- Email: [email protected]
Gut feelings about recovery after stroke: the organization and reorganization of human swallowing motor cortex
VIEWPOINT
O. Paulsen and E.I. Moser – GABAergic interneurones and hippocampus-dependent memory
29 Magee, J.C. and Johnston, D. (1997) Science 275, 209–213 30 Markram, H. et al. (1997) Science 275, 213–215 31 Tsubokawa, H. and Ross, W.N. (1996) J. Neurophysiol. 76, 2896–2906 32 Davies, C.H. et al. (1991) Nature 349, 609–611 33 Pitler, T.A. and Alger, B.E. (1992) J. Neurosci. 12, 4122–4132 34 Frotscher, M. and Leranth, C. (1985) J. Comp. Neurol. 239, 237–246 35 Freund, T.F. and Antal, M. (1988) Nature 336, 170–173 36 Winson, J. (1978) Science 201, 160–163 37 Ylinen, A. et al. (1995) Hippocampus 5, 78–90 38 Cobb, S.R. et al. (1995) Nature 378, 75–78 39 Paulsen, O. and Vida, I. (1996) J. Physiol. 495, 50P–51P 40 O’Keefe, J. and Recce, M. (1993) Hippocampus 3, 317–330 41 Jonas, P. and Spruston, N. (1994) Curr. Opin. Neurobiol. 4, 366–372 42 Whittington, M.A., Traub, R.D. and Jefferys, J.G.R. (1995) Nature 373, 612–615 43 Lisman, J.E. and Idiart, M.A.P. (1995) Science 267, 1512–1515 44 Buzsáki, G. (1989) Neuroscience 31, 551–570 45 Treves, A. and Rolls, E.T. (1992) Hippocampus 2, 189–199 46 Hasselmo, M.E., Wyble, B.P. and Wallenstein, G.V. (1996) Hippocampus 6, 693–708
47 Debanne, D. et al. (1997) Nature 389, 286–289 48 Freund, T.F. et al. (1983) J. Comp. Neurol. 221, 263–278 49 Buzsáki, G. et al. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9921–9925 50 Zola-Morgan, S.M. and Squire, L.R. (1990) Science 250, 288–290 51 Lisman, J.E. (1997) Trends Neurosci. 20, 38–43 52 Ali, A.B. and Thomson, A.M. (1998) J. Physiol. 507, 185–199 53 Ali, A.B., Deuchars, J., Pawelzik, H. and Thomson, A.M. (1998) J. Physiol. 507, 201–217 54 McClelland, J.L., McNaughton, B.L. and OReilly, R.C. (1995) Psychol. Rev. 102, 419–457 55 Squire, L.R. and Alvarez, P. (1995) Curr. Opin. Neurobiol. 5, 169–177 56 Winson, J. and Abzug, C. (1978) J. Neurophysiol. 41, 716–732 57 Leonard, B.J., McNaughton, B.L. and Barnes, C.A. (1987) Brain Res. 425, 174–177 58 Wilson, M.A. and McNaughton, B.L. (1994) Science 265, 676–679 59 Skaggs, W.E. and McNaughton, B.L. (1996) Science 271, 1870–1873 60 McCormick, D.A. (1992) Prog. Neurobiol. 39, 337–388 61 Wilson, M.A. and Tonegawa, S. (1997) Trends Neurosci. 20, 102–106
PERSPECTIVES Gut feelings about recovery after stroke: the organization and reorganization of human swallowing motor cortex Shaheen Hamdy and John C. Rothwell Swallowing problems can affect as many as one in three patients in the period immediately after a stroke.In some cases this can lead to serious morbidity,in particular malnutrition and pulmonary aspiration. Despite this, swallowing usually recovers completely in the vast majority of patients within weeks. This impressive propensity for recovery is likely to relate to how the area of the motor cortex concerned with swallowing is organized and then reorganized after cerebral injury. Recent studies have indicated that swallowing has a bilateral but asymmetric inter-hemisphere representation within motor and premotor cortex.Damage to the hemisphere that has the greater swallowing output appears to predispose that individual to swallowing problems.However,because there is additional substrate for swallowing in the undamaged hemisphere, the capacity for compensatory reorganization in the contralateral motor cortex might be increased, leading to a greater likelihood of recovery. Swallowing might be an excellent system for studying cortical plasticity, and might prove useful in the development of new therapies aimed at accelerating reorganization in the undamaged hemisphere after unilateral cerebral injury. Trends Neurosci. (1998) 21, 278–282
Shaheen Hamdy and John C. Rothwell are at the MRC Human Movement and Balance Unit, Institute of Neurology, Queen Square, London, UK WC1N 3BG.
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WALLOWING INVOLVES a complex sequence of carefully timed muscular contractions that transport food from the mouth to the stomach whilst ensuring protection of the airway. The central regulation of swallowing depends on swallowing centres in the brainstem, which receive sensory input from pharynx and oesophagus and, together with local peristaltic mechanisms, control much of the swallowing sequence1–3. However, the initiation of swallowing is a voluntary action that requires the integrity of motor areas of the cerebral cortex. If these higher centres, or their conTINS Vol. 21, No. 7, 1998
nections to the brainstem, are damaged, then patients have severe difficulty in starting a swallow without choking (dysphagia)4–8. Currently, the commonest cause of damage is stroke9: up to one third of all stroke patients experience dysphagia10,11, which if persistent, can be associated with the life-threatening complications of pulmonary aspiration and malnutrition12. Fortunately, the most impressive fact about swallowing is its great potential for recovery after damage: the majority of stroke patients recover within weeks of the insult11. In this article, we examine present knowledge
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about the cortical control of swallowing in man, and examine what aspects of its organization are important for compensation and recovery after damage. In addition, we examine techniques that might be useful in speeding up the process of recovery. Swallowing could turn out to be an excellent model for studying central nervous plasticity.
