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Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2)

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Abstract

Although the cranial nerves, their nuclei and related fiber tracts are crucial for a variety of oculomotor, somatomotor, somatosensory, auditory, vestibular-related, autonomic and ingestion-related functions, knowledge regarding the extent of their involvement in spinocerebellar ataxia type 2 (SCA2) patients is incomplete. Accordingly, we performed a pathoanatomical analysis of these structures in six clinically diagnosed SCA2 patients. Unconventionally thick serial sections through the brainstem stained for lipofuscin pigment (aldehyde-fuchsin) and Nissl material (Darrow red) showed that all oculomotor, somatomotor, somatosensory, auditory, vestibular and autonomic cranial nerve nuclei may undergo neurodegeneration during SCA2. Similarly, examination of myelin-stained thick serial sections revealed that nearly all cranial nerves and associated fiber tracts may sustain atrophy and myelin loss in SCA2 patients. In view of the known functional role of the affected cranial nerves, their nuclei and associated fiber tracts, the present findings provide appropriate pathoanatomical explanations for some of the disease-related and unexplained symptoms seen in SCA2 patients: double vision, gaze palsy, slowing of saccades, ptosis, ingestion-related malfunctions, impairments of the optokinetic nystagmus and the vestibulo-ocular reaction, facial and tongue fasciculation-like movements, impaired centripetal transmission of temperature-related information from the face, dystonic posture of the neck, as well as abnormalities of the brainstem auditory evoked potentials.

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References

  1. Abele M, Bürk K, Andres F, Topka H, Laccone FA, Bösch SM, Brice A, Cancel G, Dichgans J, Klockgether T (1997) Autosomal dominant cerebellar ataxia type I. Nerve conduction and evoked potential studies in families with SCA1, SCA2 and SCA3. Brain 120:2141–2148

    Google Scholar 

  2. Auburger G, Diaz GO, Capote RF, Sanchez SG, Perez MP, Cueto ME del, Meneses MG, Farrall M, Williamson R, Chamberlain S (1990) Autosomal dominant ataxia: genetic evidence for locus heterogeneity from a Cuban founder-effect population. Am J Hum Genet 46:1163–1177

    Google Scholar 

  3. Barmack NH (2003) Central vestibular system: vestibular nuclei and posterior cerebellum. Brain Res Bull 60:511–541

    Google Scholar 

  4. Biacabe B, Chevallier JM, Avan P, Bonfils P (2001) Functional anatomy of auditory brainstem nuclei: application to the anatomical basis of brainstem auditory evoked potentials. Auris Nasus Larynx 28:85–94

    Google Scholar 

  5. Bortz J, Lienert JA, Boehnke K (1990) Verteilungsfreie Methoden in der Biostatistik, 1st edn. Springer, Berlin

  6. Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1:213–216

    Google Scholar 

  7. Braak H, Rüb U, Del Tredici K (2003) Involvement of precerebellar nuclei in multiple system atrophy. Neuropath Appl Neurobiol 29:60–76

    Google Scholar 

  8. Brown JA (1997) The trigeminal complex. Anatomy and physiology. Neurosurg Clin N Am 8:1–10

    Google Scholar 

  9. Bürk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone FA, Didierjean O, Brice A, Klockgether T (1996) Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain 119:1497–1505

    Google Scholar 

  10. Bürk K, Stevanin G, Didierjean O, Cancel G, Trottier Y, Skalej M, Abele M, Brice A, Dichgans J, Klockgether T (1997) Clinical and genetic analysis of three German kindreds with autosomal dominant cerebellar ataxia type I linked to the SCA2 locus. J Neurol 244:256–261

    Google Scholar 

  11. Bürk K, Fetter M, Abele M, Laccone FA, Brice A, Dichgans J, Klockgether T (1999) Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3. J Neurol 246:789–797

    Google Scholar 

  12. Büttner-Ennever JA, Büttner U (1992) Neuroanatomy of the ocular motor pathways. Baillière’s Clin Neurol 1:263–287

  13. Büttner-Ennever JA, Horn AK (1997) Anatomical substrates of oculomotor control. Curr Opin Neurobiol 7:872–879

    Google Scholar 

  14. Cancel G, Dürr A, Didierjean O, Imbert G, Bürk K, Lezin A, Belal S, Benomar A, Abada-Bendib M, Vial C, Guimaraes J, Chneiweiss H, Stevanin G, Yvert G, Abbas N, Saudou F, Lebre AS, Yahyaoui M, Hentati F, Vernant JC, Klockgether T, Mandel JL, Agid Y, Brice A (1997) Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet 6:709–715

