Acta Neuropathologica

, Volume 88, Issue 4, pp 277–286

On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family

  • J. -J. Martin
  • L. Krols
  • C. Ceuterick
  • C. Van Broeckhoven
  • N. Van Regemorter
  • F. Hayer-Delatte
  • J. -M. Brucher
  • T. de Barsy
  • H. Szliwowski
  • P. Evrard
  • M. -J. Tassignon
  • H. Smet-Dieleman
  • P. J. Willems
Regular Paper


We describe a family with an autosomal dominant form of retinal-cerebellar atrophy. There is an extreme variability in age of onset and severity of the clinical symptoms: some patients remain nearly asymptomatic throughout their entire life; others develop severe retinal and cerebellar symptoms after the age of 35 years; others suffer from a severe disorder with onset in adolescence and death during the third decade of life; in others the onset is in early childhood with prevalence of cerebellar symptoms. There is neither dementia nor epilepsy in any of the patients. Four out of five autopsies showed a severe retinal atrophy, and all five autopsies were also characterized by (1) a cerebellar atrophy affecting the spinocerebellar and olivocerebellar tracts, the cerebellar cortex and the efferent cerebellar pathways, (2) an involvement of the pyramidal pathways and of the motor neurons of brain stem and spinal cord, and (3) an atrophy of the subthalamic nucleus and to a much lesser extent of the pallidum, with also some damage to the substantia nigra. The posterior columns are much less affected except in one patient. In this family, we have excluded linkage with the two loci for spinocerebellar ataxia, i.e., SCA1 on chromosome 6p and SCA2 on chromosome 12q as well as with the locus for Machado-Joseph disease (MJD) on chromosome 14q. A genome-wide search is currently being performed to detect the disease locus responsible.

Key words

Autosomal dominant disease Cone dystrophy Cerebellar atrophy Multiple system atrophy Linkage 