The cortical organization of swallowing based on direct stimulation and lesional data In anaesthetized animals, electrical stimulation of either hemisphere can induce swallowing13. Thus, it has been said, as might be expected from a mid-line structure, that both hemispheres have an equal part in controlling the swallowing process14. Analogous neurosurgical studies of the motor cortex in man15,16 have usually been confined to one hemisphere, so that a direct comparison with animal data has not been possible. These human data show that the locus of cortical control lies just antero-caudal to the face area of primary motor cortex15. Despite inferential animal evidence for bilateral control, pathological studies tend to suggest that, at least in man, one or other hemisphere might be dominant17–20. Indeed, one of the earliest observations of a unilateral cerebral lesion producing dysphagia was in 1898 when Bastian reported on the case of a man who had been admitted to hospital with hemiplegia and aphasia, but who also had transient ‘difficulty in deglutition’21. Later necropsy revealed that apart from two limited lesions in the left hemisphere, the brain was healthy. More recently, Meadows reported on six cases of dysphagia20. All of them had confirmed unilateral lesions of the cerebral cortex, five of which affected the right hemisphere. Since then, a number of studies7,8,10,11,22–24 have confirmed that up to 40% of patients with unilateral hemispheric stroke have swallowing difficulties; there was an increased tendency for the pharynx to be involved if the damage was limited to the cortex of the right hemisphere23,24.
The cortical representation of human swallowing musculature using transcranial magnetic stimulation The missing piece of data in these studies has been lack of information about the normal pattern of cortical projections to swallowing muscles in normal humans. Recently, the technique of transcranial magnetic stimulation (TMS) has been able to fill the gaps in our knowledge. This technique uses a very short, rapidly changing magnetic field to induce electric current in the areas of the brain beneath the stimulator25,26. The site of stimulation is less well localized compared to an electrode applied directly to the surface of the brain, and thus the effective area of stimulation is larger than that obtained in acute experiments on anaesthetized subjects or animals. However, the centre of the most effective site for stimulation is very similar to that seen during neurosurgery, being slightly anterior to the best points for obtaining responses in muscles of the hand or arm27,28. One important difference between the techniques is that, in previous work, the relevant brain area has been stimulated with a train of several hundred stimuli at a rate of 50–60 Hz. Such stimuli can induce a full swallowing cycle visible to the experimenter15. However, because of the risk of inducing epileptic seizures in awake subjects, TMS studies usually employ only single shocks
Fig. 1. Schematic representations of the sites of stimulation on the scalp grid in relation to the head surface, and cortically evoked EMG responses. (A) Schematic representations of the sites of stimulation (black dots) on the scalp grid in relation to the head surface. (B) The cortically evoked EMG responses recorded in one normal subject from right mylohyoid muscle, left mylohyoid muscle and pharynx and oesophagus, following transcranial magnetic stimulation of the right and left hemispheres are shown. The cranial vertex on the schematic head is marked by an ‘x’. The sites of stimulation on the scalp grid from which the EMG responses were obtained are indicated by the encircled dot. Responses to three stimuli have been superimposed to show reproducibility. An initial stimulus artefact can be seen in the mylohyoid muscles (representing oral musculature) immediately after the stimulus. The response latencies are in the region of 8–10 ms, indicating that the cortico–bulbar pathway, excited by the magnetic stimulus, is paucisynaptic to the brainstem motoneurones. It is evident, however, that the pharyngeal and oesophageal responses obtained from the right hemisphere are larger than those from the left hemisphere. (* Indicates onset of EMG response, identified as the first consistent deflection from the baseline following the stimulus.) Reproduced, with kind permission, from Ref. 30.
given several seconds apart. The consequence is that a full swallow is never elicited. Instead, the response has to be monitored by recording the EMG of pharynx and oesophagus from an intraluminal catheter inserted into the oesophagus29,30. The type of response that can be observed is illustrated in Fig. 1. A single stimulus evokes a simple EMG potential that has a latency of about 8–10 ms, compatible with a fairly direct and rapidly conducting pathway from cortex via brainstem to the muscle. Mapping these projections demonstrates that the various swallowing muscles are arranged somatotopically, with the oral muscles (mylohyoid) laterally and the pharynx and oesophagus more medial. However, the most important finding from a study of a large group of subjects30 was that in the majority of individuals, the projection from one hemisphere tended to be larger than the other. That is, there was an asymmetric representation for swallowing between the two hemispheres, independent of handedness (Fig. 2). It was also observed to be discordant in a pair of identical right-handed twins, suggesting little genetic contribution to its development.
Mechanisms of dysphagia after unilateral cerebral stroke The results from patients with dysphagia tend to confirm this idea of inter-hemispheric asymmetry in TINS Vol. 21, No. 7, 1998
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Fig. 2. Topographic maps of the cortical representation of the upper oesophagus are shown for four subjects (A–D). To construct the maps, the mean value of the three EMG responses, elicited for each muscle group, at each grid point, was calculated. Scalp maps representing the area of response for each muscle group, were then generated for each subject, by assigning to each scalp grid point, an EMG response amplitude, and importing these values into the UNIRAS interactive program UNIMAP (AVS/UNIRAS systems, Waltham, MA, USA), for interpolation onto regular two-dimensional grids. All plots are oriented as indicated by the bottom pair, with the right (R) and left (L) scalp grids viewed from above. The vertex of each plot is marked with an ‘x’. Marked increments on the axes represent distance (in cm) along X- and Y-axes of the cortical grid. The intensity scale shown on the right is colour-coded as a percentage of the amplitude of the maximum response evoked from either hemisphere for each muscle group in each subject. Subject A is right handed, subject B left handed and subjects C and D are right-handed monozygotic twins. Inter-hemispheric asymmetries in the representation of the upper oesophagus are seen in each subject. Reproduced, with kind permission, from Ref. 30.
the cortical representation of swallowing. Hamdy et al. examined the projections from both hemispheres to the swallowing muscles in a large series of pure unilateral-stroke patients31. Half of the patients had dysphagia, whereas the other half did not. They reasoned
that, if there were a true asymmetry of swallowing representation in normal subjects, then perhaps dysphagia would occur if the damage had affected the side of the brain with the largest (‘most dominant’) projection. The results showed that although stimulation of the damaged hemisphere produced little or no response in either group of patients, stimulation of the undamaged hemisphere tended to evoke a much larger response in the non-dysphagic than in the dysphagic subjects. Thus, the size of the hemispheric projection to swallowing muscles might have determined the presence or absence of dysphagia.
