Advertisement

Journal of Neurology

, Volume 259, Issue 5, pp 869–878 | Cite as

New findings in the ataxia of Charlevoix–Saguenay

  • José GazullaEmail author
  • Isabel Benavente
  • Ana Carmen Vela
  • Miguel Angel Marín
  • Luis Emilio Pablo
  • Alessandra Tessa
  • María Rosario Barrena
  • Filippo Maria Santorelli
  • Claudia Nesti
  • Pedro Modrego
  • María Tintoré
  • José Berciano
Original Communication

Abstract

The aim of the study was to enhance our understanding of the pathogenesis of the ataxia of Charlevoix–Saguenay, based on the findings presented herein. Five patients with a molecular diagnosis of this disease underwent clinical, radiological, ophthalmologic and electrophysiological examinations. Five novel mutations, which included nonsense and missense variants, were identified, with these resulting in milder phenotypes. In addition to the usual manifestations, a straight dorsal spine was found in every case, and imaging techniques showed loss of the dorsal kyphosis. Cranial MRI demonstrated hypointense linear striations at the pons. Tensor diffusion MRI sequences revealed that these striations corresponded with hyperplastic pontocerebellar fibres, and tractographic sequences showed interrupted pyramidal tracts at the pons. Ocular coherence tomography demonstrated abnormal thickness of the nerve fibre layer. Electrophysiological studies showed nerve conduction abnormalities compatible with a dysmyelinating neuropathy, with signs of chronic denervation in distal muscles. The authors suggest that the hyperplastic pontocerebellar fibres compress the pyramidal tracts at the pons, and that the amount of retinal fibres traversing the optic discs is enlarged. These facts point to the contribution of an abnormal developmental mechanism in the ataxia of Charlevoix–Saguenay. Accordingly, spasticity would be mediated by compression of the pyramidal tracts, neuromuscular symptoms by secondary axonal degeneration superimposed on the peripheral myelinopathy, while the cause of the progressive ataxia remains speculative. The distinctive aspect of the dorsal spine could be of help in the clinical diagnosis.

Keywords

ARSACS Peripheral and central myelinopathy Pontocerebellar fibre hyperplasia Retinal nerve fibre hyperplasia Straight dorsal spine 

