Acta Neuropathologica

, Volume 87, Issue 1, pp 91–97 | Cite as

Tomaculous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome

  • Florian P. Thomas
  • Roger V. Lebo
  • Gorazd Rosoklija
  • Xin-Sheng Ding
  • Robert E. Lovelace
  • Norman Latov
  • Arthur P. Hays
Case Report


We performed morphological and immunohistochemical studies on sural nerve biopsies from two members of a Charcot-Marie-Tooth type 1B family, in which a mutation of the P0 gene on chromosome 1 had been found. Biopsies showed a tomaculous neuropathy with loss of myelinated fibers and frequent small onion bulbs. Immunofluorescence with antibodies to P0 showed this protein to be present in tomaculous and non-tomaculous areas of the nyelin sheath. The severity of the myelin abnormalities suggests that in this family Charcot-marie-Tooth disease may result from a generalized disturbance of Schwann cells as a result of an abnormal P0 protein.

Key words

Charcot-Marie-Tooth disease HMSNIB CMT1B P0 tomacula 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Asbury AK, Johnson PC (1978) Pathology of peripheral nerve. Saunders, PhiladelphiaGoogle Scholar
  2. 2.
    Beckett J, Holden JJA, Simpson NE, White BN, MacLeod PM (1986) Localization of X-linked dominant Charcot-Marie-Tooth disease (CMT2) to Xq13. J Neurogenet 3: 225–231Google Scholar
  3. 3.
    Behse F, Buchthal F, Carlsen F, Knappels GG (1972) Hereditary neuropathy with liability to pressure palsies. Electrophysiological and histopathological aspects. Brain 95: 777–794Google Scholar
  4. 4.
    Ben Jelloun-Dellagi S, Dellagi K, Burger D, Ben Younes-Chennoufi A, Hentati FF, Steck A, Ben Hamida M (1992) Childhood peripheral neuropathy with autoantibodies to myelin glycoprotein P0. Ann Neurol 32: 700–702Google Scholar
  5. 5.
    Bird TD, Ott J, Giblett ER (1982) Evidence for linkage of charcot-Marie-Tooth neuropathy to the Duffy locus on chromosome 1. Am J Hum Genet 34: 388–394Google Scholar
  6. 6.
    Bradley WG, Madrid R, Thrush DC, Campbell MJ (1975) Recurrent brachial plexus neuropathy. Brain 98: 381–398Google Scholar
  7. 7.
    Brunden KR, Poduslo JF (1987) A phorbol ester-sensitive kinase catalyzes the phosphorylation of P0 glycoprotein in myelin. J Neurochem 49: 1863–1872Google Scholar
  8. 8.
    Brunner HG, Spaans F, Smeets HJM, Coerwinkel-Driessen M, Hulsebos T, Wieringa B, Ropers H-H (1991) Genetic linkage with chromosome 19 but not chromosome 17 in a family with myotonic dystrophy associated with hereditary motor and senory neuropathy. Neurology 41: 80–84Google Scholar
  9. 9.
    Burger D, Perruisseau G, Simon M, Steck AJ (1992) Comparison of the N-linked oligosaccharide structures of the two major human myelin glycoproteins MAG and P0: assessment and relative occurrence of oligosaccharide structures by serial lectin affinity chromatography of [14C]glycopeptides. J Neurochem 58: 845–853Google Scholar
  10. 10.
    Burger D, Perruisseau G, Simon M, Steck AJ (1992) Comparison of the N-linked oligosaccharide structures of the two major human myelin glycoproteins MAG and P0: assessment of the structures bearing the epitope for HNK-1 and human monoclonal immunoglobulin M found in demyelinating neuropathy. J Neurochem 58: 854–861Google Scholar
  11. 11.
    Chance PF, Bird TD, O'Connell P, Lipe H, Lalouel J-M, Leppert M (1990) Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth disease (Hereditary motor and sensory neuropathy type I). Am J Hum Genet 47: 915–925Google Scholar
  12. 12.
    Chance PF, Alderson MK, Leppig KA, Lensch MW, Matsunami N, Smith B, Swanson PD, Odelberg SJ, Disteche CM, Bird TD (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72: 143–151Google Scholar
  13. 13.
    Dayan AD, Graveson GS, Robinson PK, Woodhouse MA (1968) Globular neuropathy. A disorder of axons and Schwann cells. J Neurol Neurosurg Psychiatry 31: 552–560Google Scholar
  14. 14.
