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PM P22 mice. The absence of PMP22 resulted in abnormal myelin formation in development.

P4 In the pectineus nerve of P4 mice a population of large calibre axons had separated from the fetal bundles and were ensheathed singly by Schwann cells (Adlkofer et al. 1995). In wildtype animals 60% of these large calibre axons were surrounded by compact myelin whereas only 19% were myelinated in PMP22 mice. In the population of axons that were myelinated, the myelin sheaths were already abnormally thickened with respect to axon diameter.

P24 In the femoral nerve of P24 mice many fibres had redundant myelin loops with normal myelin periodicity and a corresponding compression of the axon (Adlkofer et al. 1995). The myelin of some tomacula was disorganised and the axons were displaced, the authors considered this to reflect an early stage of degeneration. Many thinly myelinated axons, basal lamina-covered Schwann cells and onion bulbs were seen. Some large calibre axons were seen completely devoid of myelin and the Schwann cells ensheathing them were occasionally associated with degenerating myelin. Teased fibre analysis showed tomacula associated with every axon-Schwann cell unit. They were preferentially found at paranodal regions of myelinated fibres but intemodal tomacula were also seen. Axonal loss was shown in the pectinous nerve at P24.

10 weeks Tomacula were rare and established signs of degeneration were observed in 10 wk mice. No abnormalities were noted outside the PNS. Axonal loss could not be quantified due to the presence of axonal sprouts

PMP22 mice have abundant tomacula at a young age but show demyelination and reduced MNCVs (similar to CMTl) with progressing age. This suggests that tomacula are unstable transient structures that degenerate during maturation, their presence indicating a predisposition to demyelination. Aldkofer et al. concluded that focal hypermyelination followed by myelin degeneration is likely to be a common

Tomacula.

The term ‘tomacula’ was coined by Madrid and Bradley ( 1975) to describe elongated or sausage-shaped thickenings of the myelin sheath {tomaculum, Latin = sausage). The first description of globular thickenings of the myelin sheath is credited to Dayan et al. (1968). They also noted that the structures occurred in the presence of extensive segmental demyelination. Behse et al. (1972) also described sausage-like swellings of the myelin sheath and considered them to have arisen by the wrapping of redundant loops of myelin around the axon. Madrid and Bradley (1975) examined tomacula in patients with different clinical syndromes including hereditary neuropathy with liability to pressure palsies, recurrent familial brachial plexus neuropathy and chronic distal sensorimotor neuropathy. They described focal enlargements of the myelin sheath usually continuous with a myelin sheath of normal thickness. In thickened areas the myelin was frequently swollen, vacuolated and irregular in appearance. The tomacula appeared to be formed in different ways, with each of the different forms being found in each of the cases examined. Hypermyelination. The most simple tomaculum is an excessive thickening of the myelin sheath. It is thought to result from the Schwann cell failing to stop rotating at the appropriate stage of myelination resulting in the production of too many myelin lamellae for the diameter of the axon. The simple tomaculum was not found particularly frequently (Madrid & Bradley 1975). Folding.

The most common form of tomaculum consisted of folding of the myelin sheath. This varied from simple outpouchings to various degrees of complex folding. Redundant myelin loops secondarily wrapped around the original myelinated axon either around the outside or turned inwards and wrapped internally around the axon. Occasionally redundant loops were derived internally within the myelin itself. Degenerative changes. Degenerate swollen myelin usually appeared to lie between a relatively preserved part of the myelin sheath and a structurally normal but compressed axon (Madrid & Bradley 1975). Focal myelin thickening was associated with constriction of the axon resulting in densely packed neurofilaments and neurotubules. Some intemodes were diffusely thickened but more frequently the ‘sausages’ were paranodal and less frequently intemodal. Occasionally there were several thickenings within one intemode. All the cases examined by Madrid and Bradley (1975) showed extensive segmental demyelination and remyelination with the incidence of tomacula being highest when segmental demyelination was most prominent. Other features of the tomacula- associated demyelinating neuropathy included extensive variability of intemodal length, abnormally thin myelin sheaths and occasionally onion bulb formation or acute segmental demyelination with the presence of myelin ovoids.

mechanism in neuropathies involving tomaculum-like structures (Adlkofer et al. 1995).

PM P22 mice. Tomacula were less frequently seen in the femoral and pectineus nerves of P24 PMP22®'^^ mice when compared with age matched PMP22°^® mice. Their frequency increased with age so that by 10 wk almost every myelinating Schwann cell had formed intemodal or paranodal tomacula. Onion bulbs were occasionally seen in the quadriceps nerves but there was no significant change in axon number.

In animals from 5 to 15 mo tomacula were prominent (Adlkofer et al. 1997). At 5 mo multiple tomacula were found within the same intemodal segment. They were seen both intemodally and paranodally but were more frequent in paranodal regions. By 10 mo the presence of many very thick tomacula became obvious. These expanded stmctures were interpreted as early onset degeneration in former tomacula (Adlkofer et al. 1997). In animals older than 10 mo the axon appeared compressed inside hypermyelinated stmctures. Splitting of the major dense line and intramyelin oedema was frequently seen as were Schwann cells with myelin debris present in the cytoplasm. At 15 mo tomacula were still seen frequently. Some myelin sheaths looked abnormally thin and were surrounded by cellular or basal lamina-type onion bulbs.