The cortical reorganization of swallowing musculature after stroke
This group of patients also provided an intriguing clue as to the mechanism of recovery from dysphagia. Two patients with very similar cerebral infarcts were studied longitudinally for several months30. One of the patients was initially dysphagic, whereas the other was not. The dysphagic patient subsequently recovered swallowing after three months but continued to have a dense hemiparesis. Transcranial magnetic stimulation of the hemispheres revealed that the area of pharyngeal representation in
Fig. 3. Topographical maps of the pharynx in two patients (non-dysphagic and dysphagic) who were studied at presentation and at three months after a right hemisphere stroke. The non-dysphagic patient had normal swallowing throughout, whereas the dysphagic patient had evidence of laryngeal penetration on videofluoroscopic evaluation at presentation, but recovered normal swallowing by three months. It can be seen that the dysphagic patient has a smaller area of pharyngeal representation on the unaffected hemisphere than the non-dysphagic patient at presentation, but by three months it has enlarged to an area comparable with that of the non-dysphagic patient. By contrast, on the affected hemisphere of both patients, the pharyngeal area is small and remains unchanged with time. The vertex of each plot is marked with an ‘x’. Marked increments on the axes represent distance along X- and Y-axes (in cm) of the cortical grid. The intensity scale shown on the right is colour-coded as a percentage of the amplitude of the maximum response evoked from either hemisphere for each muscle group in each subject. Reproduced, with kind permission, from Ref. 30.
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S. Hamdy and J.C. Rothwell – Motor cortex plasticity after stroke
the unaffected hemisphere had increased markedly by three months in the patient who recovered, whereas there was no change in the representation in the other patient (Fig. 3). The observations are currently being confirmed in a larger series of patients with similar unilateral stroke31,32. It seems likely that the recovery of swallowing function after stroke depends on the presence of an intact (albeit small) projection from the undamaged hemisphere that can develop increased control over brainstem centres over a period of weeks. The situation is different in limb muscles where the cortical projections are primarily contralateral, with relatively little representation, at least of distal muscles, in the ipsilateral hemisphere33. In such cases, the scope for expansion of a normal connection from the undamaged part of the brain might be a limiting factor in recovery. Indeed, some TMS studies have indicated that limb recovery is more likely to result from increases in the activity of remaining viable cortex in the damaged hemisphere34,35. However, TMS can only evaluate function in the large diameter, direct corticospinal pathways, and it might be that smaller diameter connections from the undamaged hemisphere could be important in recovery of limb function36,37. This would be compatible with PET activation studies in which patients who have recovered function in the affected hand show activity of the undamaged cortex during movement38–40. Such activity might help both to control the affected hand and to prevent mirror or associated movements of the normal hand40.
Future prospects for accelerating cortical-swallowing reorganization and recovery Given that the intact hemisphere plays an important role in the recovery of swallowing after stroke, we are then provided with an interesting opportunity for studying plasticity of an intact (normal) pathway. Indeed, it could be suggested that any future therapies aimed at enhancing swallowing recovery should be targeted towards manipulating reorganization on the intact side. One potential candidate for such a therapy might be the manipulation of sensory input to the cortex. Sensory input from the gut not only has a major influence on the activity of brainstem swallowing centres, but also converges onto cortical sensory and motor areas1,14. Indeed, we have shown that the excitability of the cortical projection to swallowing muscles can be influenced by stimulation of afferent fibres in the vagal and trigeminal nerves41. The single stimuli used in those studies had very short-lasting effects, but recent work has shown that prolonged electrical stimulation of the pharynx can induce changes in cortical excitability that outlast the stimulus by up to 30 min (Fig. 4)42. If this approach could be adopted in dysphagic stroke patients, then it could prove to be a potential mechanism for speeding recovery of function by the intact representation in the undamaged hemisphere. An alternative approach might come from the application of repetitive cortical stimuli to specific cortical swallowing areas on the intact hemisphere, in an attempt to induce directly re-organization within motor cortex43. The use of repeated micro-stimulation of areas within both motor44 and sensory cortices45 in animals, has been shown to provoke changes in cortical motor and sensory maps, respectively. Consequently, the prospect of influencing motor plasticity on an undamaged
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Fig. 4. Topographical maps of both the pharynx and upper oesophagus in one subject, before and after sensory pharyngeal stimulation. The application of a 10 min period of repeated (10 Hz), afferent pharyngeal stimulation induces an asymmetric expansion in the motor representation for pharynx but a reciprocal contraction in the motor representation for oesophagus, these effects lasting at least 30 min after the initial input. The vertex of each plot is marked with an ‘x’. Marked increments on the axes represent distance along X- and Y-axes (in cm) of the cortical grid. The intensity scale shown on the right is colour-coded as a percentage of the amplitude of the maximum response evoked from either hemisphere for each muscle group in each subject.
healthy cortex could provide an exciting window of opportunity for the application of cortical stimulation techniques, particularly with the recent advances in the development of rapid-rate magnetic stimulators that provide a non-invasive method of stimulating brain in conscious adult subjects. Control of swallowing provides a useful model for how mid-line musculature is organized and reorganized within motor cortex after stroke, and gives new insight both into mechanisms of functional recovery and potential therapies for neuro-rehabilitation. The application of these principles to other midline bodily functions, such as those performed by facial, trunk, pelvic and sphincter muscles should, in the future, allow a better understanding of how the human brain controls these under-investigated, but essential, motor activities, both in health and disease. Selected references 1 Miller, A.J. (1982) Physiol. Rev. 62, 129–184 2 Jean, A. (1990) in Neurophysiology of the Jaws and Teeth (Taylor, A., ed.), pp. 294–321, Macmillan Press 3 Jean, A. and Car, A. (1979) Brain Res. 178, 567–572 4 Horner, J.M. (1988) Neurology 38, 1359–1362 5 Alberts, J.M. et al. (1992) Dysphagia 7, 170–173 6 Daniels, S.K. and Foundas, A.L. (1997) Dysphagia 12, 146–156 7 Chen, M.Y.M. et al. (1990) Radiology 176, 641–643 8 Veis, S.L. and Logemann, J.A. (1985) Arch. Phys. Med. Rehabil. 66, 372–375 9 Wiles, C.M. (1991) J. Neurol. Neurosurg. Psychiatr. 54, 1037–1039 10 Gordon, C., Langton-Hewer, R. and Wade, D.T. (1987) Br. Med. J. 295, 411–414 11 Barer, D.H. (1989) J. Neurol. Neurosurg. Psychiatr. 52, 236–241 12 Smithard, D.G. et al. (1996) Stroke 27, 1200–1204 13 Sumi, T. (1969) Brain Res. 15, 107–120 14 Martin, R.E. and Sessle, B.J. (1993) Dysphagia 8, 195–202 15 Penfield, W. and Boldrey, E. (1937) Brain 60, 389–443 16 Woolsey, C.N., Erikson, T.C. and Gilson, W.E. (1979) J. Neursurg. 51, 476–506 17 Tuch, B.E. and Nielsen, J.M. (1941) Bull. Los Angeles Neurol. Soc. 6, 52–54 18 Starkstein, S.E., Bertbier, M. and Leiguarda, R. (1988) Brain Lang. 34, 253–261 19 Daniels, S.K. et al. (1996) J. Stroke Cerebrovasc. Dis. 6, 30–34
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Acknowledgements The contributions of Dr Qasim Aziz, Professor Raymond C. Tallis and Professor David G. Thompson are gratefully acknowledged. The authors also thank Mr Steve Larkin in the Manchester Visualization Centre, Manchester Computing, University of Manchester for generating the colour figures.