    Defesche JC, Hoogendijk JE, de Visser M, Ongerboer de Visser BW, Bolhuis PA (1990) Genetic linkage of hereditary motor and sensory neuropathy type I (Charcot-Marie-Tooth disease) to markers of chromosomes 1 and 17. Neurology 40: 1450–1453Google Scholar
  15. 15.
    Dunn JS (1970) Developing myelin in human peripheral nerve. Scott Med J 15: 108–117Google Scholar
  16. 16.
    D'Urso D, Brophy PJ, Staugaitis SM, Gillespie CS, Frey AB, Stempak JG, Colman DR (1990) Protein zero of peripheral nerve myelin: biosynthesis, membrane insertion, and evidence for homotypic interaction. Neuron 2: 449–460Google Scholar
  17. 17.
    Dyck PJ Chance P, Lebo R, Carney JA (1993) Hereditary motor and sensory neuropathies. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduseo JF (eds) Peripheral neuropathy, 3rd edn. Saunders, Philadelphia, pp 1094–1136Google Scholar
  18. 18.
    Dyck PJ, Giannini C, Lais A (1993) Pathologic alterations of nerves. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduseo JF (eds) Peripheral neuropathy, 3rd edn. Saunders, Philadelphia, pp 514–595Google Scholar
  19. 19.
    Filbin MT, Walsh FS, Trapp BD, Pizzey JA, Tennekon GI (1990) Role of myelin P0 protein as a homophilic adhesion molecule. Nature 344: 871–872Google Scholar
  20. 20.
    Filbin MT, Tennekoon GI (1992) Myelin P0-protein, more than just a structural protein? BioEssays 14: 541–547Google Scholar
  21. 21.
    Fischbeck KH, ar-Rushdi N, Pericak-Vance M, Rozear M, Roses AD, Fryns JP (1986) X-linked neuropathy: gene localization with DNA probes. Ann Neurol 20: 527–532Google Scholar
  22. 22.
    Fryns JP, van den Berghe H (1980) Sex-linked recessive inheritance in Charcot-Marie-Tooth disease with partical clinical manifestations in female carriers. Hum Genet 55: 413–415Google Scholar
  23. 23.
    Gal A, Mucke J, Theile H, Wieacker PF, Ropers HH, Wienker TF (1985) X-linked dominant Charcot-Marie-Tooth disease: suggestion of linkage with a cloned DNA sequence from the proximal Xq. Hum Genet 70: 38–42Google Scholar
  24. 24.
    Giese KP, Martini R, Lemke G, Soriano P, Schachner M (1992) Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell 71: 565–576Google Scholar
  25. 25.
    Greenfield S, Brostoff S, Eylar EH, Morrell P (1973) Protein composition of myelin of the peripheral nervous system. J Neurochem 20: 1207–1216Google Scholar
  26. 26.
    Guiloff RJ, Thomas PK, Contreras M, Armitage S, Schwartz G, Sedgwick EM (1982) Linkage of autosomal dominant type I hereditary motor and sensory neuropathy to the Duffy locus on chromosome 1. Ann Hum Genet 46: 25–27Google Scholar
  27. 27.
    Hayasaka K, Himoro M, Sato W, Takada G, Uyemura K, Shimizu N, Bird T, Conneally M, Chance PF (1993) CMT neuropathy 1B is associated with mutations of the myelin P0 gene. Nature Genet 5: 31–34Google Scholar
  28. 28.
    Ionasescu VV, Burns TL, Searby C, Ionasescu R (1988) X-linked dominant Charcot-Marie-Tooth neuropathy with 15 cases in a family genetic linkage study. Muscle Nerve 11: 1154–1156Google Scholar
  29. 29.
    Ionasescu VV, Trofatterr J, Haines JL, Ionasescu R, Searby C (1992) Charcot-Marie-Tooth disease related to chromosome 1. Am J med Genet 42: 728–732Google Scholar
  30. 30.
    Joy JL, Oh SJ (1989) Tomaculous neuropathy presenting as acute recurrent polyneuropathy. Ann Neurol 26: 98–100Google Scholar
  31. 31.
    Kulkens T, Bolhuis PA, Wolterman RA, Kemp S, te Nijenhuis S, Valentijn LJ, Hensels GW, Jennekens FGI, de Visser M, Hoogendijk JE, Baas F (1993) Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B. Nature Genet 5: 35–39Google Scholar
  32. 32.