    Google Scholar 

  15. Dodd J, Kelly JP (1991) Trigeminal system. In: Kandel ER, Schwartz JH, Jessell TM (eds) Principles of neural science, 3rd edn. Elsevier, New York, pp 701–710

  16. Dürr A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J, Bellance R, Buisson GG, Chneiweiss H, Dellanave J, Agid Y, Brice A, Vernant J (1995) Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 118:1573–1581

    Google Scholar 

  17. Eng LF, Ghirnikar RS (1994) GFAP and astrogliosis. Brain Pathol 4:229–237

    Google Scholar 

  18. Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25:1439–1451

    Google Scholar 

  19. Estrada R, Galarraga J, Orozco G, Nodarse A, Auburger G (1999) Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol 97:306–310

    Google Scholar 

  20. Evidente VG, Gwinn-Hardy KA, Caviness JN, Gilman S (2000) Hereditary ataxias. Mayo Clin Proc 75:475–490

    Google Scholar 

  21. Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49:377–391

    Google Scholar 

  22. Gerrits NM (1990) Vestibular nuclear complex. In: Paxinos G (eds) The human nervous system, 1st edn. Academic Press, San Diego, pp 863–888

  23. Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM (1997) The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am J Hum Genet 60:842–850

    Google Scholar 

  24. Gilman S (2000) The spinocerebellar ataxias. Clin Neuropharmacol 23:296–303

    Google Scholar 

  25. Heinsen H, Heinsen YL (1991) Serial thick, frozen, gallocyanin stained sections of human central nervous system. J Histotechnol 14:167–173

    Google Scholar 

  26. Hernández A, Magarino C, Gispert S, Santos N, Lunkes A, Orozco G, Heredero L, Beckmann J, Auburger G (1995) Genetic mapping of the spinocerebellar ataxia 2 (SCA2) locus on chromosome 12q23-q24.1. Genomics 25:433–435

    Google Scholar 

  27. Horn AK, Büttner T, Büttner-Ennever JA (1999) Brainstem and cerebellar structures for eye movement generation. Adv Otorhinolaryngol 55:1–25

    Google Scholar 

  28. Hutchins B, Weber JT (1983) A rapid myelin stain for frozen sections: modification of the Heidenhain procedure. J Neurosci Methods 7:289–294

    Google Scholar 

  29. Huynh DP, Del Bigio MR, Ho DH, Pulst SM (1999) Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol 45:232–241

    Google Scholar 

  30. Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, Dürr A, Didierjean O, Stevanin G, Agid Y, Brice A (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 14:285–291

    Google Scholar 

  31. Iwabuchi K, Tsuchiya K, Uchihara T, Yagishita S (1999) Autosomal dominant spinocerebellar degenerations. Clinical, pathological, and genetic correlations. Rev Neurol 155:255–270

    Google Scholar 

  32. Kaas JH (1990) Somatosensory system. In: Paxinos G (eds) The human nervous system, 1st edn. Academic Press, San Diego, pp 813–844

  33. Klockgether T (2003) Ataxias. In: Goetz CG (eds) Textbook of clinical neurology, 2nd edn. Saunders, Philadelphia, pp 741–757

  34. Klockgether T, Evert B (1998) Genes involved in hereditary ataxias. Trends Neurosci 21:413–418

    Google Scholar 

  35. Klockgether T, Wüllner U, Spauschus A, Evert B (2000) The molecular biology of the autosomal-dominant cerebellar ataxias. Mov Disord 15:604–612

    Google Scholar 

  36. Koyano S, Uchihara T, Fujigasaki H, Nakamura A, Yagashita S, Iwabuchi K (1999) Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study. Neurosci Lett 273:117–120

    Google Scholar 

  37. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    Google Scholar 

  38. Lang J (1981) Neuroanatomy of the optic, trigeminal, facial, glossopharyngeal, vagus, accessory and hypoglossal nerves. Arch Otorhinolaryngol 231:1–69

    Google Scholar 

  39. Leigh RJ, Zee DS (1991) The neurology of eye movements, 2nd edn. Davis, Philadelphia

  40. Leigh RJ, Zee DS (1992) Oculomotor control: normal and abnormal. In: Asbury AK, McKhann GM, McDonald WI (eds) Diseases of the nervous system: clinical neurobiology, 2nd edn. Saunders, Philadelphia, pp 368–389

