Skip to main content
NCBI home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2002 Feb;72(2):230–235. doi: 10.1136/jnnp.72.2.230

Immunological study of hereditary motor and sensory neuropathy type 1a (HMSN1a)

C Gabriel 1, N Gregson 1, N Wood 1, R Hughes 1
PMCID: PMC1737757  PMID: 11796774

Abstract

Objectives: Fifty three patients were studied to investigate whether autoimmune or inflammatory mechanisms could explain the phenotypic heterogeneity of patients with hereditary motor and sensory neuropathy type 1a (HMSN1a). Methods: Serum samples were examined for antibodies to peripheral nerve myelin protein 22 (PMP22), ganglioside GM1 and cauda equina homogenate, and interleukin-6 (IL-6) and soluble tumour necrosis factor receptor 1 (sTNF R1) concentrations. Serological results were compared with those from patients with other neuropathies (ONPs, n=30) and with normal subjects (n=51).

Results: In the group as a whole, no relation emerged between clinical severity and any immune parameters. Immunohistochemical examination of four sural nerve biopsies did not show significant inflammatory infiltration. In a subset of 12 patients who experienced stepwise progression of disease, there was a trend towards a higher proportion having anti-PMP22 antibodies (33% v 15% of those with gradual disease progression, 3% ONPs, and no normal controls) and complement fixing antibodies to human cauda equina (25% v 5% with gradual progression, 8.6% ONPs, 3.9% normal controls, p=0.07).

Conclusions: Patients with HMSN1a and a stepwise disease progression may have an inflammatory, autoimmune component superimposed on the genetic condition.