    Lebo RV, Chance PF, Dyck PJ, Redila-Flores MT, Lynch ED, Golbus MS, Bird TD, King MC, Anderson LA, Hall J, Wiegant J, Jiang Z, Dazin PF, Punnett HH, Schonberg SA, Moore K, Shull MM, Gendler S, Hurko O, Lovelace RE, Latov N, Trofatter J, Conneally PM (1991) Chromosome 1 Charcot-Marie-Tooth disease (CMT1B) locus in the Fcγ receptor gene region. Hum Genet 88: 1–12Google Scholar
  33. 33.
    Lebo RV, Lynch E, Wiegant J, Moore K, Trounstine M, van der Ploeg M (1991) Multicolor fluorescence in situ hybridization and pulsed-field electrophoresis dissect CMT1B gene region. Hum Genet 88: 13–20Google Scholar
  34. 34.
    Lebo RV, Lynch ED, Bird TD, Golbus MS, Barker DF, O'Connell P, Chance PF (1992) Multicolor in situ hybridization and linkage analysis order Charcot-Marie-Tooth type 1 (CMT1A) gene-region markers. Am J Hum Genet 50: 42–55Google Scholar
  35. 35.
    Lemke G, Lamar E, Patterson J (1988) Isolation and analysis of gene encoding peripheral myelin protein zero. Neuron 1: 73–83Google Scholar
  36. 36.
    Madrid R, Bradley WG (1975) The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy). Studies on the formation of the abnormal myelin sheath. J Neurol Sci 25: 415–448Google Scholar
  37. 37.
    Matsunami N, Smith B, Ballard L, Lensch MW, Robertson M, Albertsen H, Hanemann CO, Müller HW, Bird TD, White R, Chance PF (1992) Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. Nature Gene 1: 176–179Google Scholar
  38. 38.
    Nardelli E, Pizzighella S, Tridente G, Rizzuto N (1981) Peripheral neuropathy associated with immunoglobulin disorders. An immunological and ultrastructural study. Acta Neuropathol (Berl) [suppl] VII: 258–261Google Scholar
  39. 39.
    Nordborg C, Conradi N, Sourander P, Hagberg B, Westerberg B (1984) Hereditary motor and sensory neuropathy of demyelinating and remyelinating type in children. Ultrastructural and morphometric studies on sural nerve biopsy speciments from 10 sporadic cases. Acta Neuropathol (Berl) 65: 1–9Google Scholar
  40. 40.
    Ochoa J (1971) The sural nerve of the human foetus: electron microscope observations and counts of axons. J Anat 108: 231–245Google Scholar
  41. 41.
    Oh SJ, Joy JL, Sunwoo IN (1989) Tomaculous neuropathy presenting as demyelinating mononeuropathy. Ann Neurol 26: 168–169Google Scholar
  42. 42.
    Ohnishi A, Murai Y, Ikeda M, Fujita T, Furuya H, Kuroiwa Y (1989) Autosomal recessive motor and sensory neuropathy with excessive myelin outfolding. Muscle Nerve 12: 568–575Google Scholar
  43. 43.
    Patel PI, Roa BB, Welcher AA, Schoener-Scott R, Trask BJ, Pentao L, Snipes GJ, Garcia CA, Francke U, Shooter EM, Lupski JR, Suter U (1992) The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nature Genet 1: 159–165Google Scholar
  44. 44.
    Raine CS, Bornstein MB (1979) Experimental allergic neuritis. Ultrastructure of serum-induced myelin aberrations in peripheral nervous system cultures. Lab Invest 40: 423–432Google Scholar
  45. 45.
    Raine CS, Wisniewski H, Prineas J (1969) An ultrastructural study of experimental demyelination and remyelination. II. Chronic experimental allergic encephalomyelitis in the peripheral nervous system. Lab Invest 21: 316–327Google Scholar
  46. 46.
    Roa BH, Garcia CA, Suter U, Kulpa DA, Wise CA, Mueller J, Welcher AA, Snipes GJ, Shooter EM, Patel PI, Lupski JR (1993) Charcot-Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 Gene. N Engl J Med 329: 96–101Google Scholar
  47. 47.
    Schady W, Ochoa J (1984) Ehlers-Danlos in association with tomaculous neuropathy. Neurology 34: 1270Google Scholar
  48. 48.
    Stebbins NB, Conneally PM (1982) Linkage of dominantly inherited Charcot-Marie-Tooth neuropathy to the Duffy locus in an Indiana family. Am J Hum Genet 34: 195AGoogle Scholar
  49. 49.