  41. Martin JH, Jessell TM (1991) Anatomy of the somatic sensory system. In: Kandel ER, Schwartz JH, Jessell TM (eds) Principles of neural science, 3rd edn. Elsevier, New York, pp 353–366

  42. Mizusawa H, Clark HB, Koeppen AH (2003) Spinocerebellar Ataxias. In: Dickson D (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders, 1st edn. The International Society of Neuropathology Press, Basel, pp 242–256

  43. Møller AR (1999) Neural mechanisms of BAEP. In: Barber C, Celesia GG, Hashimoto I, Kakigi R (eds) Functional neuroscience: evoked potentials and magnetic fields, 1st edn. Elsevier Science, Amsterdam, pp 27–35

  44. Møller AR, Jannetta PJ (1983) Auditory evoked potentials recorded from the cochlear nucleus and its vicinity in man. J Neurosurg 59:1013–1018

    Google Scholar 

  45. Møller AR, Jho HD, Yokota M, Jannetta PJ (1995) Contribution from crossed and uncrossed brainstem structures to the brainstem auditory evoked potentials: a study in humans. Laryngoscope 105:596–605

    Google Scholar 

  46. Nechiporuk A, Lopes-Cendes I, Nechiporuk T, Starkman S, Andermann E, Rouleau GA, Weissenbach JS, Kort E, Pulst SM (1996) Genetic mapping of the spinocerebellar ataxia type 2 gene on human chromosome 12. Neurology 46:1731–1735

    Google Scholar 

  47. Olszewski J, Baxter D (1982) Cytoarchitecture of the human brain stem, 2nd edn. Karger, Basel

  48. Pang JT, Giunti P, Chamberlain S, An SF, Vitaliani R, Scaravilli T, Martinian L, Wood NW, Scaravilli F, Ansorge O (2002) Neuronal intranuclear inclusions in SCA2: a genetic, morphological and immunohistochemical study of two cases. Brain 125:656–663

    Google Scholar 

  49. Paulson HL (2000) Toward an understanding of polyglutamine neurodegeneration. Brain Pathol 10:293–299

    Google Scholar 

  50. Paulson HL, Ammache Z (2001) Ataxia and hereditary disorders. Neurol Clin 19:759–782

    Google Scholar 

  51. Paxinos G, Törk I, Halliday G, Mehler WR (1990) Human homologs to brainstem nuclei identified in other animals as revealed by acetylcholinesterase activity. In: Paxinos G (ed) The human nervous system, 1st edn. Academic Press, San Diego, pp 149–202

  52. Peretti A, Santoro L, Lanzillo B, Filla A, De Michele G, Barbieri F, Martino G, Ragno M, Cocozza S, Caruso G (1996) Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCA1 and SCA2 patients. J Neurol Sci 142:45–53

    Google Scholar 

  53. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa CP, Sahba S (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14:237–238

    Google Scholar 

  54. Riley HA (1943) An atlas of the basal ganglia, brainstem and spinal cord, 1st edn. Williams & Wilkins, Baltimore

  55. Robitaille Y, Lopes-Cendes I, Becher M, Rouleau G, Clark AW (1997) The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 7:901–926

    Google Scholar 

  56. Rüb U, Brunt ER, Del Turco D, Vos RA de, Gierga K, Paulson HL, Braak H (2003) Guidelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patient. Neuropathol Appl Neurobiol 29:1–13

    Google Scholar 

  57. Rüb U, Brunt ER, Gierga K, Schultz C, Paulson HL, Vos RA de, Braak H (2003) The nucleus raphe interpositus in spinocerebellar ataxia type 3 (Machado-Joseph disease). J Chem Neuroanat 25:115–127

    Google Scholar 

  58. Rüb U, Del Turco D, Del Tredici K, Vos RA de, Brunt ER, Reifenberger G, Seifried C, Schultz C, Auburger G, Braak H (2003) Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance. Brain 126:2257–2272

    Google Scholar 

  59. Rüb U, Schultz C, Del Tredici K, Gierga K, Reifenberger G, Vos RA de, Seifried C, Braak H, Auburger G (2003) Anatomically based guidelines for systematic investigation of the central somatosensory system and their application to a spinocerebellar ataxia type 2 (SCA2) patient. Neuropathol Appl Neurobiol 29:418–433

