John R. Muddle

A novel RAB7 mutation associated with ulcero-mutilating neuropathy

There are two known autosomal dominant genes for the hereditary ulcero‐mutilating neuropathies: SPTLC1 (hereditary sensory neuropathy type 1) and RAB7 (Charcot–Marie–Tooth disease type 2B). We report a family with autosomal dominant ulcero‐mutilating neuropathy, developing in the teens and characterized by ulcers, amputations, sensory involvement in the feet but no motor features. Sequencing the RAB7 gene showed a novel heterozygous A to C mutation, changing asparagine to threonine at codon 161. The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7. Ann Neurol 2004;56:586–590

Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons

Dysfunction of the ubiquitin‐proteasomal system (UPS) has been implicated in the pathogenesis of Parkinsons disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinsons disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase–positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase–positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinsons disease. Ann Neurol 2006;60:253–255

Comparison of a new pmp22 transgenic mouse line with other mouse models and human patients with CMT1A.

Charcot‐Marie‐Tooth disease type 1A is a dominantly inherited demyelinating disorder of the peripheral nervous system. It is most frequently caused by overexpression of peripheral myelin protein 22 (PMP22), but is also caused by point mutations in the PMP22 gene. We describe a new transgenic mouse model (My41) carrying the mouse, rather than the human, pmp22 gene. The My41 strain has a severe phenotype consisting of unstable gait and weakness of the hind limbs that becomes obvious during the first 3 weeks of life. My41 mice have a shortened life span and breed poorly. Pathologically, My41 mice have a demyelinating peripheral neuropathy in which 75% of axons do not have a measurable amount of myelin. We compare the peripheral nerve pathology seen in My41 mice, which carry the mouse pmp22 gene, with previously described transgenic mice over‐expressing the human PMP22 protein and Trembler‐J (TrJ) mice which have a P16L substitution. We also look at the differences between CMT1A duplication patients, patients with the P16L mutation and their appropriate mouse models.

Hereditary motor and sensory neuropathy‐russe: New autosomal recessive neuropathy in balkan gypsies

A novel peripheral neuropathy of autosomal recessive inheritance has been identified in Balkan Gypsies and termed hereditary motor and sensory neuropathy‐Russe (HMSN‐R). We investigated 21 affected individuals from 10 families. Distal lower limb weakness began between the ages of 8 and 16 years, upper limb involvement beginning between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in two instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve. HMSN‐R is a new form of autosomal recessive inherited HMSN caused by a single founder mutation in a 1Mb interval on chromosome 10q.

Peripheral neuropathy in the Chediak-Higashi syndrome

SummaryThe clinical features of a brother and sister with the Chediak-Higashi syndrome (CHS) are reported. Both showed evidence of a sensory neuropathy associated with central nervous system involvement. Nerve conduction studies indicated an “axonal” neuropathy. Sural nerve biopsy in the brother demonstrated a loss of myelinated nerve fibres, particularly those of larger size, and of unmyelinated axons. In contradistinction to some previous reports, giant lysosomes in Schwann cells were not observed and there were no inflammatory changes. Electron microscopy and teased-fibre studies showed no evidence of demyelination. It is concluded that the neuropathy of CHS is of axonal type. Its mechanism remains obscure.

Opiate receptor subtypes in the nucleus tractus solitarii of the cat: the effect of vagal section

The distribution of mu, delta and kappa opioid receptors in the lower brainstem of the cat has been determined autoradiographically by studying the binding of tritiated [D-Ala2,MePhe4,Glyol5][tyrosyl-3,5-3H]enkephalin (DAGO), [D-Pen2,D-Pen5][tyrosyl-3,5-(n)-3H]enkephalin (DPDPE) and [9-3H]ethylketazocine (EKC), respectively. General opiate receptor binding was established using [3H]naloxone (NX). High densities of [3H]NX and DAGO binding sites were found most prominently in the nucleus tractus solitarii. There was no DPDPE and very weak EKC binding within this nucleus, although both these ligands bound to the cerebellum. The effect of unilateral vagotomy on receptor density was examined. Sectioning the cervical vagus had no effect on the density of mu receptors in the brainstem. Sectioning the vagus, accompanied by nodose ganglion excision, led to a marked depletion of mu receptors which was restricted to dorsal and medial regions of the ipsilateral nucleus tractus solitarii at, and rostral to, the obex. These results suggest that mu opiate receptors are located presynaptically on vagal afferents terminating within a restricted region of the nucleus tractus solitarii.