Full Text

The Full Text of this article is available as a PDF (175.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arahata K., Ishihara T., Fukunaga H., Orimo S., Lee J. H., Goto K., Nonaka I. Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve Suppl. 1995;2:S56–S66. [PubMed] [Google Scholar]
  2. Bird S. J., Sladky J. T. Corticosteroid-responsive dominantly inherited neuropathy in childhood. Neurology. 1991 Mar;41(3):437–439. doi: 10.1212/wnl.41.3.437. [DOI] [PubMed] [Google Scholar]
  3. Donaghy M., Sisodiya S. M., Kennett R., McDonald B., Haites N., Bell C. Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation. J Neurol Neurosurg Psychiatry. 2000 Dec;69(6):799–805. doi: 10.1136/jnnp.69.6.799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dunne J. W., Stewart-Wynne E. G. Neurologic improvement of adrenomyeloneuropathy after steroid replacement therapy. Muscle Nerve. 1993 Oct;16(10):1133–1135. [PubMed] [Google Scholar]
  5. Dyck P. J., Sherman W. R., Hallcher L. M., Service F. J., O'Brien P. C., Grina L. A., Palumbo P. J., Swanson C. J. Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann Neurol. 1980 Dec;8(6):590–596. doi: 10.1002/ana.410080608. [DOI] [PubMed] [Google Scholar]
  6. Dyck P. J., Swanson C. J., Low P. A., Bartleson J. D., Lambert E. H. Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc. 1982 Apr;57(4):239–246. [PubMed] [Google Scholar]
  7. Fitzsimons R. B. Facioscapulohumeral dystrophy: the role of inflammation. Lancet. 1994 Oct 1;344(8927):902–903. doi: 10.1016/s0140-6736(94)92263-2. [DOI] [PubMed] [Google Scholar]
  8. Gabreëls-Festen A. A., Gabreëls F. J., Hoogendijk J. E., Bolhuis P. A., Jongen P. J., Vingerhoets H. M. Chronic inflammatory demyelinating polyneuropathy or hereditary motor and sensory neuropathy? Diagnostic value of morphological criteria. Acta Neuropathol. 1993;86(6):630–635. doi: 10.1007/BF00294303. [DOI] [PubMed] [Google Scholar]
  9. Gabreëls-Festen A. A., Joosten E. M., Gabreëls F. J., Jennekens F. G., Janssen-van Kempen T. W. Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I). J Neurol Sci. 1992 Feb;107(2):145–154. doi: 10.1016/0022-510x(92)90282-p. [DOI] [PubMed] [Google Scholar]
  10. Gabriel C. M., Gregson N. A., Hughes R. A. Anti-PMP22 antibodies in patients with inflammatory neuropathy. J Neuroimmunol. 2000 May 1;104(2):139–146. doi: 10.1016/s0165-5728(99)00269-6. [DOI] [PubMed] [Google Scholar]
  11. Gabriel C. M., Hughes R. A., Moore S. E., Smith K. J., Walsh F. S. Induction of experimental autoimmune neuritis with peripheral myelin protein-22. Brain. 1998 Oct;121(Pt 10):1895–1902. doi: 10.1093/brain/121.10.1895. [DOI] [PubMed] [Google Scholar]
  12. Gabriel J. M., Erne B., Pareyson D., Sghirlanzoni A., Taroni F., Steck A. J. Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies. Neurology. 1997 Dec;49(6):1635–1640. doi: 10.1212/wnl.49.6.1635. [DOI] [PubMed] [Google Scholar]
  13. Gregory R., Thomas P. K., King R. H., Hallam P. L., Malcolm S., Hughes R. A., Harding A. E. Coexistence of hereditary motor and sensory neuropathy type Ia and IgM paraproteinemic neuropathy. Ann Neurol. 1993 Jun;33(6):649–652. doi: 10.1002/ana.410330615. [DOI] [PubMed] [Google Scholar]
  14. Gregson N. A., Jones D., Thomas P. K., Willison H. J. Acute motor neuropathy with antibodies to GM1 ganglioside. J Neurol. 1991 Dec;238(8):447–451. doi: 10.1007/BF00314652. [DOI] [PubMed] [Google Scholar]
  15. Harding A. E., Thomas P. K. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain. 1980 Jun;103(2):259–280. doi: 10.1093/brain/103.2.259. [DOI] [PubMed] [Google Scholar]
  16. Hoogendijk J. E., De Visser M., Bolhuis P. A., Hart A. A., Ongerboer de Visser B. W. Hereditary motor and sensory neuropathy type I: clinical and neurographical features of the 17p duplication subtype. Muscle Nerve. 1994 Jan;17(1):85–90. doi: 10.1002/mus.880170112. [DOI] [PubMed] [Google Scholar]
  17. Hoogendijk J. E., Hensels G. W., Zorn I., Valentijn L., Janssen E. A., de Visser M., Barker D. F., Ongerboer de Visser B. W., Baas F., Bolhuis P. A. The duplication in Charcot-Marie-Tooth disease type 1a spans at least 1100 kb on chromosome 17p11.2. Hum Genet. 1991 Dec;88(2):215–218. doi: 10.1007/BF00206075. [DOI] [PubMed] [Google Scholar]
  18. Hughes R. A., Gray I. A., Gregson N. A., Kadlubowski M., Kennedy M., Leibowitz S., Thompson H. Immune responses to myelin antigens in Guillain-Barré syndrome. J Neuroimmunol. 1984 Aug;6(5):303–312. doi: 10.1016/0165-5728(84)90019-5. [DOI] [PubMed] [Google Scholar]
  19. Inaba A., Yokota T., Shiojiri T., Yamada M. Two siblings with nerve conduction abnormalities indicating an acquired type of demyelinating neuropathy. Muscle Nerve. 1997 May;20(5):608–610. doi: 10.1002/(sici)1097-4598(199705)20:5<608::aid-mus11>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  20. Khalili-Shirazi A., Atkinson P., Gregson N., Hughes R. A. Antibody responses to P0 and P2 myelin proteins in Guillain-Barré syndrome and chronic idiopathic demyelinating polyradiculoneuropathy. J Neuroimmunol. 1993 Jul;46(1-2):245–251. doi: 10.1016/0165-5728(93)90255-w. [DOI] [PubMed] [Google Scholar]
  21. Killian J. M., Tiwari P. S., Jacobson S., Jackson R. D., Lupski J. R. Longitudinal studies of the duplication form of Charcot-Marie-Tooth polyneuropathy. Muscle Nerve. 1996 Jan;19(1):74–78. doi: 10.1002/(SICI)1097-4598(199601)19:1<74::AID-MUS10>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  22. Kleyweg R. P., van der Meché F. G., Schmitz P. I. Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve. 1991 Nov;14(11):1103–1109. doi: 10.1002/mus.880141111. [DOI] [PubMed] [Google Scholar]
  23. Lewis R. A., Sumner A. J., Shy M. E. Electrophysiological features of inherited demyelinating neuropathies: A reappraisal in the era of molecular diagnosis. Muscle Nerve. 2000 Oct;23(10):1472–1487. doi: 10.1002/1097-4598(200010)23:10<1472::aid-mus3>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  24. Lupski J. R., de Oca-Luna R. M., Slaugenhaupt S., Pentao L., Guzzetta V., Trask B. J., Saucedo-Cardenas O., Barker D. F., Killian J. M., Garcia C. A. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991 Jul 26;66(2):219–232. doi: 10.1016/0092-8674(91)90613-4. [DOI] [PubMed] [Google Scholar]
  25. MacMillan J. C., Harper P. S. The Charcot-Marie-Tooth syndrome: clinical aspects from a population study in South Wales, UK. Clin Genet. 1994 Mar;45(3):128–134. doi: 10.1111/j.1399-0004.1994.tb04009.x. [DOI] [PubMed] [Google Scholar]
  26. Malandrini A., Villanova M., Dotti M. T., Federico A. Acute inflammatory neuropathy in Charcot-Marie-Tooth disease. Neurology. 1999 Mar 10;52(4):859–861. doi: 10.1212/wnl.52.4.859. [DOI] [PubMed] [Google Scholar]
  27. McGuinness M. C., Griffin D. E., Raymond G. V., Washington C. A., Moser H. W., Smith K. D. Tumor necrosis factor-alpha and X-linked adrenoleukodystrophy. J Neuroimmunol. 1995 Sep;61(2):161–169. doi: 10.1016/0165-5728(95)00084-f. [DOI] [PubMed] [Google Scholar]
  28. Meléndez-Vásquez C., Redford J., Choudhary P. P., Gray I. A., Maitland P., Gregson N. A., Smith K. J., Hughes R. A. Immunological investigation of chronic inflammatory demyelinating polyradiculoneuropathy. J Neuroimmunol. 1997 Mar;73(1-2):124–134. doi: 10.1016/s0165-5728(96)00189-0. [DOI] [PubMed] [Google Scholar]
  29. Prineas J. W. Acute idiopathic polyneuritis. An electron microscope study. Lab Invest. 1972 Feb;26(2):133–147. [PubMed] [Google Scholar]
  30. Prineas J. W., McLeod J. G. Chronic relapsing polyneuritis. J Neurol Sci. 1976 Apr;27(4):427–458. doi: 10.1016/0022-510x(76)90213-6. [DOI] [PubMed] [Google Scholar]
  31. Ritz M. F., Lechner-Scott J., Scott R. J., Fuhr P., Malik N., Erne B., Taylor V., Suter U., Schaeren-Wiemers N., Steck A. J. Characterisation of autoantibodies to peripheral myelin protein 22 in patients with hereditary and acquired neuropathies. J Neuroimmunol. 2000 May 1;104(2):155–163. doi: 10.1016/s0165-5728(99)00250-7. [DOI] [PubMed] [Google Scholar]
  32. Schmid C. D., Stienekemeier M., Oehen S., Bootz F., Zielasek J., Gold R., Toyka K. V., Schachner M., Martini R. Immune deficiency in mouse models for inherited peripheral neuropathies leads to improved myelin maintenance. J Neurosci. 2000 Jan 15;20(2):729–735. doi: 10.1523/JNEUROSCI.20-02-00729.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sharrack B., Hughes R. A. Clinical scales for multiple sclerosis. J Neurol Sci. 1996 Jan;135(1):1–9. doi: 10.1016/0022-510x(95)00261-y. [DOI] [PubMed] [Google Scholar]
  34. Sladky J. T., Brown M. J., Berman P. H. Chronic inflammatory demyelinating polyneuropathy of infancy: a corticosteroid-responsive disorder. Ann Neurol. 1986 Jul;20(1):76–81. doi: 10.1002/ana.410200113. [DOI] [PubMed] [Google Scholar]
  35. Steinman L., Smith M. E., Forno L. S. Genetic control of susceptibility to experimental allergic neuritis and the immune response to P2 protein. Neurology. 1981 Aug;31(8):950–954. doi: 10.1212/wnl.31.8.950. [DOI] [PubMed] [Google Scholar]
  36. Thomas P. K., Marques W., Jr, Davis M. B., Sweeney M. G., King R. H., Bradley J. L., Muddle J. R., Tyson J., Malcolm S., Harding A. E. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain. 1997 Mar;120(Pt 3):465–478. doi: 10.1093/brain/120.3.465. [DOI] [PubMed] [Google Scholar]
  37. Timmerman V., Raeymaekers P., De Jonghe P., De Winter G., Swerts L., Jacobs K., Gheuens J., Martin J. J., Vandenberghe A., Van Broeckhoven C. Assignment of the Charcot-Marie-Tooth neuropathy type 1 (CMT 1a) gene to 17p11.2-p12. Am J Hum Genet. 1990 Oct;47(4):680–685. [PMC free article] [PubMed] [Google Scholar]
  38. Vallat J. M., Sindou P., Preux P. M., Tabaraud F., Milor A. M., Couratier P., LeGuern E., Brice A. Ultrastructural PMP22 expression in inherited demyelinating neuropathies. Ann Neurol. 1996 Jun;39(6):813–817. doi: 10.1002/ana.410390621. [DOI] [PubMed] [Google Scholar]
  39. Van Zee K. J., Kohno T., Fischer E., Rock C. S., Moldawer L. L., Lowry S. F. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4845–4849. doi: 10.1073/pnas.89.11.4845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Vance J. M., Barker D., Yamaoka L. H., Stajich J. M., Loprest L., Hung W. Y., Fischbeck K., Roses A. D., Pericak-Vance M. A. Localization of Charcot-Marie-Tooth disease type 1a (CMT1A) to chromosome 17p11.2. Genomics. 1991 Apr;9(4):623–628. doi: 10.1016/0888-7543(91)90355-i. [DOI] [PubMed] [Google Scholar]
  41. Vital A., Vital C., Julien J., Fontan D. Occurrence of active demyelinating lesions in children with hereditary motor and sensory neuropathy (HMSN) type I. Acta Neuropathol. 1992;84(4):433–436. doi: 10.1007/BF00227671. [DOI] [PubMed] [Google Scholar]
  42. Williams L. L., Shannon B. T., O'Dougherty M., Wright F. S. Activated T cells in type I Charcot-Marie-Tooth disease: evidence for immunologic heterogeneity. J Neuroimmunol. 1987 Nov;16(3):317–330. doi: 10.1016/0165-5728(87)90108-1. [DOI] [PubMed] [Google Scholar]
  43. Williams L. L., Shannon B. T., Wright F. S. Circulating cytotoxic immune components in dominant Charcot-Marie-Tooth syndrome. J Clin Immunol. 1993 Nov;13(6):389–396. doi: 10.1007/BF00920014. [DOI] [PubMed] [Google Scholar]
  44. Williams L. L., Wright F. S. Arachidonic fatty acid in red blood cell membranes, lymphocytes, and cultured skin fibroblasts of dominant Charcot-Marie-Tooth syndrome. J Neurol Sci. 1993 Dec 15;120(2):195–200. doi: 10.1016/0022-510x(93)90273-2. [DOI] [PubMed] [Google Scholar]
  45. Zielasek J., Ritter G., Magi S., Hartung H. P., Toyka K. V. A comparative trial of anti-glycoconjugate antibody assays: IgM antibodies to GM1. J Neurol. 1994 Jul;241(8):475–480. doi: 10.1007/BF00919708. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES