The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy): Studies on the formation of the abnormal myelin sheath

doi:10.1016/0022-510X(75)90263-4

Journal of the Neurological Sciences

Volume 25, Issue 4, August 1975, Pages 415-448

https://doi.org/10.1016/0022-510X(75)90263-4 Get rights and content

Abstract

The sural nerves of 4 patients showed similar pathological features of sausage-shaped thickenings of the myelin sheaths ranging in length from 80 to 250 μm, of up to 27 μm diameter and affecting fibres of all sizes. From 25 to 82% of internodes in the different cases showed these thickenings, which were both in the paranodal and internodal areas. Segmental demyelination with remyelination and early onion-bulb formation were also features of the affected nerves.

The term “tomaculous neuropathy” (tomaculum, Latin = sausage) is proposed for this pathological condition.

Study of the ultrastructure of these sausage-shaped thickenings and of the apparently normal areas of the myelin sheaths demonstrated various abnormalities which may have led to the formation of the thickenings:

1.
(1) Hypermyelination with an excessive number of myelin lamellae for the axonal circumference. Observed values of the ratio (number of lamellae) : (axonal circumference in μm) were up to 73.5, while normal values were from 4.25 to 7.25.
2.
(2) Redundant loop formation, with a surplus loop of the myelin sheath secondarily wrapping around the original myelin sheath. The structure of some of these loops was extremely complex.
3.
(3) Branching and duplication of the mesaxon, leading to an increase in the number of myelin lamellae.
4.
(4) Transnodal myelination, with spread of the myelin sheath of 1 internode into the region of the next internode. This completely obliterated many nodes of Ranvier whose sites could only be detected by the electron-microscopic demonstration of Schwann cell interdigitating pseudopodia and blind-ending myelin loops.
5.
(5) The participation of 2 or more Schwann cells in the formation of 1 myelin sheath.
6.
(6) The degeneration of myelin in the adaxonal and/or intramyelin regions between an outer intact layer of the myelin sheath, and the axon.

Changes (1), (2), (4) and (6) appeared to be responsible for most of the sausage-shaped thickenings, redundant loop formation being the commonest.

Axonal constriction of marked degree was seen within many of the sausage-shaped thickenings.

This study indicates that, in pathological conditions of the myelin sheath and/or Schwann cell, the formation of the myelin sheath both during original myelinogenesis and during remyelination after segmental demyelination may be different from the generally accepted normal regular helical construction.

Tomaculous neuropathy can occur in a number of different diseases of the peripheral nerves. The clinical picture of the 4 cases described here differed considerably. Two women had familial recurrent brachial plexus neuropathy, 1 patient had recurrent pressure-sensitive neuropathy, and the last patient had a chronic distal sensorimotor neuropathy affecting predominantly the upper limbs. The underlying biochemical or biophysical abnormality of the myelin or Schwann cell leading to the sausage-shaped thickenings of the myelin sheath has not been elucidated.

