Onion bulb neuropathy in the trembler mouse: A model of hypertrophic interstitial neuropathy (Dejerine-Sottas) in man

Ayers, Margaret; Anderson, R. McD.

doi:10.1007/bf00686858

Cited by 112 publications

(35 citation statements)

References 21 publications

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“…C57Bl/6J mice, either littermates or closely age-matched, were used as controls. The Tr-J mutation was confirmed by clinical and morphological criteria (Ayers and Anderson, 1973) (Fig. 1).…”

Section: Methodsmentioning

confidence: 81%

“…First, we examined BDNF and CNTF mRNA expression in the Trembler-J (Tr-J) mutant mouse, which has a point-mutation in the gene for the peripheral myelin protein pmp-22 (Suter et al, 1992). In Tr-J peripheral nerves, SC myelin formation is deficient, the few lamellae that form break down (Ayers and Anderson, 1973), and SC division continues throughout life (Perkins et al, 1981). Second, because many fibers in normal autonomic and sensory nerves remain unmyelinated in the mature animal, we measured BDNF mRNAs in one such nerve, the cervical sympathetic trunk (CST) before and after axonal interruption to determine whether growth factor expression is indeed influenced by the SC's acquisition of the myelinating phenotype.…”

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confidence: 99%

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A Distinct Pattern of Trophic Factor Expression in Myelin-Deficient Nerves ofTremblerMice: Implications for Trophic Support by Schwann Cells

et al. 1996

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Distal to a peripheral nerve transection, myelin degradation and Schwann cell (SC) proliferation are accompanied by a marked upregulation of brain-derived neurotrophic factor (BDNF) and a decrease of ciliary neurotrophic factor (CNTF) in non-neuronal cells. To investigate the role of SC differentiation in trophic factor regulation, we studied BDNF and CNTF expression in sciatic nerves from Trembler-J (Tr-J) mice. In these animals, a mutation in the pmp-22 gene causes a failure of myelination and continuous SC proliferation, but axonal continuity is preserved. In spite of the severe abnormalities in Tr-J nerves, BDNF levels remained as low as in the intact controls. Thus, the primary SC disorder in Tr-J produces a different pattern of BDNF expression from that caused by axonal breakdown due to nerve transection. Furthermore, the upregulation of BDNF mRNA triggered by transection was 70-fold in control nerves, but only 30-fold in Tr-J sciatic nerves. Because these results raised the possibility that axonal loss may influence neurotrophin expression only in SCs that have differentiated toward a myelinating phenotype, we measured BDNF mRNA after axotomy in the cervical sympathetic trunk (CST), a predominantly unmyelinated autonomic nerve. In contrast to the sciatic nerves, the BDNF mRNA level barely increased in the injured CST, supporting the idea that not all SCs are equal sources of trophic molecules. In Tr-J sciatic nerves, CNTF mRNA levels were fourfold lower than normal, implying that the downregulation of this cytokine is a sensitive indicator of a spectrum of SC perturbations that affect myelinating cells.

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Section: Methodsmentioning

confidence: 81%

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confidence: 99%

A Distinct Pattern of Trophic Factor Expression in Myelin-Deficient Nerves ofTremblerMice: Implications for Trophic Support by Schwann Cells

et al. 1996

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“…Demyelination, remyelination, inflammatory cell infiltration, and onion bulb formation have been found in spinal nerve roots in acute 18 and chronic 15,30,31,35 inflammatory demyelinating polyradiculoneuropathies. Demyelinative changes in both peripheral nerves and spinal nerve roots have also been reported in hypertrophic hereditary motor and sensory neuropathy, 4 protein zero-deficient mice, 9,26 peripheral myelin protein-22 deficient mice, 40 Trembler mice, 2 and Trembler-J mice 13 and in animal models of inflammatory demyelinating neuropathy. 1,14,17,24,38,39 In 2 mice with POEMS, which is a monoclonal plasma cell disorder characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal gammopathy (M), and skin changes (S), spinal nerve roots and sural nerves showed the same pathologic changes of demyelination, remyelination, and inflammatory cell infiltration, 42,47 and in 3 cases of diabetic neuropathy, there was severe loss of both large and small MF in sural nerves while segmental demyelination and remyelination was the main finding in both dorsal and ventral spinal roots.…”