    Su Y, Brooks DG, Li L, Lepercq JA, Ravetch JV, Lebo RV (1993) Myelin protein zero gene mutated in Charcot-Marie-Tooth disease type 1B patients. Proc Natl Acad Sci USA 90: 10856–10860Google Scholar
  50. 50.
    Suzuki M, Sakamoto Y, Kitamura K, Fukunaga K, Yamamoto H, Miyamoto E, Uyemura K (1990) Phosphorylation of P0 glycoprotein in peripheral nerve myelin. J Neurochem 55: 1966–1971Google Scholar
  51. 51.
    Takatsu M, Hays AP, Latov N, Abrams GM, Nemni R, Sherman WH, Nobile-Orazio E, Saito T, Freddo L (1985) Immunofluorescence study of patients with neuropathy and IgM M-proteins. Ann Neurol 18: 173–181Google Scholar
  52. 52.
    Timmermann V, Nelis E, van Hul W, Nieuwenhuijsen BW, Chen KL, Wang S, Othman KB, Cullen B, Leach RJ, Hanemann CO, de Jonghe P, Raeymaekers P, van Ommen G-JB, Martin J-J, Müller HW, Vance JM, Fischbeck KH, van Broeckhoven C (1992) The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. Nature Genet 1: 171–175Google Scholar
  53. 53.
    Valentijn LJ, Bolhius PA, Zorn I, Hoogendijk JE, van den Bosch N, Hensels GW, Stanton VP Jr, Housman DE, Fischbeck KH, Ross DA, Nicholson GA, Meershoek EJ, Dauwerse HG, van Ommen G-JB, Baas F (1992) The peripheral myelin gene PMP-22/ GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. Nature Genet 1: 166–170Google Scholar
  54. 54.
    Vallat JM, Gil R, Leboutet MJ, Hugon J, Moulies D (1987) Congenital hypo- and hypermyelination neuropathy. Acta Neuropathol (Berl) 74: 197–201Google Scholar
  55. 55.
    Vance JM, Nicholson GA, Yamaoka LH, Stajich J, Stewart CS, Speer MC, Hung WY, Roses AD, Barker D, Pericak-Vance MA (1989) Linkage of Charcot-Marie-Tooth neuropathy type 1a to chromosome 17. Exp Neurol 104: 186–189Google Scholar
  56. 56.
    van den Berg LH, Sadiq SA, Thomas FP, Latov N (1990) Characterization of HNK-1 bearing glycoproteins in human peripheral nerve myelin. J Neurosci Res 25: 295–299Google Scholar
  57. 57.
    Vedeler CA (1987) Demonstration of Fcγ receptors on human peripheral nerve fibers. J Neuroimmunol 15: 207–216Google Scholar
  58. 58.
    Vedeler CA, Matre R, Kristoffersen EK (1989) Solubilization of human peripheral nerve Fcγ receptors and purification of a functional 40-kDA receptor. Immunol Lett 22: 281–286Google Scholar
  59. 59.
    Vital C, Pautrizel B, Lagueny A, Vital A, Bergouignan FX, David B, Loiseau P (1985) Hypermyélinisation dans un cas de neuropathie périphérique avec gammapathie monoclonale bénigne à IgM. Rev Neurol (Paris) 141: 729–734Google Scholar
  60. 60.
    Windebank AJ (1993) Inherited recurrent focal neuropathies. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF (eds) Peripheral neuropathy, 3rd edn. Saunders, Philadelphia, pp 1137–1148Google Scholar
  61. 61.
    Woratz G (1964) Neurale Muskelatrophie mit dominantem X-chromosomalem Erbgang. Abh Dtsche Akad Wiss Berl 2Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Florian P. Thomas
    • 1
    • 2
    • 3
  • Roger V. Lebo
    • 4
    • 5
    • 6
  • Gorazd Rosoklija
    • 1
  • Xin-Sheng Ding
    • 1
  • Robert E. Lovelace
    • 2
  • Norman Latov
    • 2
  • Arthur P. Hays
    • 1
  1. 1.Department of Pathology (Division of Neuropathology), College of Physicians & SurgeonsColumbia UniversityNew YorkUSA
  2. 2.Neurological Institute, College of Physicians & SurgeonsColumbia UniversityNew YorkUSA
  3. 3.Clinical Research Institute of MontrealMontrealCanada
  4. 4.Department of ObstetricsUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of GynecologyUniversity of CaliforniaSan FranciscoUSA
  6. 6.Department of PediatricsUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations