Clinical and electrophysiological investigations and nerve biopsies were carried out on 61 patients shown to have a chromosome 17p11.2 duplication (hereditary motor and sensory neuropathy-HMSN Ia). Of these, 50 showed a Charcot-Marie-Tooth (CMT) phenotype and eight could be classified as having the Roussy-Lévy syndrome. Of the patients with a CMT phenotype, three had associated pyramidal signs and of these one had 'complicated' HMSN and also signs of cerebellar and bulbar involvement. Diaphragmatic weakness was present in three severely affected cases, one of whom also had denervation of the anal sphincter associated with faecal incontinence. One unusual case presented in middle life with incapacitating muscle cramps associated with calf hypertrophy and only mild clinical signs of neuropathy. Prominent distal sensory loss was a consistent feature in one family, resulting in acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT and Roussy-Lévy phenotypes, in seven patients. Upper limb motor nerve conduction velocity was 19.9 m/s +/- 1.3 (SEM), range 5-34 m/s. This corresponds to values previously obtained for autosomal dominant HMSN I. This series consisted mainly of older patients with more advanced disease. In contrast to the findings in younger patients, in their nerve biopsies, myelin thickness tended to be relatively reduced for axon size, indicating remyelination and/or hypomyelination; there was also regression of the onion bulbs. It is concluded that the possession of two copies of the peripheral myelin protein 22 gene within the duplicated region on chromosome 17p gives rise to a range of phenotypes and not solely to a CMT syndrome, and that the pattern of histological change in the peripheral nerves alters with advance of the disease.
Connective tissue remodeling provides mammals with a rapid mechanism to repair wounds after injury. Inappropriate activation of this reparative process leads to scarring and fibrosis. Here, we studied the effects of platelet-derived growth factor receptor- blockade in vivo using the platelet-derived growth factor receptor (PDGFR)- inhibitor imatinib mesylate on tissue repair. After 7 days, healing of wounds was delayed with significantly reduced wound closure and concomitant reduction in myofibroblast frequency, expression of fibronectin ED-A, and collagen type I. Using a collagen type I transgenic reporter mouse, we showed that inhibiting PDGFR- activation restricted the distribution of collagen-synthesizing cells to wound margins and dramatically reduced cell proliferation in vivo. By 14 days, treated wounds were fully closed. Blocking PDGFR- signaling did not prevent the differentiation of myofibroblasts in vitro but potently inhibited fibroblast proliferation and migration. In addition, PDGFR- inhibition in vivo was accompanied by abnormal microvascular morphogenesis reminiscent of that observed in PDGFR- ؊/؊ mice with significantly reduced immunostaining of the pericyte marker NG2. Imatinib treatment also inhibited pericyte proliferation and migration in vitro. This study highlights the significance of PDGFR- signaling for the recruitment, proliferation, and functional activities of fibroblasts and pericytes during the early phases of wound healing.
Classically, the course of Charcot-Marie-Tooth (CMT) disease is gradually progressive. We describe eight atypical patients who developed acute or subacute deterioration. Seven of these had genetically proven CMT disease type 1A (CMT1A) due to chromosome 17p11.2-12 duplication, and one had X-linked disease (CMTX) due to a mutation in the GJB1 gene. In this group there was sufficient clinical, electrophysiological and neuropathological information to indicate a diagnosis of a superimposed inflammatory polyneuropathy. The age range of the patients was 18-69 years, with a mean of 39 years. A family history of a similar neuropathic condition was present in only four patients. All eight had an acute or subacute deterioration following a long asymptomatic or stable period. Seven had neuropathic pain or prominent positive sensory symptoms. Nerve biopsy demonstrated excess lymphocytic infiltration in all eight patients. Five patients were treated with steroids and/or intravenous immunoglobulin, with variable positive response; three patients received no immunomodulatory treatment. Inflammatory neuropathy has previously been recognized in patients with hereditary neuropathy, with uncharacterized genetic defects and with CMT1B. We present detailed assessments of patients with CMT1A and CMTX, including nerve biopsy, and conclude that coexistent inflammatory neuropathy is not genotype-specific in hereditary motor and sensory neuropathy. Although this was not a formal epidemiological study, estimates of the prevalence of CMT disease and chronic inflammatory demyelinating polyneuropathy indicate that the association is more frequent than would be expected by chance. This has implications for understanding the pathogenesis of inflammatory neuropathies and raises important considerations in the management of patients with hereditary neuropathies. If a patient with CMT disease experiences an acute or subacute deterioration in clinical condition, treatment of a coexistent inflammatory neuropathy with steroids or immunoglobulin should be considered.
Observations have been made on a selected series of insulin-dependent patients with neuropathy, subdivided into three groups: (1) severe autonomic neuropathy with an accompanying painless sensory neuropathy; (2) severe autonomic neuropathy with a chronic painful sensory neuropathy; and (3) chronic or acute painful sensory neuropathy with no autonomic neuropathy. All three groups showed a loss of large and small myelinated nerve fibres in sural nerve biopsy specimens which was greater in Groups 1 and 2. Regenerative activity was prominent in all three groups, but least in Group 3. Teased fibre studies showed evidence both of axonal regeneration and remyelination. Active fibre degeneration was rare. Measurements of g ratio (axon diameter:total fibre diameter) gave no indication of axonal atrophy. The density of unmyelinated axons was reduced in all three groups, as was their median diameter. Vibration sense threshold was positively correlated with the total number of myelinated fibres and thermal sensory threshold with median unmyelinated axon diameter but not with total unmyelinated axon numbers. No correlation between the occurrence of pain and active degeneration of myelinated fibres or with regenerative activity either in myelinated or unmyelinated axons was detectable. Assessment of differential loss of large or small myelinated nerve fibres was difficult because of the presence of large numbers of small regenerating myelinated axons. The results are discussed in relation to the concept of 'diabetic small fibre neuropathy' and the causation of pain in diabetic 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.
We analyzed clinical and pathological disease in 2 peripheral myelin protein-22 (PMP22) overexpressing mouse models for 1.5 years. C22 mice have 7 and C3-PMP mice have 3 to 4 copies of the human PMP22 gene. C3-PMP mice showed no overt clinical signs at 3 weeks and developed mild neuromuscular impairment; C22 mice showed signs at 3 weeks that progressed to severe impairment. Adult C3-PMP mice had very similar, stable, low nerve conduction velocities similar to adults with human Charcot-Marie-Tooth disease type 1A (CMT1A); velocities were much lower in C22 mice. Myelination was delayed, and normal myelination was not reached in either model but the degree of dysmyelination in C3-PMP mice was considerably less than that in C22 mice; myelination was stable in the adult mice. Numbers of myelinated, fibers were reduced at 3 weeks in both models, suggesting that normal numbers of myelinated fibers are not reached during development in the models. In adult C3-PMP and wild-type mice, there was no detectable loss of myelinated fibers,whereas there was clear loss of myelinated fibers in C22 mice.In C3-PMP mice, there is a balance between myelination status and axonal function early in life, whereas in C22 mice, early reduction of axons is more severe and there is major loss of axons in adulthood. We conclude that C3-PMP mice may be an appropriate model for most CMT1A patients, whereas C22 mice may be more relevant to severely affected patients in the CMT1 spectrum.
These findings show that the no-touch technique for saphenous vein graft harvesting for coronary bypass grafting preserves an intact vasa vasorum. This could represent one of the mechanisms underlying the improved patency of saphenous vein grafts harvested with this technique.
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