressure palsies or the demyelinating forms of Charcot–Marie–Tooth disease. In animals, a tomaculous neuropathy has been reported in cattle and chickens but not in carnivores. Here we report a demyelinating peripheral neuropathy with tomacula in two Miniature Schnauzer dogs.

Monoclonal IgM from patients with peripheral demyelinating neuropathies cross-react with bacterial polypeptides.

Human monoclonal IgM associated with a demyelinating peripheral neuropathy often feature a distinct antibody activity directed against a glucuronyl sulphate epitope shared by myelin-associated glycoprotein (MAG), nerve glycolipids and low molecular weight peripheral nerve polypeptides. Earlier studies showed that these IgM use a diverse repertoire of VH and VL genes which exhibit somatic mutations, possibly indicative of an antigen-driven process. Here, we investigated whether such monoclonal IgM may react with environmental bacterial antigens. We found that six patients' sera and purified monoclonal IgM, as well as IgM from supernatants of three clonal anti-MAG-secreting cell lines reacted with unique 90-100 kD polypeptides from extracts of two out of 10 bacterial species. Purified MAG was able to inhibit this reactivity. These results indicate molecular mimicry as a possible mechanism of this immunomediated neuropathy and associated clonal lymphoid disease.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated With Multiple Sclerosis

To describe temporal profile of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with definite, relapsing multiple sclerosis (MS). Peripheral demyelinating neuropathy has been rarely reported in association with central nervous system demyelinating disorder indistinguishable from MS. In addition to usual diagnostic studies for CIDP and MS in all 5 patients, we studied proximal segments of nerves using deep tendon reflex latency measurements of biceps reflex, patellar reflex, and ankle reflex. All patients with MS subsequently (4-22 years) developed definite CIDP. Two of these patients developed multiple cranial nerve and spinal root enhancement on subsequent imaging without new intraparenchymal enhancement after a diagnosis of CIDP. The deep tendon reflex latencies were prolonged at more than 2 sites in all patients. Cerebral spinal fluid protein increased (70 +/- 19 to 144.8 +/- 17.4 mg/dL, P = 0.0001) at time of diagnosis of CIDP. Clinical improvement was observed in all patients after intravenous immunoglobulin therapy. When patients with MS develop CIDP, manifestations of central and peripheral disease involvement seem to respond to intravenous immunoglobulin. These cases suggest that there may be common antigenic targets in central and peripheral nervous system in this subset of patients.

Loss of the inactive phosphatase Mtmr13 leads to a Charcot‐Marie‐Tooth type 4B2‐like peripheral neuropathy in mice

Charcot‐Marie‐Tooth disease type 4B (CMT4B) is a demyelinating peripheral neuropathy characterized by slowed nerve conduction velocity (NCV), severe axonal loss, and myelin outfolding and infolding. CMT4B is caused by recessive mutations in either myotubularin‐related protein 2 (MTMR2; CMT4B1) or MTMR13 (CMT4B2). Myotubularins are a large family of phosphoinositide (PI) 3‐phosphatases that dephosphorylate phosphatidylinositol 3‐phosphate (PtdIns3P) and PtdIns(3,5)P2, two PIs that regulate membrane traffic within the endosomal‐lysosomal system. Intriguingly, nearly half of the metazoan myotubularins are catalytically inactive. MTMR2 and MTMR13 are active and inactive PI 3‐phosphatases, respectively, and the two proteins have been shown to directly associate, although the functional significance of this association is not well understood. In hopes of establishing a mouse model of CMT4B2, we have disrupted the Mtmr13 gene. Mtmr13‐deficient mice develop a peripheral neuropathy characterized by reduced NCV and myelin outfolding and infolding. Notably, axonal loss and hypomyelination, two prominent features CMT4B2, are largely not observed in Mtmr13‐deficient mice. Thus, loss of Mtmr13 in mice leads to a dysmyelinating peripheral neuropathy with many of the key features of CMT4B2. Our mouse model will likely be an essential tool for future studies of how the loss of MTMR13 leads to CMT4B2.

