Hereditary motor and sensory neuropathy with minifascicle formation in a patient with 46XY pure gonadal dysgenesis: a new clinical entity

This case report is of a patient with 46XY pure gonadal dysgenesis, who presented with chronic progressive motor and sensory polyneuropathy. The sural nerve biopsy exhibited minifascicle formations accompanied by a marked decrease in myelinated fibers. This is the first report of polyneuropathy with minifascicle formations in 46XY pure gonadal dysgenesis. Because a similar polyneuropathy was recently reported in a case with 46XY partial gonadal dysgenesis, it is possible that these cases represent a new type of hereditary motor and sensory neuropathy associated with gonadal dysgenesis.     

Motor-sensory neuropathy without minifascicles in a patient with 46XY gonadal dysgenesis

We report a 36-year-old patient with 46XY pure gonadal dysgenesis (GD), who manifested a syndrome of progressive motor-sensory neuropathy. Sural nerve biopsy showed severe axonal neuropathy. Since reported cases of chronic motor-sensory neuropathy and pure gonadal dysgenesis have been characterized by nerve biopsy evidence of minifascicle formation, we suggest that this clinical association may be a new type of hereditary motor-sensory neuropathy, not necessarily associated with minifascicle formation.     

Polyneuropathy with minifascicle formation in a patient with 46XY mixed gonadal dysgenesis

A patient with mixed gonadal dysgenesis showed glove and stocking-type sensory impairment and slowing of motor and sensory nerve conduction. Sural nerve biopsy revealed minifascicular formation with decreased density of myelinated fibers. As far as we are aware, this is the first report of polyneuropathy with minifascicular formation in 46XY mixed gonadal dysgenesis. Received: 21 September 1998 / Revised: 14 December 1998, 15 February 1999 / Accepted: 15 February 1999     

Endoneurial ATPase activity in tangier disease and other peripheral neuropathies

Endoneurial sodium, potassium adenosine triphosphatase (Na⁺, K⁺-ATPase) and Mg²⁺-ATPase activities were determined in routine sural nerve biopsies from patients being evaluated for peripheral neuropathy. A significant reduction of endoneurial Na⁺, K⁺-ATPase and Mg²⁺-ATPase activities was shown in six sural nerve biopsies from patients with Tangier disease complicated by mononeuopathy multiplex or progressive axonal neuropathy. Peripheral nerve ATPase activities did not correlate with myelinated or unmyelinated nerve fiber densities in these biopsies. Other peripheral neuronal disorders with reduced endoneurial Na⁺, K⁺-ATPase and Mg²⁺-ATPase activities included severe vasculitic neuropathy, diabetic neuropathy, tomaculous neuropathy, and motoneuron disease. Such reduced levels of ATPase activity in peripheral nerve may relate to altered endoneurial lipid metabolism and impaired axoplasmic flow.     

Generalized peripheral neuropathy in a dental technician exposed to methyl methacrylate monomer.

A 58-year-old dental prosthetic technician developed generalized sensorimotor peripheral neuropathy. Neurophysiologic studies showed a generalized sensorimotor neuropathy of axonal degeneration type. Examination of a sural nerve biopsy showed a moderately severe axonal neuropathy with loss of large myelinated fibers and unmyelinated axons. There was evidence of slow ongoing degeneration and considerable fiber regeneration. Electron microscopy showed increased numbers of filaments in a few fibers. These findings show resemblances to the nerve changes caused by another acrylic resin, acrylamide. We suggest that the neuropathy may have been caused by 30 years of occupational cutaneous and inhalational exposure to methyl methacrylate monomer since we excluded other recognized causes of neuropathy.     