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20 Meadows, J. (1973) J. Neurol. Neurosurg. Psychiatry 36, 853–860 21 Bastian, H.C. (1898) A Treatise on Aphasia and Other Speech Defects, Lewis 22 Kidd, D. et al. (1995) Q. J. Med. 88, 409–413 23 Robbins, J. and Levine, R.L. (1988) Dysphagia 3, 11–14 24 Robbins, J. et al. (1993) Arch. Phys. Med. Rehabil. 74, 1295–1300 25 Barker, A.T., Jalinous, R. and Freestone, I.L. (1985) Lancet i, 1106–1107 26 Rothwell, J.C. et al. (1991) Exp. Physiol. 76, 159–200 27 Wassermann, E.M. et al. (1992) Electroencephalogr. Clin. Neurophysiol. 85, 1–8 28 Metman, L.V. et al. (1993) Brain Topogr. 6, 13–19 29 Aziz, Q. et al. (1996) Gastroenterology 111, 855–862 30 Hamdy, S. et al. (1996) Nat. Med. 2, 1217–1224 31 Hamdy, S. et al. (1997) Lancet 350, 686–692 32 Hamdy, S. et al. (1997) Gastroenterology 111, A743 (abstr.) 33 Wassermann, E.M., Pascual-Leone, A. and Hallett, M. (1994) Exp. Brain Res. 100, 121–132
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34 Traversa, R. et al. (1997) Stroke 28, 110–117 35 Palmer, E., Ashby, P. and Hajeck, V.E. (1992) Ann. Neurol. 32, 519–525 36 Turton, A. et al. (1996) Electroencephalogr. Clin. Neurophysiol. 101, 316–328 37 Caramia, M.D., Iani, C. and Bernandi, G. (1996) NeuroReport 7, 1756–1760 38 Chollet, F. et al. (1991) Ann. Neurol. 29, 63–71 39 Weiller, C. et al. (1992) Ann. Neurol. 31, 463–472 40 Chollet, F. and Weiller, C. (1994) Curr. Opin. Neurobiol. 4, 226–230 41 Hamdy, S. et al. (1997) Am. J. Physiol. 272, G802–G808 42 Hamdy, S. et al. (1998) Nat. Neurosci. 1, 64–68 43 Diamant, N.E. (1996) Nat. Med. 11, 1190–1191 44 Nudo, R.J., Jenkins, W.M. and Merzenich, M.M. (1990) Somatosens. Mot. Res. 7, 463–483 45 Dinse, H.R., Recanzone, G.H. and Merzenich, M.M. (1993) NeuroReport 5, 173–176
ON DISEASE
Pathogenesis of Charcot–Marie–Tooth 1A (CMT1A) neuropathy C. Oliver Hanemann and Hans Werner Müller The hereditary neuropathy Charcot–Marie–Tooth (CMT) type 1A is,in the majority of cases,caused by duplication of the gene for the peripheral myelin protein PMP22, which leads to abnormally increased PMP22 expression. Recent in vitro and in vivo data indicate a novel function of PMP22 in Schwann-cell growth and differentiation other than its role in myelination, and suggest that overproduction of PMP22 leads to a new Schwann-cell phenotype in CMT1A.Taking these data into account, we developed a new hypothesis on the pathogenesis of CMT1A neuropathy: that the defective myelin stability and turnover observed in the disease is caused by altered PMP22 gene dosage and its resultant effect on abnormal Schwann-cell growth and differentiation. Trends Neurosci. (1998) 21, 282–286
I C. Oliver Hanemann and Hans Werner Müller are at the Molecular Neurobiology Lab, Dept of Neurology, Heinrich-HeineUniversity, D-40225 Düsseldorf, Germany. Hans Werner Müller is also at the Biomedical Research Center, Heinrich-HeineUniversity, D-40225 Düsseldorf, Germany.
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N THE PAST FIVE YEARS, there has been rapid progress in understanding the genetics of hereditary demyelinating neuropathies1 (HMSNs) such as CMT1. CMT1 neuropathy has a prevalence of approximately 1:2500 (Ref. 2) and is characterized clinically by distal muscular atrophy and weakness and minor sensory symptoms; symptoms usually start in late childhood (at approximately age 12 years) and disease progression is slow. An electrophysiological hallmark of the disease is the homogeneously reduced nerve conduction velocity (NCV)3. HMSNs are most often inherited in an autosomal dominant manner, but some X-linked cases have been reported4 and autosomal-recessive cases have been described in a few single kinships5–7. The vast majority (approximately 70–80%) of HMSNs are of the CMT1A type and are caused by a dominantly inherited, 1.5 Mb duplication on chromosome 17p11.2, which contains the gene for the peripheral myelin protein (PMP) 22 (Refs 8–12). The remaining, dominantly inherited or X-linked CMT1 cases are, at present, atributed to point mutations in the genes of PMP22 in CMT1A, the major myelin protein P0 in CMT1B, and the gap junction protein Connexin 32 in CMTX (Refs 4,12–14). TINS Vol. 21, No. 7, 1998
The PMP22 point mutations that occur in certain CMT1A cases have provided conclusive evidence that PMP22 gene mutations are likely to be causal in CMT1A. Interestingly, the condition ‘Hereditary neuropathy with pressure palsies’ (HNPP) is due to the deletion of the same 1.5 Mb DNA region that is duplicated in CMT1A, and results in only one copy of the PMP22 gene15. In this review, we concentrate on the pathogenesis of CMT1A with PMP22 duplication because it is the most common form of CMT1 disease and the form for which most genetic, histopathological and cell biological data are available. For the purpose of this review, unless stated otherwise, ‘CMT1A’ refers exclusively to CMT1A caused by duplication of PMP22.