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Citation Excerpt :
Such profiles are also encountered in chronic neuropathies, including hereditary neuropathy with liability to pressure palsies (also known as tomaculous neuropathy), demyelinating neuropathies, and hereditary motor-sensory neuropathies.( Madrid and Bradley, 1975; Bilbao and Schmidt, 2014) Excess myelin figures are also encountered during development (Cullen and Webster, 1979; Djannatian et al., 2021) and can also be observed after genetic perturbation of the axoglial adhesion and myelination apparatus e.g. with mutations of the myelin-associated glycoprotein, or ablation of Cdc42, Rac1 or N-Wasp genes (Fujita et al., 1998; Thurnherr et al., 2006; Katanov et al., 2020). Whether excess myelin figures are a consequence of a disruption in axoglial signaling due to the circumstances of the injury or an aberrant repair mechanism is not known, but this type of pathological signature suggests the engagement of an active myelination process.
Traumatic axonal injury (TAI) and the associated axonopathy are common consequences of traumatic brain injury (TBI) and contribute to significant neurological morbidity. It has been previously suggested that TAI activates a highly conserved program of axonal self-destruction known as Wallerian degeneration (WD). In the present study, we utilize our well-established impact acceleration model of TBI (IA-TBI) to characterize the pathology of injured myelinated axons in the white matter tracks traversing the ventral, lateral, and dorsal spinal columns in the mouse and assess the effect of Sterile Alpha and TIR Motif Containing 1 (Sarm1) gene knockout on acute and subacute axonal degeneration and myelin pathology. In silver-stained preparations, we found that IA-TBI results in white matter pathology as well as terminal field degeneration across the rostrocaudal axis of the spinal cord. At the ultrastructural level, we found that traumatic axonopathy is associated with diverse types of axonal and myelin pathology, ranging from focal axoskeletal perturbations and focal disruption of the myelin sheath to axonal fragmentation. Several morphological features such as neurofilament compaction, accumulation of organelles and inclusions, axoskeletal flocculation, myelin degeneration and formation of ovoids are similar to profiles encountered in classical examples of WD. Other profiles such as excess myelin figures and inner tongue evaginations are more typical of chronic neuropathies. Stereological analysis of pathological axonal and myelin profiles in the ventral, lateral, and dorsal columns of the lower cervical cord (C6) segments from wild type and Sarm1 KO mice at 3 and 7 days post IA-TBI (n = 32) revealed an up to 90% reduction in the density of pathological profiles in Sarm1 KO mice after IA-TBI. Protection was evident across all white matter tracts assessed, but showed some variability. Finally, Sarm1 deletion ameliorated the activation of microglia associated with TAI. Our findings demonstrate the presence of severe traumatic axonopathy in multiple ascending and descending long tracts after IA-TBI with features consistent with some chronic axonopathies and models of WD and the across-tract protective effect of Sarm1 deletion.
Distinctive patterns of sonographic nerve enlargement in Charcot-Marie-Tooth type 1A and hereditary neuropathy with pressure palsies
2015, Clinical Neurophysiology
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CMT type I can usually be linked to three genes, which produce products essential for myelin function (PMP22, myelin protein zero (MPZ) and connexin-32 (Cx32)) (Keller and Chance, 1999; Shy et al., 2002; Pareyson and Marchesi, 2009). Hereditary neuropathy with liability to pressure palsies (HNPP) is also known as a ‘tomaculous neuropathy’, which refers to the sausage shaped swellings of the myelin sheath, that can be found on teased fiber studies (Madrid and Bradley, 1975; Yoshikawa and Dyck, 1991; Dubourg et al., 2000; Li et al., 2002). CMT-1A is caused by a mutation and HNPP by a deletion in the same PMP22 gene (Li et al., 2013).
The extent of sonomorphologic differences of peripheral nerves between CMT and HNPP is unknown.
We recruited 9 patients with CMT-1A and 9 with HNPP. Patients underwent a standardized sonographic protocol, which evaluated nerve size and vascularization. We quantitatively assessed fascicle size and echogenicity.
All 18 patients demonstrated nerve enlargement, but no increased vascularization. HNPP demonstrated larger nerves at sites of entrapment (median nerve at the carpal tunnel p = 0.049, ulnar nerve at the sulcus p < 0.001), greater swelling ratios of median (p < 0.001), ulnar (p = 0.017) and fibular nerve (p = 0.005) than CMT-1A. CMT-1A revealed larger nerves proximal to sites of entrapment (median and fibular nerve, brachial plexus p < 0.001). Nerve fascicles where larger (p < 0.001) and more hypo-echogenic in CMT-1A. Nerve, fascicle size nor echogenicity correlated with age, gender or MRC sum-score.