Docetaxel neuropathy: a distal axonopathy

Docetaxel has been implicated as a causative agent in peripheral neuropathy, but pathological changes in peripheral nerve have not been described. During docetaxel treatment a 54-year-old man developed a sensorimotor polyneuropathy when the overall docetaxel dosage was 540 mg/m². Neurophysiological investigation revealed a sensorimotor axonal neuropathy. Fascicular sural nerve biopsy showed an axonal neuropathy with a preferentially loss of large myelinated fibers. There was evidence of considerable fiber regeneration. Sensory and motor symptoms progressively improved after docetaxel withdrawal. Received: 21 January 1999 / Revised, accepted: 25 March 1999     

Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes

BACKGROUND: Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy. Axonal degeneration in the late-onset H10P mutation may be caused by the disruption of axoglial interaction. OBJECTIVE: To evaluate sural nerve biopsy samples from a patient with early-onset Charcot-Marie-Tooth disease type 1B caused by an arg69-to-cys (R69C) mutation. Design and PARTICIPANTS: Biopsies of sural nerves were performed 20 years apart in a patient with an R69C mutation (early onset). In addition, peripheral nerves were obtained from autopsy material from a patient with a T95M mutation (late onset). These nerves were analyzed using light microscopy of semithin sections, teased nerve fiber immunohistochemical analysis, electron microscopy, and immunologic electron microscopy. MAIN OUTCOME MEASURES: Pathological changes in sural nerve. RESULTS: Both R69C biopsy samples showed prominent demyelination and onion bulb formation, unlike the late-onset T95M mutation, which showed primarily axonal degeneration with no onion bulbs. The sural biopsy sample obtained 20 years earlier from the R69C patient showed minimal difference from the present sample, consistent with the lack of clinical progression during the 2 decades. Teased fiber immunohistochemical analysis of R69C revealed voltage-gated sodium channel subtype 1.8 expressions at the nodes of Ranvier around the areas of segmental demyelination. Internodal length in all R69C nerve fibers was invariably short (>94% of all internodes are <150 mum). CONCLUSIONS: Morphologic abnormalities in this early-onset R69C neuropathy were severe in childhood but progressed very slowly after adolescence. The switch to voltage-gated sodium channel subtype 1.8 expression at the nodes may provide clues into the pathogenesis of this case of early-onset neuropathy, and the short internodes may contribute to the extremely slowed conduction velocities in this case (<10 m/s).     

Subacute axonal neuropathy in Parkinson's disease with cobalamin and vitamin B6 deficiency under duodopa therapy

We describe two patients who developed subacute axonal peripheral neuropathy under duodopa treatment. Comprehensive diagnostic workup including muscle and sural nerve biopsy revealed that the most probable cause of subacute axonal peripheral neuropathy was cobalaminand vitamin B6 deficiency in both the patients. © 2010 Movement Disorder Society     

Progressive idiopathic axonal neuropathy

Abstract. Patients with a progressive disabling idiopathic axonal neuropathy could have a potentially treatable immune mediated neuropathy. To evaluate whether progressive idiopathic axonal neuropathy could be a pathologically difficult to prove vasculitic neuropathy pathologically difficult to prove or if it could be a separate clinical entity (i. e. with the axon as the primary immunological target), we performed a comparative clinical and histopathological study in 10 patients with progressive idiopathic axonal neuropathy, 10 patients with vasculitic neuropathy, and 12 patients with chronic idiopathic axonal polyneuropathy (CIAP). The clinical features and disease course in patients with progressive idiopathic axonal neuropathy and patients with vasculitic neuropathy were similar. Six patients with progressive idiopathic axonal neuropathy had been treated with prednisone and/or intravenous immunoglobulin. Disability decreased in all these six patients, but also in two of the four non-treated patients. Upon reviewing the sural nerve biopsy specimens, vasculitis was found in one patient with progressive idiopathic axonal neuropathy. Vasculitis-associated signs of ischemic injury or inflammation (most notably: large variation in fascicular axonal degeneration, perivascular inflammation, inflammation of the blood vessel wall without lumen obstruction) were found in four patients with progressive idiopathic axonal neuropathy, in all patients with vasculitic neuropathy, but were absent in patients with CIAP. The findings show that there is a small chance of finding sural nerve vasculitis upon scrutinising biopsy examination in progressive idiopathic axonal neuropathy. The presence of vasculitisassociated signs in progressive idiopathic axonal neuropathy suggests that some of these patients could have vasculitic neuropathy, even if vasculitic lesions cannot be demonstrated. However, if inflammatory changes cannot be demonstrated this does not preclude an immune-mediated origin.     