Duplication of the PMP22 gene and gene-dosage mechanism Because the PMP22 gene is not disrupted within the 1.5 Mb duplication and duplications of a larger chromosome-17 fragment have been described that lead to a similar phenotype16,17, a ‘gene-dosage’ mechanism has been postulated in CMT1A. Duplication of the PMP22 gene thus leads to three instead of two gene
Copyright © 1998, Elsevier Science Ltd. All rights reserved. 0166 - 2236/98/$19.00
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O. Paulsen and E.I. Moser – GABAergic interneurones and hippocampus-dependent memory
29 Magee, J.C. and Johnston, D. (1997) Science 275, 209–213 30 Markram, H. et al. (1997) Science 275, 213–215 31 Tsubokawa, H. and Ross, W.N. (1996) J. Neurophysiol. 76, 2896–2906 32 Davies, C.H. et al. (1991) Nature 349, 609–611 33 Pitler, T.A. and Alger, B.E. (1992) J. Neurosci. 12, 4122–4132 34 Frotscher, M. and Leranth, C. (1985) J. Comp. Neurol. 239, 237–246 35 Freund, T.F. and Antal, M. (1988) Nature 336, 170–173 36 Winson, J. (1978) Science 201, 160–163 37 Ylinen, A. et al. (1995) Hippocampus 5, 78–90 38 Cobb, S.R. et al. (1995) Nature 378, 75–78 39 Paulsen, O. and Vida, I. (1996) J. Physiol. 495, 50P–51P 40 O’Keefe, J. and Recce, M. (1993) Hippocampus 3, 317–330 41 Jonas, P. and Spruston, N. (1994) Curr. Opin. Neurobiol. 4, 366–372 42 Whittington, M.A., Traub, R.D. and Jefferys, J.G.R. (1995) Nature 373, 612–615 43 Lisman, J.E. and Idiart, M.A.P. (1995) Science 267, 1512–1515 44 Buzsáki, G. (1989) Neuroscience 31, 551–570 45 Treves, A. and Rolls, E.T. (1992) Hippocampus 2, 189–199 46 Hasselmo, M.E., Wyble, B.P. and Wallenstein, G.V. (1996) Hippocampus 6, 693–708
47 Debanne, D. et al. (1997) Nature 389, 286–289 48 Freund, T.F. et al. (1983) J. Comp. Neurol. 221, 263–278 49 Buzsáki, G. et al. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9921–9925 50 Zola-Morgan, S.M. and Squire, L.R. (1990) Science 250, 288–290 51 Lisman, J.E. (1997) Trends Neurosci. 20, 38–43 52 Ali, A.B. and Thomson, A.M. (1998) J. Physiol. 507, 185–199 53 Ali, A.B., Deuchars, J., Pawelzik, H. and Thomson, A.M. (1998) J. Physiol. 507, 201–217 54 McClelland, J.L., McNaughton, B.L. and OReilly, R.C. (1995) Psychol. Rev. 102, 419–457 55 Squire, L.R. and Alvarez, P. (1995) Curr. Opin. Neurobiol. 5, 169–177 56 Winson, J. and Abzug, C. (1978) J. Neurophysiol. 41, 716–732 57 Leonard, B.J., McNaughton, B.L. and Barnes, C.A. (1987) Brain Res. 425, 174–177 58 Wilson, M.A. and McNaughton, B.L. (1994) Science 265, 676–679 59 Skaggs, W.E. and McNaughton, B.L. (1996) Science 271, 1870–1873 60 McCormick, D.A. (1992) Prog. Neurobiol. 39, 337–388 61 Wilson, M.A. and Tonegawa, S. (1997) Trends Neurosci. 20, 102–106
PERSPECTIVES Gut feelings about recovery after stroke: the organization and reorganization of human swallowing motor cortex Shaheen Hamdy and John C. Rothwell Swallowing problems can affect as many as one in three patients in the period immediately after a stroke.In some cases this can lead to serious morbidity,in particular malnutrition and pulmonary aspiration. Despite this, swallowing usually recovers completely in the vast majority of patients within weeks. This impressive propensity for recovery is likely to relate to how the area of the motor cortex concerned with swallowing is organized and then reorganized after cerebral injury. Recent studies have indicated that swallowing has a bilateral but asymmetric inter-hemisphere representation within motor and premotor cortex.Damage to the hemisphere that has the greater swallowing output appears to predispose that individual to swallowing problems.However,because there is additional substrate for swallowing in the undamaged hemisphere, the capacity for compensatory reorganization in the contralateral motor cortex might be increased, leading to a greater likelihood of recovery. Swallowing might be an excellent system for studying cortical plasticity, and might prove useful in the development of new therapies aimed at accelerating reorganization in the undamaged hemisphere after unilateral cerebral injury. Trends Neurosci. (1998) 21, 278–282
Shaheen Hamdy and John C. Rothwell are at the MRC Human Movement and Balance Unit, Institute of Neurology, Queen Square, London, UK WC1N 3BG.
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WALLOWING INVOLVES a complex sequence of carefully timed muscular contractions that transport food from the mouth to the stomach whilst ensuring protection of the airway. The central regulation of swallowing depends on swallowing centres in the brainstem, which receive sensory input from pharynx and oesophagus and, together with local peristaltic mechanisms, control much of the swallowing sequence1–3. However, the initiation of swallowing is a voluntary action that requires the integrity of motor areas of the cerebral cortex. If these higher centres, or their conTINS Vol. 21, No. 7, 1998
nections to the brainstem, are damaged, then patients have severe difficulty in starting a swallow without choking (dysphagia)4–8. Currently, the commonest cause of damage is stroke9: up to one third of all stroke patients experience dysphagia10,11, which if persistent, can be associated with the life-threatening complications of pulmonary aspiration and malnutrition12. Fortunately, the most impressive fact about swallowing is its great potential for recovery after damage: the majority of stroke patients recover within weeks of the insult11. In this article, we examine present knowledge
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S. Hamdy and J.C. Rothwell – Motor cortex plasticity after stroke
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about the cortical control of swallowing in man, and examine what aspects of its organization are important for compensation and recovery after damage. In addition, we examine techniques that might be useful in speeding up the process of recovery. Swallowing could turn out to be an excellent model for studying central nervous plasticity.