Ultrasonography of nerves reveals specific phenotypes differentiating CMT-1A from HNPP. In CMT-1A enlargement of nerves and fascicles is multifocal among multiple nerves, whereas in HNPP nerve enlargement is restricted to sites of entrapment.
Our findings of specific sonomorphological phenotypes, differentiating CMT-1A from HNPP, may help to improve our pathophysiological insights in CMT and HNPP.
Hereditary neuropathy with liability to pressure palsy (HNPP): A diagnostic trap
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Les auteurs rapportent deux cas cliniques d’une pathologie peu rencontrée en pratique quotidienne orthopédique : l’hypersensibilité nerveuse familiale, qui entraîne dysesthésies, hypoesthésies et paralysies réversibles. Les conditions d’apparition, les signes cliniques et électromyographiques de cette pathologie familiale sont décrites. Une implication médicolégale peut découler de cette pathologie dans la période postopératoire immédiate. La connaissance de l’hypersensibilité nerveuse familiale permet de prendre certaines précautions pour l’intervention chirurgicale et d’éviter des reprises chirurgicales inutiles.
The authors report two clinical cases of a rarely observed pathology in orthopedic surgery daily practice: hereditary neuropathy with liability to pressure palsy (HNPP), which leads to dysesthesiae, hypoesthesiae and regressive palsies. Onset, clinical signs and electromyographic abnormalities are described. Forensic consequences can occur in early postoperative period. Knowledge of this familial pathology allows precautionary measures at surgery and avoids unnecessary surgical revisions.
Ultrasound aids in the diagnosis of hereditary neuropathy with liability to pressure palsies
2009, Surgical Neurology
Demyelinating polyneuropathy with focally folded myelin sheaths in a family of Miniature Schnauzer dogs
2008, Journal of the Neurological Sciences
Citation Excerpt :
Tomacula represent a pathological focal thickening of peripheral nerve myelin resulting from excessive myelin folding [1] and abnormal compaction.
A spontaneous demyelinating polyneuropathy in two young Miniature Schnauzer dogs was characterized clinically, electrophysiologically and histopathologically. Both dogs were related and a third dog, belonging to the same family, had similar clinical signs. On presentation, clinical signs were restricted to respiratory dysfunction. Electrophysiological tests showed a dramatic decrease in both motor and sensory nerve conduction velocities. Microscopic examination of peripheral nerve biopsies (light and electron microscopy, teased nerve fibers), showed that this neuropathy was characterized by segmental demyelination and focally folded myelin sheaths. Various clinical syndromes associated with tomacula or focal thickening of the myelin sheath of the peripheral nerves have been described in humans and shown to be caused by gene mutations affecting the myelin proteins, such as the hereditary neuropathy with liability to pressure palsies or the demyelinating forms of Charcot–Marie–Tooth disease. In animals, a tomaculous neuropathy has been reported in cattle and chickens but not in carnivores. Here we report a demyelinating peripheral neuropathy with tomacula in two Miniature Schnauzer dogs.
Hereditary Neuropathy with liability to Pressure Palsies (HNPP) in hand surgery: reminds and warn against a usually unrecognised disease
2007, Annales de Chirurgie Plastique Esthetique
La neuropathie tomaculaire est une maladie héréditaire méconnue due à une délétion sur le chromosome 17. Sa traduction clinique est très hétérogène, mais repose sur une atteinte nerveuse périphérique chronique, caractérisée par la survenue d'épisodes récidivants de paralysies et de paresthésies suite à la compression ou au traumatisme parfois mineur d'un nerf. L'électromyogramme, la biopsie nerveuse et l'analyse génétique confirment le diagnostic. Des mesures de prévention simples sont essentielles pour les patients et leur famille, chez lesquels un conseil génétique est indiqué. Il n'existe pas de traitement spécifique, mais la chirurgie peut parfois être utile dans la prise en charge symptomatique des patients. Cependant, toute intervention chez ces malades augmente le risque de lésions nerveuses secondaires. Malades et chirurgiens doivent donc connaître le diagnostic afin de mettre en œuvre les moyens de prévention qui s'imposent.
Tomacula is a rare hereditary disease due to a deletion on chromosome 17. Clinical presentation varies but patients usually complain of recurrent paraesthesiaes and palsies related to compression or trauma of a peripheral nerve. Diagnosis is based on electrophysiological studies, nerve biopsies and genetic tests. Implications for the patient and family members are a genetic counselling and some simple preventive measures. Although there is no curative treatment for this neuropathy, surgery can be useful for decompression of nerves and neurolysis. However, the surgical act increases the risk of nerve damage. Knowing about the diagnosis can help the patient and the surgical team avoid causing lesions.