The spectrum of Charcot-Marie-Tooth disease due to myelin protein zero: An electrodiagnostic,nerve ultrasound and histological study

Objective

Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology.

Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2

Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot-Marie-Tooth disease (CMT). The aim of this study was to describe a de novo MFN2 p.R104W mutation and characterize the associated phenotype. We screened the entire coding region of MFN2 gene and characterized its clinical phenotype, nerve conduction studies and sural nerve biopsy. Neuropsychological tests and brain MRI were also performed. A de novo mutation was found in exon 4 (c.310C > T; p.R104W). In addition to a severe and early onset axonal neuropathy, the patient presented learning problems, obesity, glucose intolerance, leukoencephalopathy, brain atrophy and evidence of myelin involvement and mitochondrial structural changes on sural nerve biopsy. These results suggest that MFN2 p.R104W mutation is as a hot-spot for MFN2 gene associated to a large and complex range of phenotypes.     

The peripheral neuropathy of vitamin B12 deficiency

Nerve conduction studies and sural nerve biopsy were performed on three patients with vitamin B12 deficiency and symptoms of peripheral neuropathy. The pathological findings were those of axonal degeneration; there was no evidence of demyelination. The patients were reviewed at intervals of 5-15 years commencement of treatment; progression of the neuropathy had been arrested by treatment, but in all cases residual neurological abnormalities persisted. In one patient with autonomic neuropathy, the postural hypotension resolved rapidly and fully with treatment.     

BAG3 mutations: another cause of giant axonal neuropathy

Mutations in Bcl-2 associated athanogene-3 (BAG3) are a rare cause of myofibrillar myopathy, characterised by rapidly progressive proximal and axial myopathy, cardiomyopathy and respiratory compromise. Neuropathy has been documented neurophysiologically in previously reported cases of BAG3-associated myofibrillar myopathy and in some cases giant axons were observed on nerve biopsies; however, neuropathy was not thought to be a dominant feature of the disease. In the context of inherited neuropathy, giant axons are typically associated with autosomal recessive giant axonal neuropathy caused by gigaxonin mutations but have also been reported in association with NEFL- and SH3TC2-associated Charcot-Marie-Tooth disease. Here, we describe four patients with heterozygous BAG3 mutations with clinical evidence of a sensorimotor neuropathy, with predominantly axonal features on neurophysiology. Three patients presented with a significant neuropathy. Muscle magnetic resonance imaging (MRI) in one patient revealed mild to moderate atrophy without prominent selectivity. Examination of sural nerve biopsies in two patients demonstrated giant axons. This report confirms the association of giant axonal neuropathy with BAG3-associated myofibrillar myopathy, and highlights that neuropathy may be a significant feature.     

Rapid axonal transport velocity is reduced in experimental ethylene oxide neuropathy

Chronic exposure of rats to ethylene oxide (EO) causes distal axonal neuropathy of lumbosacral primary sensory neurons. To study the pathogenesis of this neuropathy, we measured rapid axonal transport in peripheral nerves. Rats were exposed for 6 h to 500 ppm EO in a chamber three times a wk for 15 wk. Rapid axonal transport and quantitative histological alterations of peripheral nerves were studied. After [³⁵S]methionine injection into the dorsal root ganglion, the velocity of rapid anterograde axonal transport of radioisotope-labeled protein was measured. The velocity in the rats exposed to EO was 33% less than that in control rats exposed to filtered room air. However, histological differences were slight. Morphometric studies showed that in EO-exposed rats, only the distal portions of the sural nerve had significantly greater incidental degeneration of myelinated fibers than did controls. There were significantly fewer large myelinated fibers only in the distals peroneal nerve. Therefore, a decrease in the velocity of anterograde anxonal transport, related to these slight histological abnormalities of the peripheral nerve, may play a causative role in the development of distal axonal neuropathy owing to chronic EO exposure.     

