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.

No abstract

The complement (C) system plays an important role in myelin breakdown during Wallerian degeneration (WD). The pathway and mechanism involved are, however, not clear. In a crush injury model of the sciatic nerve, we show that C6, necessary for the assembly of the membrane attack complex (MAC), is essential for rapid WD. At 3 d after injury, pronounced WD occurred in wild-type animals, whereas the axons and myelin of C6-deficient animals appeared intact. Macrophage recruitment and activation was inhibited in C6-deficient rats. However, 7 d after injury, the distal part of the C6-deficient nerves appeared degraded. As a consequence of a delayed WD, more myelin breakdown products were present than in wild-type nerves. Reconstitution of the C6-deficient animals with C6 restored the wild-type phenotype. Treatment with rhC1INH (recombinant human complement 1 inhibitor) blocked deposition of activated C-cleaved products after injury. These experiments demonstrate that the classical pathway of the complement system is activated after acute nerve trauma and that the entire complement cascade, including MAC deposition, is essential for rapid WD and efficient clearance of myelin after acute peripheral nerve trauma.

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 1 Mb interval on chromosome 10q.

Observations have been made on the peripheral nerve changes in four patients, ranging in age from 4 to 32 years, with the congenital cataracts facial dysmorphism neuropathy syndrome. Myelinated fibre density was within normal limits. The salient abnormality was diffuse hypomyelination which, in the older patients, was associated with demyelination and then axonal degeneration. These findings could be correlated with the relative preservation of sensory action potential amplitude despite markedly reduced nerve conduction velocity. Unmyelinated axon density was preserved. The morphological observations suggest the operation of a developmental process affecting myelination with a later superimposed degenerative disorder.

The use of galactosaemia as a model for some aspects of diabetic polyneuropathy allows the influence of glycation to be studied independently of other effects. There are well-studied abnormalities of the peripheral nerves in galactosaemic rats, one of which is that the efficiency of regeneration is initially reduced. One possible cause could be that glycated myelin debris in macrophages is less degradable and interferes with macrophage function. Macrophage recognition and ingestion of myelin glycosylated in vitro increases with the duration of incubation in a sugar-rich medium. This study was performed to investigate a possible correlation between galactosaemia and regeneration, together with the role of macrophages. Galactosaemia was induced by adding galactose to the rats' diet for 2 months before injury. Following a crush lesion to the sciatic nerve, regeneration was found to be delayed, demonstrated by a reduction in mean myelinated fibre size and density 1 month after crush, although, 2 and 3 months later, the differences did not reach statistical significance. There were also more macrophages in the galactosaemic rats than in the control animals at all time points. The initial delay in regeneration in galactosaemic rats was therefore only temporary and there was little evidence of long-term deleterious effects. In addition to the morphometric results, immunohistochemistry showed that there were more macrophages in the galactosaemic rats than in the control animals at all time points. Correlating macrophage and myelinated fibre counts suggests that the persistence of debris-containing macrophages does not appear to have a significant inhibitory effect on nerve regeneration. No evidence was found for persistent basal laminal tubes around the regenerating clusters.

2002) Neuropathology and Applied Neurobiology 28, 381-389 Peripheral nerve regeneration in galactosaemic ratsThe use of galactosaemia as a model for some aspects of diabetic polyneuropathy allows the influence of glycation to be studied independently of other effects. There are wellstudied abnormalities of the peripheral nerves in galactosaemic rats, one of which is that the efficiency of regeneration is initially reduced. One possible cause could be that glycated myelin debris in macrophages is less degradable and interferes with macrophage function. Macrophage recognition and ingestion of myelin glycosylated in vitro increases with the duration of incubation in a sugar-rich medium. This study was performed to investigate a possible correlation between galactosaemia and regeneration, together with the role of macrophages. Galactosaemia was induced by adding galactose to the rats' diet for 2 months before injury. Following a crush lesion to the sciatic nerve, regeneration was found to be delayed, demonstrated by a reduction in mean myelinated fibre size and density 1 month after crush, although, 2 and 3 months later, the differences did not reach statistical significance. There were also more macrophages in the galactosaemic rats than in the control animals at all time points. The initial delay in regeneration in galactosaemic rats was therefore only temporary and there was little evidence of long-term deleterious effects. In addition to the morphometric results, immunohistochemistry showed that there were more macrophages in the galactosaemic rats than in the control animals at all time points. Correlating macrophage and myelinated fibre counts suggests that the persistence of debris-containing macrophages does not appear to have a significant inhibitory effect on nerve regeneration. No evidence was found for persistent basal laminal tubes around the regenerating clusters.