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^☆

This work was aided by grants from the Muscular Dystrophy Group of Great Britain, the Muscular Dystrophy Associations of America, Inc., and the Medical Research Council.

R.M. is in receipt of a grant from the Friedreich's Ataxia Group.

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The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy): Studies on the formation of the abnormal myelin sheath☆

Abstract

Exp. Cell Res.

Exp. Neurol.

Brain Res.

Fine structure and electrolyte analysis of cerebral edema induced by alkyltin intoxication

J. Neuropath. exp. Neurol.

Repair of segmental demyelination in peripheral nerves — An electron microscope study

Brain

Ultrastructural neuropathology of multiple sclerosis

Giant axonal neuropathy A unique case with segmental neurofilamentous masses

Acta neuropath. (Berl.)

Electron-microscopic observations on demyelination and remyelination in experimental allergic neuritis, Part 2 (Remyelination)

J. neurol. Sci.

Hereditary neuropathy with liability to pressure palsies — Electrophysiological and histopathological aspects

Brain

Infantile neuroaxonal dystrophy or Seitelberger's disease, Part 2 (Peripheral nerve involvement — Electron-microscopic study in one case)

Acta neuropath. (Berl.)

Postnatal development of feline paranodal myelin-sheath segments, Part 2 (Electron microscopy)

Acta Soc. med. upsalien

Disorders of Peripheral Nerves

Hereditary chronic polyneuropathy — Electrophysiological and pathological studies in an affected family

J. Neurol. Sci.

The syndrome of brachial plexus neuropathy

Brain

Globular neuropathy — A disorder of axons and Schwann cells

J. Neurol. Neurosurg. Psychiat.

Transnodal remyelination

J. Path.

Peripheral nerve biopsy as an aid to diagnosis in infantile neuroaxonal dystrophy

Neurology (Minneap.)

Developing myelin in human peripheral nerve

Scot. med. J.

Evidence for segmental demyelination secondary to axonal degeneration in Friedreich's ataxia

Severe hypomyelination and marked abnormality of conduction in Dejerine-Sottas hypertrophic neuropathy — Myelin thickness and compound action potential of sural nerve in vitro

Histologic and teased-fibre measurements of sural nerve in disorders of lower motor and primary sensory neurons

Experimental allergic encephalomyelitis — An electron-microscopic study

Amer. J. Path.

Principles of quantitative organization of peripheral nerve fibres and their relations to growth and pathological changes

Z. Neurol. (Berl.)

Myelin formation in the sciatic nerve of the rat — A quantitative electron-microscopic, histochemical and radioautographic study

J. Neuropath. exp. Neurol.

Pressure neuropathy in the hind foot of the guinea pig

J. Neurol. Neurosurg. Psychiat.

Median and ulnar neuropathy in the guinea pig

J. Neurol. Neurosurg. Psychiat.

Further electron-microscopic studies of human fetal peripheral nerves

J. Anat. (Lond.)

Triethyltin sulfate-induced splitting of peripheral myelin in rats

Lab. Invest.

Quantitative teased-fiber and histologic studies of human sural nerve during postnatal development

J. comp. Neurol.

Electron microscope observations on the effects of localized crush injuries on the connective tissues of peripheral nerve

J. Anat. (Lond.)

Remyelination in the central nervous system after cyanide intoxication

J. Neuropath. exp. Neurol.

Myelin in the central nervous system as observed in experimentally induced edema in the rat

J. Cell Biol.