Section: Discussionmentioning

confidence: 89%

Selective Vulnerability of Peripheral Nerves in Avian Riboflavin Deficiency Demyelinating Polyneuropathy

et al. 2009

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Abstract. Riboflavin (vitamin B2) deficiency in young chickens produces a demyelinating peripheral neuropathy. In this study, day-old broiler meat chickens were fed a riboflavin-deficient diet (1.8 mg/kg) and killed on posthatch days 6, 11, 16, 21, and 31, while control chickens were given a conventional diet containing 5.0 mg/kg riboflavin. Pathologic changes were found in sciatic, cervical, and lumbar spinal nerves of riboflavin-deficient chickens from day 11 onwards, characterized by endoneurial oedema, hypertrophic Schwann cells, tomacula (redundant myelin swellings), demyelination/remyelination, lipid deposition, and fibroblastic onion bulb formation. Similar changes were also found in large and medium intramuscular nerves, although they were less severe in the latter. However, by contrast, ventral and dorsal spinal nerve roots, distal intramuscular nerves, and subcutaneous nerves were normal at all time points examined. These findings demonstrate, for the first time, that riboflavin deficiency in young, rapidly growing chickens produces selective injury to peripheral nerve trunks, with relative sparing of spinal nerve roots and distal nerve branches to muscle and skin. These novel findings suggest that the response of Schwann cells in peripheral nerves with riboflavin deficiency differs because either there are subsets of these cells in, or there is variability in access of nutrients to, different sites within the nerves.Key words: Avian species; demyelination; neuropathy; peripheral nerves; riboflavin deficiency.The normal functioning of the nervous system depends on a constant supply of nutrients. A deficiency of vitamins, particularly groups B (thiamine, cobalamin, pyridoxine, and niacin) and E, generally produces an axonal type of polyneuropathy.22,41 However, riboflavin (vitamin B2) deficiency is characterized by demyelination with hypertrophy of Schwann cells, marked lipid accumulation, paranodal tomacula, and fibroblastic onion bulbs. [6][7][8]19,20 There is, at least initially, sparing of axons, and spinal cord and brain are apparently unaffected. 7 Riboflavin (7,8-dimethyl-10-ribityl-isoalloxazine) is a water-soluble vitamin and a dietary requirement in both chickens and humans. It is a precursor of flavin mononucleotide and flavin adenine dinucleotide, and decreased levels of these coenzymes impair oxidative phosphorylation. 36 Riboflavin deficiency leads to decreased beta-oxidation of fatty acids with relative preservation of the tricarboxylic acid cycle. 37 The lipid deposition in Schwann cells and the formation of paranodal redundant loops of normal myelin (paranodal tomacula) suggest a disturbance of lipid metabolism and control of myelin membrane formation in the myelinating Schwann cell.The novel findings in this study that Schwann cells in spinal nerve roots and subcutaneous and distal intramuscular nerves do not show these pathologic changes suggest that Schwann cells in different parts of the peripheral nerve system respond differently to riboflavin deficiency. Materials and MethodsOur a...