    Google Scholar 

  60. Rüb U, Brunt ER, Vos RA de, Del Turco D, Del Tredici K, Gierga K, Schultz C, Ghebremedhin E, Bürk K, Auburger G, Braak H (2004) Degeneration of the central vestibular system in spinocerebellar ataxia type 3 patients and its possible clinical significance. Neuropathol Appl Neurobiol 30:401–414

    Google Scholar 

  61. Rüb U, Bürk K, Schöls L, Brunt ER, Vos RA de, Orozco-Diaz G, Gierga K, Ghebremedhin E, Schultz C, Del Turco D, Mittelbronn M, Auburger G, Deller T, Braak H (2004) Damage to the reticulotegmental nucleus of the pons in spinocerebellar ataxia type 1, 2, and 3. Neurology 63:1258–1263

    Google Scholar 

  62. Rüb U, Del Turco D, Bürk K, Orozco-Diaz G, Auburger G, Mittelbronn M, Gierga K, Ghebremedhin E, Schultz C, Schöls L, Bohl JR, Braak H, Deller T (2005) Extended pathoanatomical studies point to a consistent affection of the thalamus in spinocerebellar ataxia type 2. Neuropathol Appl Neurobiol 31:127–140

    Google Scholar 

  63. Schoenen J, Grant G (1990) Spinal cord: Connections. In: Paxinos G (ed) The human nervous system, 1st edn. Academic Press, San Diego, pp 77–92

  64. Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen JT, Riess O (1997) Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 42:924–932

    Google Scholar 

  65. Schöls L, Gispert S, Vorgerd M, Menezes Vieira-Saecker AM, Blanke P, Auburger G, Amoiridis G, Meves S, Epplen JT, Przuntek H, Pulst SM, Riess O (1997) Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds. Arch Neurol 54:1073–1080

    Google Scholar 

  66. Smithson KG, MacVicar BA, Hatton GI (1983) Polyethylene glycol embedding: a technique compatible with immunocytochemistry, enzyme histochemistry, histofluorescence and intracellular staining. J Neurosci Methods 7:27–41

    Google Scholar 

  67. Törk I, McRitchie DA, Rikard-Bell GC, Paxinos G (1990) Autonomic regulatory centers in the medulla oblongata. In: Paxinos G (ed) The human nervous system, 1st edn. Academic Press, San Diego, pp 221–259

  68. Voogd J, Nieuwenhuys R, Van Dongen DAM, Ten Donkelaar HJ (1998) Mammals. In: Nieuwenhuys R, Ten Donkelaar HJ, Nicholson C (eds) The central nervous system of vertebrates, 1st edn. Springer, Berlin, pp 1637–2097

  69. Webster WR, Garey LJ (1990) Auditory system. In: Paxinos G (ed) The human nervous system, 1st edn. Academic Press, San Diego, pp 889–944

  70. Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217–247

    Google Scholar 

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (RU1215/1–1), the Deutsche Heredo-Ataxie-Gesellschaft and the ADCA-Vereniging Nederland. The skillful assistance of M. Babl, B. Meseck-Selchow (tissue processing and immunohistochemistry), M. Hütten (technical support) and Ms. I. Szász (graphics) is thankfully acknowledged.

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Authors and Affiliations

  1. Institute of Clinical Neuroanatomy, J.W. Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt/Main, Germany

    K. Gierga, C. Schultz, M. Vuksic, H. Braak, T. Deller & U. Rüb

  2. Department of Neurology, University of Ulm, 89075, Ulm, Germany

    K. Bürk

  3. Department of Neuropathology, Psychiatric Center Northern Baden, 69155, Wiesloch, Germany

    M. Bauer

  4. Department of Neurology, V. I. Lenin Hospital, Holguín, Cuba

    G. Orozco Diaz

  5. Section Molecular Neurogenetics, Department of Neurology, J.W. Goethe University, 60590, Frankfurt/Main, Germany

    G. Auburger

  6. Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany

    L. Schöls

  7. Laboratorium Pathologie Oost Nederland, Burg. Edo Bergsmalaan 1, 7512 AD, Enschede, The Netherlands

    R. A. I. de Vos

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  1. K. Gierga
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  9. R. A. I. de Vos
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Gierga, K., Bürk, K., Bauer, M. et al. Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2). Acta Neuropathol 109, 617–631 (2005). https://doi.org/10.1007/s00401-005-1014-8

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