Relapsing demyelinating disease affecting both the central and peripheral nervous systems

Background: Clinical and electromyographic findings of chronic inflammatory demyelinating polyradiculopathy (CIDP) are occasionally observed in patients with multiple sclerosis (MS). Objective: To define a new inflammatory demyelinating disease unlike MS...

Multiple Sclerosis and Peripheral Multifocal Demyelinating Neuropathies Occurring in a Same Patient

The co-occurrence of multiple sclerosis and peripheral demyelinating neuropathy is rare. It has been disputed whether these are pathologically related or coincidental findings. We report a 36-year-old woman who presented with diplopia, right facial palsy and left-sided weakness. Brain magnetic resonance imaging showed a lesion indicative of central demyelinating disease. Nerve conduction studies revealed peripheral multifocal demyelinating neuropathies. We suggest that the central and the peripheral lesions may be continua of a demyelinating process.

Deletions at the SOX10 Gene Locus Cause Waardenburg Syndrome Types 2 and 4

Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.

Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain

Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (PCWH) is a complex neurocristopathy caused by SOX10 mutations. Most PCWH-associated SOX10 mutations result in premature termination codons (PTCs), for which the molecular mechanism has recently been delineated. However, the first mutation reported to cause PCWH was a disruption of the native stop codon that by conceptual translation extends the protein into the 3' untranslated region (3'-UTR) for an additional 82 residues. In this study, we sought to determine the currently unknown molecular pathology for the SOX10 extension mutation using in vitro functional assays. Despite the wild-type SOX10 coding sequence remaining intact, the extension mutation led to severely diminished transcription and DNA-binding activities. Nevertheless, it showed no dominant-negative interference with wild-type SOX10 in vitro. Within the 82-amino acid tail, an 11-amino acid region (termed the WR domain) was responsible primarily for the deleterious properties of the extension. The WR domain, presumably forming an alpha-helix structure, inhibited SOX10 transcription activities if inserted in the carboxyl-terminal half of the protein. The WR domain can also affect other transcription factors with a graded effect when fused to the carboxyl termini, suggesting that it probably elicits a toxic functional activity. Together, molecular pathology for the SOX10 extension mutation is distinct from that of more common PTC mutations. Failure to properly terminate SOX10 translation causes the generation of a deleterious functional domain that occurs because of translation of the normal 3'-UTR; the mutant fusion protein causes a severe neurological disease.

CONDUCTION VELOCITY DISTRIBUTION: EARLY DIAGNOSTIC TOOL FOR PERIPHERAL NEUROPATHIES

In order to get early information on the functional state of smaller myelinated fibers this article investigated the applicability of conduction velocity distribution on compound action potential recorded in experimentally demyelinated frog sciatic nerve. Conduction velocity distribution histograms were estimated by using the mathematical model the authors enhanced. The results suggest that by using appropriate conduction velocity distribution model the diagnosis time in demyelinating neuropathy may be shortened at least three times as compared with conventional conduction velocity assessment. Therefore, it may be concluded that a well-defined model designed for the estimation of the conduction velocity distribution may be used as a diagnostic tool for the early phase of peripheral demyelinating neuropathies.

Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: A case report and review of the literature

Shah-Waardenburg syndrome is a rare congenital disorder with variable clinical expression, characterised by aganglionosis of the rectosigmoïd (Hirschsprung disease), and abnormal melanocyte migration, resulting in pigmentary abnormalities and sensorineural deafness (Waardenburg syndrome). Mutations in the EDN, EDNRB and SOX10 genes can be found in patients with this syndrome. SOX10 mutations are specifically associated with a more severe phenotype called PCWH: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease. Neuronal expression of SOX10 occurs in neural crest cells during early embryonic development and in glial cells of the peripheral and central nervous systems during late embryonic development and in adults. We present a 4-year-old girl with the PCWH phenotype associated with a de novo nonsense mutation (S384X) in SOX10. Main clinical features were mental retardation, peripheral neuropathy, deafness, Hirschsprung disease, distal arthrogryposis, white hairlock, and growth retardation. She presented with hypotonia, developmental delay, reduced peripheral nerve conduction velocities, and radiologically assessed central hypomyelination. Subsequently, the formation of abnormal myelin within the central and peripheral nervous system was functionally and radiologically assessed. Children presenting with features of Waardenburg syndrome and neurological dysfunction should be tested for mutations in the SOX10 gene to enable diagnosis and counselling.

Chronic inflammatory demyelinating polyradiculoneuropathy with tumefactive central demyelination

A 46-year-old man with a 1-year history of distal paresthesias and mild distal weakness subacutely developed paralysis of the left hand. Electrodiagnostic evaluation revealed a demyelinating peripheral neuropathy that met criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Magnetic resonance imaging of the brain revealed a mass that enhanced with contrast, but revealed focal myelin loss with intense macrophage activity and axonal preservation on biopsy. The mass and hand weakness improved following steroid therapy. The combination of CIDP and central demyelination with mass effect broadens the spectrum of demyelinating disease in association with CIDP.

Contacts cellulaires des fibres myélinisées du système nerveux périphérique

Myelination allows the fast propagation of action potentials at a low energetic cost. It provides an insulating myelin sheath regularly interrupted at nodes of Ranvier where voltage-gated Na+ channels are concentrated. In the peripheral nervous system, the normal function of myelinated fibers requires the formation of highly differentiated and organized contacts between the myelinating Schwann cells, the axons and the extracellular matrix. Some of the major molecular complexes that underlie these contacts have been identified. Compact myelin which forms the bulk of the myelin sheath results from the fusion of the Schwann cell membranes through the proteins P0, PMP22 and MBP. The basal lamina of myelinating Schwann cells contains laminin-2 which associates with the glial complex dystroglycan/DPR2/L-periaxin. Non compact myelin, found in paranodal loops, periaxonal and abaxonal regions, and Schmidt-Lanterman incisures, presents reflexive adherens junctions, tight junctions and gap junctions, which contain cadherins, claudins and connexins, respectively. Axo-glial contacts determine the formation of distinct domains on the axon, the node, the paranode, and the juxtaparanode. At the paranodes, the glial membrane is tightly attached to the axolemma by septate-like junctions. Paranodal and juxtaparanodal axoglial complexes comprise an axonal transmembrane protein of the NCP family associated in cis and in trans with cell adhesion molecules of the immunoglobulin superfamily (IgSF-CAM). At nodes, axonal complexes are composed of Na+ channels and IgSF-CAMs. Schwann cell microvilli, which loosely cover the node, contain ERM proteins and the proteoglycans syndecan-3 and -4. The fundamental role of the cellular contacts in the normal function of myelinated fibers has been supported by rodent models and the detection of genetic alterations in patients with peripheral demyelinating neuropathies such as Charcot-Marie-Tooth diseases. Understanding more precisely their molecular basis now appears essential as a requisite step to further examine their involvement in the pathogenesis of peripheral neuropathies in general.

SIMPLE interacts with NEDD4 and TSG101: Evidence for a role in lysosomal sorting and implications for Charcot-Marie-Tooth disease

Mutation of the SIMPLE gene (small integral membrane protein of the lysosome/late endosome) is the molecular basis of Charcot-Marie-Tooth disease type 1C (CMT1C), a demyelinating peripheral neuropathy. Although the precise function of SIMPLE is unknown, prior reports suggest it localizes to the lysosome/late endosome. Furthermore, murine Simple interacts with Nedd4 (neural precursor cell expressed, developmentally downregulated 4), an E3 ubiquitin ligase that is important for regulating lysosomal degradation of plasma membrane proteins. To bring insights into the biochemical function of human SIMPLE, we confirmed that human SIMPLE interacts with NEDD4 and also report a novel interaction with tumor susceptibility gene 101 (TSG101), a class E vacuolar sorting protein. TSG101 is known to function downstream of NEDD4, sorting ubiquitinated substrates into multivesicular bodies (MVBs), which then deliver their cargo into the lysosomal lumen for degradation. Given the interaction with NEDD4 and TSG101, and the localization of SIMPLE along the lysosomal degradation pathway, we hypothesize that SIMPLE plays a role in the lysosomal sorting of plasma membrane proteins. We examine three CMT1C-associated SIMPLE mutations and show that they do not affect the interaction with NEDD4 or TSG101, nor do they lead to altered subcellular localization.

Unusual neurophysiological features in Cockayne's syndrome: a report of two cases as a contribution to diagnosis and classification

To clarify the diagnostic value of neurophysiological investigations in patients with Cockayne's syndrome (CS). The study involved two patients with clinical diagnoses of classical and severe CS, who were neurophysiologically evaluated by means of: (1) multimodal visual (VEPs), brainstem auditory (BAEPs) and upper limb somatosensory (SEPs) evoked potentials; (2) electroretinography; and (3) nerve conduction and needle electromyography studies. Both patients showed multimodal evoked potential (EP) signs of central nervous system involvement that overlapped in severity and extent, and were consistent with demyelination along the central sensory pathways. Flash VEPs and SEPs were more altered than pattern VEPs and BAEPs. No signs of retinopathy or hearing loss of cochlear origin were detected. The nerve conduction and needle electromyography studies showed severe signs of sensory and motor demyelinating and axonal peripheral neuropathy. Peripheral neuropathy was clinically uncertain. There were no significant differences between the two patients. Our results show that combined multimodal EP and nerve conduction studies are diagnostically highly sensitive even in the early stage of CS, but their ability to distinguish classical and severe CS is limited. The unusual features were characterised by the absence of clinical and electrophysiological signs of otherwise common retinopathy and neurosensory hearing loss. BAEPs seem to be more useful than VEPs or SEPs in the diagnostic work-up of patients with suspected CS.

Niemann-pick type C disease associated with peripheral neuropathy

Niemann-Pick type C disease is an autosomal-recessive, inherited neurovisceral lipid storage disorder. This disease results from either protein NPC1 or HE1 deficiency, which leads to cholesterol metabolism disturbance and is characterized by early hepatosplenomegaly and progressive ataxia, dystonia, cataplexy, dysarthria, and dementia. We describe a 3 1/2-year-old patient with Niemann-Pick type C disease, who presented with regression in both cognitive and motor domains. Almost 10 months before admission to the hospital, the child developed progressive speech and behavioral changes, as well as gait disturbances with frequent falls. The examination demonstrated hepatosplenomegaly, ataxia, and vertical gaze palsy. Nerve conduction velocities demonstrated mild demyelinating peripheral neuropathy. Bone marrow examination revealed foam cells, and cholesterol esterification studies found massive accumulation of unesterified cholesterol and very low intracellular esterification of exogenous lipoprotein-derived cholesterol. These results indicate Niemann-Pick type C disease. Peripheral neuropathy is a rare complication in patients with Niemann-Pick type C disease, which certainly contributes to their neurologic deterioration.

LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice

In previous overexpression studies we revealed a role for the lysosomal membrane protein LIMP-2/LGP85 in lysosomal biogenesis. LIMP-2-deficient mice show an increased postnatal mortality which is associated with a development of a uni- or bilateral hydronephrosis caused by an obstruction of the ureteropelvic junction. An accumulation of lysosomes in epithelial cells of the ureter adjacent to the ureteral lumen and a disturbed apical expression of uroplakin was observed, suggesting an impairment of membrane transport processes. Serious hearing impairment in LIMP-2-deficient animals was indicated by deficits in acoustic startle responses, in brainstem evoked auditory potentials and a reduced endochondral potential. LIMP-2-deficient mice suffer from a massive decline of spiral ganglia in the cochlea concomitant with that of the inner and outer hair cells. These pathological changes begin at the age of 3 months and are probably secondary to a degeneration of the stria vascularis. LIMP-2-deficient mice are also characterized by a peripheral demyelinating neuropathy. Demyelinization was found to be associated with a massive loss of peripheral myelin proteins and an increased activity and expression of lysosomal proteins highlighting a hitherto unknown role of the lysosomal compartment in the development of this myelination disorder. The phenotype of LIMP-2-deficient mice stimulates the search for mutations in human disorders associated with degeneration of the stria vascularis and/or demyelinization of peripheral nerves.