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“…Demyelination and onion bulb formation have been reported as subsequent events in older trembler mice. 3 The nodal changes seen in our teased nerve studies, namely apparent nodal lengthening, paranodal globule formation, and short internodal lengths, may reflect an overall nodal disruption rather than demyelination. In some forms of hypomyelination in children, it has been reported that individual Schwann cells occupy abnormally short distances along the nerve fiber producing short internodes, and that multiple anomalies exist at the node of Ranvier.l0 In the trembler mouse mutant model of peripheral hypomyelination, nodal abnormalities have also been reported, including poor myelin compaction, widening of the nodes, and presence of many herninode~.~~ A more definitive qualitative and quantitative study of teased nerve abnormalities is clearly needed in affected golden retrievers in order to confirm or rule out the teased nerve findings.…”

Section: _1mentioning

confidence: 99%

Congenital Hypomyelinating Polyneuropathy in Two Golden Retriever Littermates

et al. 1989

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Abstract. Serial peripheral nerve biopsies from two golden retriever littermates with chronic neurologic disease were taken for morphologic and morphometric evaluation. Teased nerve preparations were difficult to interpret due to the lightness of myelin staining. Light and electron microscopic findings were characterized by the following: reduced number of myelinated axons, presence of myelinated sheaths inappropriately thin for the caliber of the fiber, poor myelin compaction, increased numbers of Schwann cell nuclei, increased concentration of neurofilaments in myelinated axons, many Schwann cells with voluminous cytoplasm, and increased perineurial collagen. Onion bulb formation was not seen. In contrast to control data, a poor correlation was seen between numbers of myelin lamellae (ML) and axonal circumference (AC). The frequency distribution of ML ranged from 5 to 55 lamellae in affected animals (mean, 28 lamellae) compared to 20 to 140 lamellae in controls (mean, 66 lamellae). The MWAC ratio was significantly reduced (P < 0.001) in nerves of affected dogs.Morphometric results indicated that fibers of all calibers were hypomyelinated.Abnormal myelination of the nervous system has been reported in a variety of animal species,9,14,16,21,32 including a number of dog breeds springer spaniels,2o lurcher weimaraner^,^^ Samoyeds,I3 and a DalmatianIs). Heredity has been implicated as the cause of canine hypomyelinating conditions. In all of these breeds, hypomyelination involved the central nervous system, and peripheral nerves were normal.In the present report, severe hypomyelination of the peripheral nervous system is described for the first time in two golden retriever littermates. Materials and MethodsTwo golden retriever littermates, one male and one female, were studied from 7 weeks to 5 months of age. Both dogs were initially presented for hind limb ataxia at 7 weeks of age. One other littermate from the litter of seven was reported to be slightly affected but was not examined. Both dogs had a crouched stance, mild pelvic limb atrophy, and weakness. Circumduction was evident in the pelvic limbs when walking, and a "bunny hop" gait was present when running. Segmental reflexes were depressed or absent in pelvic limbs of both dogs and in thoracic limbs of the male. Motor nerve conduction velocities were markedly reduced in sciatic-tibia1 and ulnar nerves. Needle electromyographic studies revealed rare denervation potentials in a few muscle groups (M.E. Matz et al., unpublished observations).Under general anesthesia, 2-cm fascicular segments of common peroneal nerve at the level of the stifle were removed, stretched on wooden tongue depressors with pins, 21 and fixed in a mixture of 4% formalin/l% glutaraldehyde. After fixation for 12 hours, nerve samples were divided into halves and washed in Millonig phosphate buffer (pH 7.3) at 4 C overnight. One half was post-fixed in 1% osmium tetroxide for 6 to 8 hours. These samples were then placed in 66% glycerin for 24 hours and stored in 100% glycerin for single teas...

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Onion bulb neuropathy in the trembler mouse: A model of hypertrophic interstitial neuropathy (Dejerine-Sottas) in man

Cited by 112 publications

References 21 publications

A Distinct Pattern of Trophic Factor Expression in Myelin-Deficient Nerves ofTremblerMice: Implications for Trophic Support by Schwann Cells

A Distinct Pattern of Trophic Factor Expression in Myelin-Deficient Nerves ofTremblerMice: Implications for Trophic Support by Schwann Cells

Selective Vulnerability of Peripheral Nerves in Avian Riboflavin Deficiency Demyelinating Polyneuropathy

Congenital Hypomyelinating Polyneuropathy in Two Golden Retriever Littermates

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