The cortical organization of swallowing based on direct stimulation and lesional data In anaesthetized animals, electrical stimulation of either hemisphere can induce swallowing13. Thus, it has been said, as might be expected from a mid-line structure, that both hemispheres have an equal part in controlling the swallowing process14. Analogous neurosurgical studies of the motor cortex in man15,16 have usually been confined to one hemisphere, so that a direct comparison with animal data has not been possible. These human data show that the locus of cortical control lies just antero-caudal to the face area of primary motor cortex15. Despite inferential animal evidence for bilateral control, pathological studies tend to suggest that, at least in man, one or other hemisphere might be dominant17–20. Indeed, one of the earliest observations of a unilateral cerebral lesion producing dysphagia was in 1898 when Bastian reported on the case of a man who had been admitted to hospital with hemiplegia and aphasia, but who also had transient ‘difficulty in deglutition’21. Later necropsy revealed that apart from two limited lesions in the left hemisphere, the brain was healthy. More recently, Meadows reported on six cases of dysphagia20. All of them had confirmed unilateral lesions of the cerebral cortex, five of which affected the right hemisphere. Since then, a number of studies7,8,10,11,22–24 have confirmed that up to 40% of patients with unilateral hemispheric stroke have swallowing difficulties; there was an increased tendency for the pharynx to be involved if the damage was limited to the cortex of the right hemisphere23,24.
The cortical representation of human swallowing musculature using transcranial magnetic stimulation The missing piece of data in these studies has been lack of information about the normal pattern of cortical projections to swallowing muscles in normal humans. Recently, the technique of transcranial magnetic stimulation (TMS) has been able to fill the gaps in our knowledge. This technique uses a very short, rapidly changing magnetic field to induce electric current in the areas of the brain beneath the stimulator25,26. The site of stimulation is less well localized compared to an electrode applied directly to the surface of the brain, and thus the effective area of stimulation is larger than that obtained in acute experiments on anaesthetized subjects or animals. However, the centre of the most effective site for stimulation is very similar to that seen during neurosurgery, being slightly anterior to the best points for obtaining responses in muscles of the hand or arm27,28. One important difference between the techniques is that, in previous work, the relevant brain area has been stimulated with a train of several hundred stimuli at a rate of 50–60 Hz. Such stimuli can induce a full swallowing cycle visible to the experimenter15. However, because of the risk of inducing epileptic seizures in awake subjects, TMS studies usually employ only single shocks
Fig. 1. Schematic representations of the sites of stimulation on the scalp grid in relation to the head surface, and cortically evoked EMG responses. (A) Schematic representations of the sites of stimulation (black dots) on the scalp grid in relation to the head surface. (B) The cortically evoked EMG responses recorded in one normal subject from right mylohyoid muscle, left mylohyoid muscle and pharynx and oesophagus, following transcranial magnetic stimulation of the right and left hemispheres are shown. The cranial vertex on the schematic head is marked by an ‘x’. The sites of stimulation on the scalp grid from which the EMG responses were obtained are indicated by the encircled dot. Responses to three stimuli have been superimposed to show reproducibility. An initial stimulus artefact can be seen in the mylohyoid muscles (representing oral musculature) immediately after the stimulus. The response latencies are in the region of 8–10 ms, indicating that the cortico–bulbar pathway, excited by the magnetic stimulus, is paucisynaptic to the brainstem motoneurones. It is evident, however, that the pharyngeal and oesophageal responses obtained from the right hemisphere are larger than those from the left hemisphere. (* Indicates onset of EMG response, identified as the first consistent deflection from the baseline following the stimulus.) Reproduced, with kind permission, from Ref. 30.
given several seconds apart. The consequence is that a full swallow is never elicited. Instead, the response has to be monitored by recording the EMG of pharynx and oesophagus from an intraluminal catheter inserted into the oesophagus29,30. The type of response that can be observed is illustrated in Fig. 1. A single stimulus evokes a simple EMG potential that has a latency of about 8–10 ms, compatible with a fairly direct and rapidly conducting pathway from cortex via brainstem to the muscle. Mapping these projections demonstrates that the various swallowing muscles are arranged somatotopically, with the oral muscles (mylohyoid) laterally and the pharynx and oesophagus more medial. However, the most important finding from a study of a large group of subjects30 was that in the majority of individuals, the projection from one hemisphere tended to be larger than the other. That is, there was an asymmetric representation for swallowing between the two hemispheres, independent of handedness (Fig. 2). It was also observed to be discordant in a pair of identical right-handed twins, suggesting little genetic contribution to its development.
Mechanisms of dysphagia after unilateral cerebral stroke The results from patients with dysphagia tend to confirm this idea of inter-hemispheric asymmetry in TINS Vol. 21, No. 7, 1998
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Fig. 2. Topographic maps of the cortical representation of the upper oesophagus are shown for four subjects (A–D). To construct the maps, the mean value of the three EMG responses, elicited for each muscle group, at each grid point, was calculated. Scalp maps representing the area of response for each muscle group, were then generated for each subject, by assigning to each scalp grid point, an EMG response amplitude, and importing these values into the UNIRAS interactive program UNIMAP (AVS/UNIRAS systems, Waltham, MA, USA), for interpolation onto regular two-dimensional grids. All plots are oriented as indicated by the bottom pair, with the right (R) and left (L) scalp grids viewed from above. The vertex of each plot is marked with an ‘x’. Marked increments on the axes represent distance (in cm) along X- and Y-axes of the cortical grid. The intensity scale shown on the right is colour-coded as a percentage of the amplitude of the maximum response evoked from either hemisphere for each muscle group in each subject. Subject A is right handed, subject B left handed and subjects C and D are right-handed monozygotic twins. Inter-hemispheric asymmetries in the representation of the upper oesophagus are seen in each subject. Reproduced, with kind permission, from Ref. 30.
the cortical representation of swallowing. Hamdy et al. examined the projections from both hemispheres to the swallowing muscles in a large series of pure unilateral-stroke patients31. Half of the patients had dysphagia, whereas the other half did not. They reasoned
that, if there were a true asymmetry of swallowing representation in normal subjects, then perhaps dysphagia would occur if the damage had affected the side of the brain with the largest (‘most dominant’) projection. The results showed that although stimulation of the damaged hemisphere produced little or no response in either group of patients, stimulation of the undamaged hemisphere tended to evoke a much larger response in the non-dysphagic than in the dysphagic subjects. Thus, the size of the hemispheric projection to swallowing muscles might have determined the presence or absence of dysphagia.