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  1. 1.
    Auburger G, Diaz GO, Capote RF, Sanchez SG, Perez MP, del Cueto ME, Meneses MG, Farrall M, Williamson R, Chamberlain S, Baute LH (1990) Autosomal dominant ataxia: genetic evidence for locus heterogeneity from a Cuban Founder-effect population. Am J Hum Genet 46: 1163–1177Google Scholar
  2. 2.
    Bergstedt M, Johansson S, Müller R (1962) Hereditary spastic ataxia with central retinal degeneration and vestibular impairment. A clinical report on a family. Neurology 12: 124–132Google Scholar
  3. 3.
    Björk A, Lindblom U, Wadensten L (1956) Retinal degeneration in hereditary ataxia. J Neurol Neurosurg Psychiatry 19: 186–193Google Scholar
  4. 4.
    Chamberlain S, Shaw J, Rowland A, Wallis J, South S, Nakamura Y, von Gabain A, Farrall M, Williamson R (1988) Mapping of mutation causing Friedreich's ataxia to human chromosome 9. Nature 334: 248–250Google Scholar
  5. 5.
    Duinkerke-Eerola KU, Cruysberg JRM, Deutman AF (1980) Atrophic maculopathy associated with hereditary ataxia. Am J Ophthalmol 90: 597–603Google Scholar
  6. 6.
    Ferrer J, Campistol J, Tobena L, Cusi V, Galofré E, Prat J (1987) Dégénérescence systématisée optico-cochléo-dentelée. J Neurol 234: 416–420Google Scholar
  7. 7.
    Foster JB, Ingram TTS (1962) Familial cerebro-macular degeneration and ataxia. J Neurol Neurosurg Psychiatry 25: 63–68Google Scholar
  8. 8.
    Fowler HL (1984) Machado-Joseph-Azorean disease. A ten-year study. Arch Neurol 41: 921–925Google Scholar
  9. 9.
    Gatti R.A, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NG, Lange K, Lathrop GM, Leppert M, Nakamura Y, O'Connell P, Paterson M, Salser W, Sanal O, Silver J, Sparkes RS, Susi E, Weeks DE, Wei S, White R, Yoder F (1988) Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 336: 577–580Google Scholar
  10. 10.
    Gispert S, Twells R, Orozco G, Brice A, Weber J, Heredero L, Scheufler K, Riley B, Allotey R, Nothers C, Hillermann R, Lunkes A, Khati C, Stevanin G, Hernandez A, Magarino C, Klockgether T, Durr A, Chneiweiss H, Enczmann J, Farrall M, Beckmann J, Mullan M, Wernet P, Agid Y, Freund H-J, Williamson R, Auburger G, Chamberlain S (1993) Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nature Genet 4: 295–299Google Scholar
  11. 11.
    Goto I, Tobimatsu S, Ohta M, Hosokawa S, Shibasaki H, Kuroiwa Y (1982) Dentatorubro-pallidoluysian degeneration: clinical, neuro-ophthalmologic, biochemical, and pathologic studies on autosomal dominant form. Neurology 32: 1395–1399Google Scholar
  12. 12.
    Halsey JH Jr, Scott TR, Farmer TW (1967) Adult hereditary cerebello-retinal degeneration. Neurology 17: 87–90Google Scholar
  13. 13.
    Hamilton SR, Chatrian G-E, Mills RP, Kalina RE, Bird TD (1990) Cone dysfunction in a subgroup of patients with autosomal dominant cerebellar ataxia. Arch Ophthalmol 108: 551–556Google Scholar
  14. 14.
    Harding AE (1982) The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of “the Drew family of Walworth”. Brain 105: 1–28Google Scholar
  15. 15.
    Harding AE (1984) The hereditary ataxias and related disorders. Clinical Neurology and Neurosurgery Monographs. Churchill Livingstone, EdinburghGoogle Scholar
  16. 16.
    Iizuka R, Hirayama K, Maehara K (1984) Dentato-rubropallido-luysian atrophy: a clinico-pathological study. J Neurol Neurosurg Psychiatry 47: 1288–1298Google Scholar
  17. 17.
    Lazzarini A, Zimmerman TR, Johnson WG, Duvoisin RC (1992) A 17th-century founder gives rise to a large North American pedigree of autosomal dominant spinocerebellar ataxia not linked to the SCA1 locus on chromosome 6. Neurology 42: 2118–2124Google Scholar
  18. 18.
    Martin J-J (1970) Contribution à l'étude de l'anatomie du thalamus et de sa pathologie au cours des maladies dégénératives dites abiotrophiques. Thèse d' agrégation de l' Enseignement supérieur en Sciences Neurologiques. Acta Neurol Belg 70: 5–212Google Scholar
  19. 19.
    Mizutani T, Oda M, Abe H, Fukuda S, Oikawa H, Kosaka K (1983) Hereditary multisystemic degeneration with unusual combination of cerebellipetal, dentato-rubral, and nigro-subthalamo-pallidal degenerations. Clin Neuropathol 2: 147–155Google Scholar