Notes

Acknowledgments

The authors wish to thank Drs. Jorge Artal, José Luis Capablo, Manuel Gracia-Naya and Pilar Larrodé for referral of patients; Dr. Elena García, for help with the ophthalmological part of this article, and Mr. Juan Luis Fuentes, for the ophthalmologic photographs. We also thank Ms. Stephanie Lyon, for linguistic assessment. This work is dedicated to the memory of Paloma Agüeras (1958–2009).This work was supported by grants of the Italian Ministry of Health (Ricerca Corrente, RC-FSM-02/2010) and of the European Union for EUROSPA (E-RARE grant IT0807), to FMS; and by a grant of the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas and Fondo de Investigaciones Sanitarias (PI07/132E to JB).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249PubMedCrossRefGoogle Scholar
  2. 2.
    Albin RL, Greenamyre JT (1992) Alternative excitotoxic hypotheses. Neurology 42:733–738PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson JF, Siller E, Barral JM (2010) The sacsin repeating region (SSR): a novel HSP90-related supra-domain associated with neurodegeneration. J Mol Biol 400:665–674PubMedCrossRefGoogle Scholar
  4. 4.
    Anesi L, de Gemmis P, Pandolfo M, Hladnik U (2010) Two novel homozygous SACS mutations in unrelated patients including the first reported case of parental UPD as an etiologic cause of ARSACS. J Mol Neurosci 43:346–349PubMedCrossRefGoogle Scholar
  5. 5.
    Baets J, Deconinck T, Smets K, Goosens D, Van den Bergh P, Dahan K, Schmedding E, Santens P, Rasic VM, Van Damme P, Robberecht W, De Meirleir L, Michielsens B, Del-Favero J, Jordanova A, De Jonghe P (2010) Mutations in SACS cause atypical and late-onset forms of ARSACS. Neurology 75:1181–1188PubMedCrossRefGoogle Scholar
  6. 6.
    Berciano J, García A, Infante J (2010) Peripheral nerve involvement in hereditary cerebellar and multisystem degenerative disorders. In: Said G, Krarup C (eds) Peripheral Nerve Disorders. Handbook of Clinical Neurology. Elsevier Sci, Amsterdam (in press)Google Scholar
  7. 7.
    Bouchard JP (1991) Recessive spastic ataxia of Charlevoix-Saguenay. In: de Jong JMBV (ed) Handbook of Clinical Neurology. Hereditary neuropathies and spinocerebellar atrophies, vol 60. Elsevier Sci, Amsterdam, pp 452–559Google Scholar
  8. 8.
    Bouchard JP, Barbeau A, Bouchard R, Bouchard RW (1978) Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci 5:61–69PubMedGoogle Scholar
  9. 9.
    Bouchard JP, Brais B, Dupré N, Rouleau GA (2007) Hereditary ataxias and spastic parapareses in north eastern Canada. In: Brice A, Pulst SM (eds) Spinocerebellar Degenerations. The ataxias and spastic paraplegias. Butterworth Heinemann Elsevier, Philadelphia, pp 222–243CrossRefGoogle Scholar
  10. 10.
    Bouchard JP, Richter A, Melançon SB, Mathieu J, Michaud J (2000) Autosomal recessive spastic ataxia (Charlevoix-Saguenay). In: Klockgether T (ed) Handbook of ataxia disorders. Marcel Dekker, New York, pp 311–324Google Scholar
  11. 11.
    Bouhlal Y, Amouri R, El Euch-Fayache G, Hentati F (2011) Autosomal recessive spastic ataxia of Charlevoix-Saguenay: an overview. Parkinsonism Relat Disord 17:418–422PubMedCrossRefGoogle Scholar
  12. 12.
    Criscuolo C, Banfi S, Orio M, Gasparini P, Monticelli A, Scarano V, Banfi S, Filla A (2004) A novel mutation in SACS gene in a family from southern Italy. Neurology 62:100–102PubMedCrossRefGoogle Scholar
  13. 13.
    Desserre J, Devos D, Sautière BG, Debruyne P, Santorelli FM, Vuillaume I, Defoort-Dhellemmes S (2011). Thickening of Peripapillar Retinal Fibers for the Diagnosis of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay. Cerebellum. doi: 10.1007/s12311-011-0286-x
  14. 14.
    El-Euch-Fayache G, Lalani I, Amouiri R, Turki I, Ouahchi K, Hung WY, Belal S, Siddique T, Hentati F (2003) Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch Neurol 60:982–988PubMedCrossRefGoogle Scholar
  15. 15.