The cortical reorganization of swallowing musculature after stroke
This group of patients also provided an intriguing clue as to the mechanism of recovery from dysphagia. Two patients with very similar cerebral infarcts were studied longitudinally for several months30. One of the patients was initially dysphagic, whereas the other was not. The dysphagic patient subsequently recovered swallowing after three months but continued to have a dense hemiparesis. Transcranial magnetic stimulation of the hemispheres revealed that the area of pharyngeal representation in
Fig. 3. Topographical maps of the pharynx in two patients (non-dysphagic and dysphagic) who were studied at presentation and at three months after a right hemisphere stroke. The non-dysphagic patient had normal swallowing throughout, whereas the dysphagic patient had evidence of laryngeal penetration on videofluoroscopic evaluation at presentation, but recovered normal swallowing by three months. It can be seen that the dysphagic patient has a smaller area of pharyngeal representation on the unaffected hemisphere than the non-dysphagic patient at presentation, but by three months it has enlarged to an area comparable with that of the non-dysphagic patient. By contrast, on the affected hemisphere of both patients, the pharyngeal area is small and remains unchanged with time. The vertex of each plot is marked with an ‘x’. Marked increments on the axes represent distance along X- and Y-axes (in cm) of the cortical grid. The intensity scale shown on the right is colour-coded as a percentage of the amplitude of the maximum response evoked from either hemisphere for each muscle group in each subject. Reproduced, with kind permission, from Ref. 30.
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the unaffected hemisphere had increased markedly by three months in the patient who recovered, whereas there was no change in the representation in the other patient (Fig. 3). The observations are currently being confirmed in a larger series of patients with similar unilateral stroke31,32. It seems likely that the recovery of swallowing function after stroke depends on the presence of an intact (albeit small) projection from the undamaged hemisphere that can develop increased control over brainstem centres over a period of weeks. The situation is different in limb muscles where the cortical projections are primarily contralateral, with relatively little representation, at least of distal muscles, in the ipsilateral hemisphere33. In such cases, the scope for expansion of a normal connection from the undamaged part of the brain might be a limiting factor in recovery. Indeed, some TMS studies have indicated that limb recovery is more likely to result from increases in the activity of remaining viable cortex in the damaged hemisphere34,35. However, TMS can only evaluate function in the large diameter, direct corticospinal pathways, and it might be that smaller diameter connections from the undamaged hemisphere could be important in recovery of limb function36,37. This would be compatible with PET activation studies in which patients who have recovered function in the affected hand show activity of the undamaged cortex during movement38–40. Such activity might help both to control the affected hand and to prevent mirror or associated movements of the normal hand40.
Future prospects for accelerating cortical-swallowing reorganization and recovery Given that the intact hemisphere plays an important role in the recovery of swallowing after stroke, we are then provided with an interesting opportunity for studying plasticity of an intact (normal) pathway. Indeed, it could be suggested that any future therapies aimed at enhancing swallowing recovery should be targeted towards manipulating reorganization on the intact side. One potential candidate for such a therapy might be the manipulation of sensory input to the cortex. Sensory input from the gut not only has a major influence on the activity of brainstem swallowing centres, but also converges onto cortical sensory and motor areas1,14. Indeed, we have shown that the excitability of the cortical projection to swallowing muscles can be influenced by stimulation of afferent fibres in the vagal and trigeminal nerves41. The single stimuli used in those studies had very short-lasting effects, but recent work has shown that prolonged electrical stimulation of the pharynx can induce changes in cortical excitability that outlast the stimulus by up to 30 min (Fig. 4)42. If this approach could be adopted in dysphagic stroke patients, then it could prove to be a potential mechanism for speeding recovery of function by the intact representation in the undamaged hemisphere. An alternative approach might come from the application of repetitive cortical stimuli to specific cortical swallowing areas on the intact hemisphere, in an attempt to induce directly re-organization within motor cortex43. The use of repeated micro-stimulation of areas within both motor44 and sensory cortices45 in animals, has been shown to provoke changes in cortical motor and sensory maps, respectively. Consequently, the prospect of influencing motor plasticity on an undamaged
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Fig. 4. Topographical maps of both the pharynx and upper oesophagus in one subject, before and after sensory pharyngeal stimulation. The application of a 10 min period of repeated (10 Hz), afferent pharyngeal stimulation induces an asymmetric expansion in the motor representation for pharynx but a reciprocal contraction in the motor representation for oesophagus, these effects lasting at least 30 min after the initial input. The vertex of each plot is marked with an ‘x’. Marked increments on the axes represent distance along X- and Y-axes (in cm) of the cortical grid. The intensity scale shown on the right is colour-coded as a percentage of the amplitude of the maximum response evoked from either hemisphere for each muscle group in each subject.
healthy cortex could provide an exciting window of opportunity for the application of cortical stimulation techniques, particularly with the recent advances in the development of rapid-rate magnetic stimulators that provide a non-invasive method of stimulating brain in conscious adult subjects. Control of swallowing provides a useful model for how mid-line musculature is organized and reorganized within motor cortex after stroke, and gives new insight both into mechanisms of functional recovery and potential therapies for neuro-rehabilitation. The application of these principles to other midline bodily functions, such as those performed by facial, trunk, pelvic and sphincter muscles should, in the future, allow a better understanding of how the human brain controls these under-investigated, but essential, motor activities, both in health and disease. Selected references 1 Miller, A.J. (1982) Physiol. Rev. 62, 129–184 2 Jean, A. (1990) in Neurophysiology of the Jaws and Teeth (Taylor, A., ed.), pp. 294–321, Macmillan Press 3 Jean, A. and Car, A. (1979) Brain Res. 178, 567–572 4 Horner, J.M. (1988) Neurology 38, 1359–1362 5 Alberts, J.M. et al. (1992) Dysphagia 7, 170–173 6 Daniels, S.K. and Foundas, A.L. (1997) Dysphagia 12, 146–156 7 Chen, M.Y.M. et al. (1990) Radiology 176, 641–643 8 Veis, S.L. and Logemann, J.A. (1985) Arch. Phys. Med. Rehabil. 66, 372–375 9 Wiles, C.M. (1991) J. Neurol. Neurosurg. Psychiatr. 54, 1037–1039 10 Gordon, C., Langton-Hewer, R. and Wade, D.T. (1987) Br. Med. J. 295, 411–414 11 Barer, D.H. (1989) J. Neurol. Neurosurg. Psychiatr. 52, 236–241 12 Smithard, D.G. et al. (1996) Stroke 27, 1200–1204 13 Sumi, T. (1969) Brain Res. 15, 107–120 14 Martin, R.E. and Sessle, B.J. (1993) Dysphagia 8, 195–202 15 Penfield, W. and Boldrey, E. (1937) Brain 60, 389–443 16 Woolsey, C.N., Erikson, T.C. and Gilson, W.E. (1979) J. Neursurg. 51, 476–506 17 Tuch, B.E. and Nielsen, J.M. (1941) Bull. Los Angeles Neurol. Soc. 6, 52–54 18 Starkstein, S.E., Bertbier, M. and Leiguarda, R. (1988) Brain Lang. 34, 253–261 19 Daniels, S.K. et al. (1996) J. Stroke Cerebrovasc. Dis. 6, 30–34
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Acknowledgements The contributions of Dr Qasim Aziz, Professor Raymond C. Tallis and Professor David G. Thompson are gratefully acknowledged. The authors also thank Mr Steve Larkin in the Manchester Visualization Centre, Manchester Computing, University of Manchester for generating the colour figures.