Inherited motor-sensory neuropathy with upper limb predominance associated with the tropomyosin-receptor kinase fused gene

The Tropomyosin-receptor kinase fused gene (TFG) encodes TFG which is expressed in spinal motor neurons, dorsal root ganglia and cranial nerve nuclei, and plays a role in the dynamics of the endoplasmic reticulum. Two dominant missense TFG mutations have previously been reported in limited geographical areas (Far East, Iran, China) in association with hereditary motor sensory neuropathy with proximal involvement (HMSN-P) of the four limbs, or with Charcot–Marie–Tooth disease type 2 (CMT2). The 60-year-old female proband belonging to a three-generation Italian family presented with an atypical neuropathy characterized by diffuse painful cramps and prominent motor-sensory impairment of the distal upper limbs. Her sural nerve biopsy showed chronic axonal neuropathy without active degeneration or regeneration. Targeted next-generation sequencing of a panel with 98 genes associated with inherited peripheral neuropathies/neuromuscular disorders identified three candidate genes: TFG, DHTKD1 and DCTN2. In the family, the disease co-segregated with the TFG p.(Gly269Val) variant. TFG should be considered in genetic testing of patients with heterogeneous inherited neuropathy, independently of their ethnic origin.     

Is ischemia implicated in chronic multifocal demyelinating neuropathy?

We describe a patient with chronic multifocal demyelinating neuropathy associated with persistent conduction block. Multifascicular lesions in sural nerve included a complete loss of myelinated fibers, demyelination, remyelination, onion bulb formation, and axonal attenuation. On the basis of these morphometric results we hypothesize that nerve ischemia may be involved in the pathogenesis of chronic multifocal demyelinating neuropathy.     

Late‐onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2‐related diseases

Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot–Marie‐Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53‐year‐old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2‐related diseases. Sequencing of MFN2 should be considered in all patients presenting with late‐onset HSAN.     

Leber's disease with spastic paraplegia and peripheral neuropathy. Case report with nerve biopsy study

A 43-year-old patient with familial Leber's optic atrophy suffered from spastic paraplegia. Physical examination disclosed cerebellar and pyramidal signs and signs of peripheral neuropathy. On sural nerve biopsy, there were few large myelinated fibers, signs of axonal degeneration and thin myelin sheets. This case suggests an overlap syndrome with central and peripheral nervous system features of Leber's disease, spinocerebellar degeneration and peroneal muscular atrophy.     

A comparison of sural nerve conduction studies in patients with impaired oral glucose tolerance test

OBJECTIVE: Monitoring of the sural nerve is a sensitive method for detection of neuropathies. We examined different methods of studying sural nerve conduction in a group of patients with impaired glucose tolerance (IGT) in the same study. MATERIALS AND METHODS: Several parameters of sural nerve were investigated in 20 patients. First, sensory nerve conduction studies of the sural nerve were performed on the distal-leg and the proximal-leg segments. Second, dorsal sural nerve studies were conducted. Third, the sural/radial sensory nerve action potential (SNAP) amplitude ratios were calculated. The results were compared with those obtained from 21 healthy controls. RESULTS: Abnormal results revealing peripheral neuropathy were found in only one patient and dorsal sural SNAP was absent in another patient (5%). Although the results of nerve conduction studies were within normal ranges except the patient with peripheral neuropathy, the lower extremity nerves and especially sural nerves have been found to be more affected and the parameters revealed large differences between groups (P < 0.05). Only dorsal sural nerve latency related to fasting blood glucose level in patients (<0.05). DISCUSSION AND CONCLUSIONS: Sural nerve studies should be of value to determine neuropathy in IGT patients. This study supported the idea that IGT is a transitional state before diabetes and also the importance of the dorsal sural nerve latencies for early detection of neuropathy.