The sensory neuropathy of Friedreich's ataxia: an autopsy study of a case with prolonged survival

SummaryObservations have been made on a patient with Friedreichs ataxia who died 52 years after the onset of symptoms. The pathology of the brain and spinal cord was typical of this disorder. Apart from loss of dorsal root ganglion cells, severe loss of secondary sensory neurons was observed, including the nucleus dorsalis in the spinal cord, the spinal and principal trigeminal nuclei and, in particular, the mesencephalic trigeminal nucleus in the brain stem. Morphometric studies on the first sacral nerve root and on the sural nerve at levels from midthigh to ankle revealed a distally accentuated axonal loss that predominantly affected larger myelinated nerve fibres. Regenerative activity was seen, mainly in the spinal root and proximally in the sural nerve. Relative myelin thickness, assessed by g ratios, tended to be reduced. As teased fibre studies showed only limited evidence of demyelination/remyelination and of axonal regeneration, this therefore suggests the presence of hypomyelination. The results confirm the presence of a distal axonopathy and provide no evidence that this is preceded by axonal atrophy.

Ndrg1 in development and maintenance of the myelin sheath

CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.

Abnormal Schwann cell/axon interactions in the Trembler-J mouse.

The Trembler‐J (TrJ) mouse has a point mutation in the gene coding for peripheral myelin protein 22 (PMP22). Disturbances in PMP22 are associated with abnormal myelination in a range of inherited peripheral neuropathies both in mice and humans. PMP22 is produced mainly by Schwann cells in the peripheral nervous system where it is localised to compact myelin. The function of PMP22 is unclear but its low abundance (∼5% of total myelin protein) means that it is unlikely to play a structural role. Its inclusion in a recently discovered family of proteins suggests a function in cell proliferation/differentiation and possibly in adhesion. Nerves from TrJ and the allelic Trembler (Tr) mouse are characterised by abnormally thin myelin for the size of the axon and an increased number of Schwann cells. We report ultrastructural evidence of abnormal Schwann cell‐axon interactions. Schwann cell nuclei have been found adjacent to the nodes of Ranvier whereas in normal animals they are located near the centre of the internodes. In some fibres the terminal myelin loops faced outwards into the extracellular space instead of turning inwards and terminating on the axon. In severely affected nerves many axons were only partially surrounded by Schwann cell cytoplasm. All these features suggest a failure of Schwann cell–axon recognition or interaction. In addition to abnormalities related to abnormal myelination there was significant axonal loss in the dorsal roots.

The effect of the ETA receptor antagonist, FR 139317, on [125I]‐ET‐1 binding to the atherosclerotic human coronary artery

1 The distribution of [125I]‐endothelin (ET‐1) binding sites on atherosclerotic human epicardial coronary arteries has been studied by in vitro receptor autoradiography. 2 [125I]‐ET‐1 binding was to the tunica media and regions of neovascularization. 3 Competition studies were carried out in the presence of ET‐1 and the ETA receptor antagonist, FR 139317. The IC50 values for ET‐1 at the tunica media and regions of neovascularization were similar (mean ± s.e.mean of n = 4 patients, 2.5 ± 0.9 nm and 2.9 ± 0.9 nm, respectively) whereas IC50 values for FR 139317 at regions of neovascularization (607 ± 34 nm) were significantly higher than those of the tunica media (12.6 ± 2.4 nm) (P < 0.0001). 4 These results indicate that ETA receptors are present on the tunica media of the diseased human coronary artery whereas a different ET receptor subtype exists at regions of neovascularization.