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20 Meadows, J. (1973) J. Neurol. Neurosurg. Psychiatry 36, 853–860 21 Bastian, H.C. (1898) A Treatise on Aphasia and Other Speech Defects, Lewis 22 Kidd, D. et al. (1995) Q. J. Med. 88, 409–413 23 Robbins, J. and Levine, R.L. (1988) Dysphagia 3, 11–14 24 Robbins, J. et al. (1993) Arch. Phys. Med. Rehabil. 74, 1295–1300 25 Barker, A.T., Jalinous, R. and Freestone, I.L. (1985) Lancet i, 1106–1107 26 Rothwell, J.C. et al. (1991) Exp. Physiol. 76, 159–200 27 Wassermann, E.M. et al. (1992) Electroencephalogr. Clin. Neurophysiol. 85, 1–8 28 Metman, L.V. et al. (1993) Brain Topogr. 6, 13–19 29 Aziz, Q. et al. (1996) Gastroenterology 111, 855–862 30 Hamdy, S. et al. (1996) Nat. Med. 2, 1217–1224 31 Hamdy, S. et al. (1997) Lancet 350, 686–692 32 Hamdy, S. et al. (1997) Gastroenterology 111, A743 (abstr.) 33 Wassermann, E.M., Pascual-Leone, A. and Hallett, M. (1994) Exp. Brain Res. 100, 121–132
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34 Traversa, R. et al. (1997) Stroke 28, 110–117 35 Palmer, E., Ashby, P. and Hajeck, V.E. (1992) Ann. Neurol. 32, 519–525 36 Turton, A. et al. (1996) Electroencephalogr. Clin. Neurophysiol. 101, 316–328 37 Caramia, M.D., Iani, C. and Bernandi, G. (1996) NeuroReport 7, 1756–1760 38 Chollet, F. et al. (1991) Ann. Neurol. 29, 63–71 39 Weiller, C. et al. (1992) Ann. Neurol. 31, 463–472 40 Chollet, F. and Weiller, C. (1994) Curr. Opin. Neurobiol. 4, 226–230 41 Hamdy, S. et al. (1997) Am. J. Physiol. 272, G802–G808 42 Hamdy, S. et al. (1998) Nat. Neurosci. 1, 64–68 43 Diamant, N.E. (1996) Nat. Med. 11, 1190–1191 44 Nudo, R.J., Jenkins, W.M. and Merzenich, M.M. (1990) Somatosens. Mot. Res. 7, 463–483 45 Dinse, H.R., Recanzone, G.H. and Merzenich, M.M. (1993) NeuroReport 5, 173–176
ON DISEASE
Pathogenesis of Charcot–Marie–Tooth 1A (CMT1A) neuropathy C. Oliver Hanemann and Hans Werner Müller The hereditary neuropathy Charcot–Marie–Tooth (CMT) type 1A is,in the majority of cases,caused by duplication of the gene for the peripheral myelin protein PMP22, which leads to abnormally increased PMP22 expression. Recent in vitro and in vivo data indicate a novel function of PMP22 in Schwann-cell growth and differentiation other than its role in myelination, and suggest that overproduction of PMP22 leads to a new Schwann-cell phenotype in CMT1A.Taking these data into account, we developed a new hypothesis on the pathogenesis of CMT1A neuropathy: that the defective myelin stability and turnover observed in the disease is caused by altered PMP22 gene dosage and its resultant effect on abnormal Schwann-cell growth and differentiation. Trends Neurosci. (1998) 21, 282–286
I C. Oliver Hanemann and Hans Werner Müller are at the Molecular Neurobiology Lab, Dept of Neurology, Heinrich-HeineUniversity, D-40225 Düsseldorf, Germany. Hans Werner Müller is also at the Biomedical Research Center, Heinrich-HeineUniversity, D-40225 Düsseldorf, Germany.
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N THE PAST FIVE YEARS, there has been rapid progress in understanding the genetics of hereditary demyelinating neuropathies1 (HMSNs) such as CMT1. CMT1 neuropathy has a prevalence of approximately 1:2500 (Ref. 2) and is characterized clinically by distal muscular atrophy and weakness and minor sensory symptoms; symptoms usually start in late childhood (at approximately age 12 years) and disease progression is slow. An electrophysiological hallmark of the disease is the homogeneously reduced nerve conduction velocity (NCV)3. HMSNs are most often inherited in an autosomal dominant manner, but some X-linked cases have been reported4 and autosomal-recessive cases have been described in a few single kinships5–7. The vast majority (approximately 70–80%) of HMSNs are of the CMT1A type and are caused by a dominantly inherited, 1.5 Mb duplication on chromosome 17p11.2, which contains the gene for the peripheral myelin protein (PMP) 22 (Refs 8–12). The remaining, dominantly inherited or X-linked CMT1 cases are, at present, atributed to point mutations in the genes of PMP22 in CMT1A, the major myelin protein P0 in CMT1B, and the gap junction protein Connexin 32 in CMTX (Refs 4,12–14). TINS Vol. 21, No. 7, 1998
The PMP22 point mutations that occur in certain CMT1A cases have provided conclusive evidence that PMP22 gene mutations are likely to be causal in CMT1A. Interestingly, the condition ‘Hereditary neuropathy with pressure palsies’ (HNPP) is due to the deletion of the same 1.5 Mb DNA region that is duplicated in CMT1A, and results in only one copy of the PMP22 gene15. In this review, we concentrate on the pathogenesis of CMT1A with PMP22 duplication because it is the most common form of CMT1 disease and the form for which most genetic, histopathological and cell biological data are available. For the purpose of this review, unless stated otherwise, ‘CMT1A’ refers exclusively to CMT1A caused by duplication of PMP22.
Duplication of the PMP22 gene and gene-dosage mechanism Because the PMP22 gene is not disrupted within the 1.5 Mb duplication and duplications of a larger chromosome-17 fragment have been described that lead to a similar phenotype16,17, a ‘gene-dosage’ mechanism has been postulated in CMT1A. Duplication of the PMP22 gene thus leads to three instead of two gene
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