  20. 20.
    Morton NE, Lalouel J-M, Jackson JF, Currier RD, Yee S (1980) Linkage studies in spinocerebellar ataxia (SCA). Am J Med Genet 6: 251–257Google Scholar
  21. 21.
    Neetens A, Martin J-J, Libert J, Van Den Ende P (1990) Autosomal dominant cone-dystrophy-cerebellar atrophy (ADCoCA) (modified ADCA Harding II). Neurophthalmology 10: 261–275Google Scholar
  22. 22.
    Nyssen R, van Bogaert L (1934) La dégénérescence systématisée optico-cochléo-dentelée. Rev Neurol (Paris) 2: 321–345Google Scholar
  23. 23.
    Orr H T, Chung M Y, Banfi S, Kwiatkowski T J Jr, Servadio A, Beaudet A L, McCall AE, Duvick LA, Ranum LP Zoghbi HY (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet 4: 221–226Google Scholar
  24. 24.
    Rich SS, Wilkie P, Schut L, Vanve G, Orr HT (1987) Spinocerebellar ataxia: localization of an autosomal dominant locus between two markers on human chromosome 6. Am J Hum Genet 41: 524–531Google Scholar
  25. 25.
    Stanescu B, Evrard P, Michiel SJ, Lyon G (1980) Electroretinographic changes in a case of spino-cerebellar degeneration (SCD). Metab Pediatr Ophthalmol 4: 221–223Google Scholar
  26. 26.
    Sternberger LA (1986) Immunocytochemistry, 3rd edn. Wiley and Sons, New-YorkGoogle Scholar
  27. 27.
    Subramony SH, Currier RD (1991) The classification of familial ataxias. Handb Clin Neurol 60: 271–284Google Scholar
  28. 28.
    Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S, Kagawa Y, Kanazawa I, Mizuno Y, Yoshida M, Yuasa T, Horikawa Y, Oyanagi K, Nagai H, Kondo T, Inuzuka T, Onodera O, Tsuji S (1993) The gene for Machado-Joseph disease maps to chromosome 14q. Nature Genet 4: 300–304Google Scholar
  29. 29.
    Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, Cras P, Martin J-J (1992) Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3. Nature Genet 2: 335–339Google Scholar
  30. 30.
    Verougstraete C, Toussaint D (1973) Dégénérescence tapétorétinienne avec ataxie cérébelleuse: étude clinique de plusieurs membres d' une même famille. Bull Soc Belge Ophtalmol 164: 285–295Google Scholar
  31. 31.
    Weiner LP, Konigsmark BW, Stoll J Jr, Magladery JW (1967) Hereditary olivopontocerebellar atrophy with retinal degeneration. Report of a family through six generations. Arch Neurol 16: 364–376Google Scholar
  32. 32.
    Yuasa T, Ohama E, Harayama H, Yamada M, Kawase Y, Wakabayashi M, Atsumi T, Miyatake T (1986) Joseph's disease: clinical and pathological studies in a japanese family. Ann Neurol 19: 152–157Google Scholar
  33. 33.
    Zoghbi HY, Sandkuyl LA, Ott J, Daiger SP, Pollack M, O'Brien WE, Beaudet AL (1989) Assignment of autosomal dominant spinocerebellar ataxia (SCAI) centromeric to the HLA region on the short arm of chromosome 6, using multilocus linkage analysis. Am J Hum Genet 44: 255–263Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • J. -J. Martin
    • 1
    • 9
  • L. Krols
    • 1
  • C. Ceuterick
    • 1
  • C. Van Broeckhoven
    • 1
  • N. Van Regemorter
    • 2
  • F. Hayer-Delatte
    • 2
  • J. -M. Brucher
    • 3
  • T. de Barsy
    • 4
  • H. Szliwowski
    • 5
  • P. Evrard
    • 6
  • M. -J. Tassignon
    • 7
  • H. Smet-Dieleman
    • 7
  • P. J. Willems
    • 8
  1. 1.Laboratory of Neuropathology and NeurogeneticsBorn-Bunge Foundation and University of AntwerpWilrijkBelgium
  2. 2.Centre de Génétique de BruxellesFree University of BrusselsBelgium
  3. 3.Laboratory of Neuropathology, St-Luc University HospitalCatholic University of LouvainBrusselsBelgium
  4. 4.Department of Neurology, William Lennox Neurological CentreCatholic University of LouvainOttigniesBelgium
  5. 5.Département de Neurologie Pédiatrique, Hôpital ErasmeUniversité Libre de BruxellesBrusselsBelgium
  6. 6.Department of Paediatric Neurology, St-Luc University HospitalCatholic University of LouvainBrusselsBelgium
  7. 7.Department of Ophthalmology, University Hospital of AntwerpUniversity of AntwerpWilrijkBelgium
  8. 8.Department of Medical GeneticsUniversity of AntwerpWilrijkBelgium
  9. 9.Gebouw T, Lokaal 5-18, Universitaire Instelling AntwerpenWilrijk, AntwerpenBelgium

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