    Engert JC, Berube P, Mercier J, Dore C, Lepage P, Ge B, Bouchard JP, Mathieu J, Melançon SB, Schalling M, Lander ES, Morgan K, Hudson TJ, Richter A (2000) ARSACS, a spastic ataxia common in north eastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 24:120–125PubMedCrossRefGoogle Scholar
  16. 16.
    García A, Criscuolo C, De Michele G, Berciano J (2008) Neurophysiological study in a Spanish family with recessive spastic ataxia of Charlevoix-Saguenay. MuscleNerve 37:107–110Google Scholar
  17. 17.
    García-Martin E, Pinilla I, Idoipe M, Fuertes I, Pueyo V (2010). Intra and interoperator reproducibility of retinal nerve fiber and macular thickness measurements using cirrus Fourier-domain OCT. Acta Ophthalmol. doi: 10.1111/j.1755-3768.2010.02045.x
  18. 18.
    Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G, the Study Group for Hereditary Neuropathy in Japan (2003) Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 126:134–151PubMedCrossRefGoogle Scholar
  19. 19.
    Landrieu P, Kamoun F (2003) Au carrefour de la pathologie développementale et de la pathologie dégénérative: les maladies cérébelleuses de la première enfance. Démembrement et approche pratique. Rev Neurol 159:382–394PubMedGoogle Scholar
  20. 20.
    Lewis RA, Sumner AJ (1999) Electrophysiologic features of inherited demyelinating neuropathies: a reappraisal. Ann NY Acad Sci 883:321–335PubMedCrossRefGoogle Scholar
  21. 21.
    Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurological disorders. N Engl J Med 330:613–622PubMedCrossRefGoogle Scholar
  22. 22.
    Mandelli ML, De Simone T, Minati L, Bruzzone MG, Mariotti C, Fancellu R, Savoiardo M, Grisoli M (2007) Diffusion tensor imaging of spinocerebellar ataxias types 1 and 2. Am J Neuroradiol 28:1996–2000PubMedCrossRefGoogle Scholar
  23. 23.
    Martin MH, Bouchard JP, Sylvain M, St-Onge O, Truchon S (2007) Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a report of MR imaging in 5 patients. Am J Neuroradiol 28:1606–1608PubMedCrossRefGoogle Scholar
  24. 24.
    Martini R (2001) The effect of myelinating Schwann cells on axons. MuscleNerve 24:456–466Google Scholar
  25. 25.
    Okawa S, Sugawara M, Watanabe S, Toyoshima I (2006) A novel sacsin mutation in a Japanese woman showing clinical uniformity of autosomal recessive spastic ataxia of Charlevoix-Saguenay. J Neurol Neurosurg Psychiatry 77:280–282PubMedCrossRefGoogle Scholar
  26. 26.
    Ottersen OP, Walberg F (2002) Neurotransmitters in the cerebellum. In: Manto MU, Pandolfo M (eds) The cerebellum and its disorders. Cambridge University Press, Cambridge, pp 38–48Google Scholar
  27. 27.
    Ouyang Y, Takiyama Y, Sakoe K, Shimazaki H, Ogawa T, Nagano S, Yamamoto Y, Nakano I (2006) Sacsin-related ataxia (ARSACS): expanding the genotype from the gigantic exon. Neurology 66:1103–1104PubMedCrossRefGoogle Scholar
  28. 28.
    Ouyang Y, Segers K, Bouquiaux O, Wang FC, Janin N, Andris C, Shimazaki H, Sakoe K, Nakano I, Takiyama Y (2008) Novel SACS mutations in a Belgian family with sacsin-related ataxia. J Neurol Sci 264:73–76PubMedCrossRefGoogle Scholar
  29. 29.
    Pablo LE, García-Martín E, Gazulla J, Larrosa JM, Ferreras A, Santorelli FM, Benavente I, Vela A, Marín MA (2011) Retinal nerve fiber hypertrophy in ataxia of Charlevoix-Saguenay patients. Mol Vis 17:1871–1876PubMedGoogle Scholar
  30. 30.
    Parfitt DA, Michael GJ, Vermeulen EGM, Prodromou NV, Webb TR, Gallo JM, Cheetham ME, Nicoll WS, Blatch GL, Chapple JP (2010) The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Human Mol Genet 18:1556–1565CrossRefGoogle Scholar
  31. 31.
    Peyronnard JM, Charron L, Barbeau A (1979) The neuropathy of Charlevoix-Saguenay ataxia: an electrophysiological and pathological study. Can J Neurol Sci 6:199–203PubMedGoogle Scholar
  32. 32.
    Schorge S, van de Leemput J, Singleton A, Houlden H, Hardy J (2010) Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signalling. Trends Neurosci 33:211–219PubMedCrossRefGoogle Scholar
  33. 33.
    Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I (2005) A phenotype without spasticity in sacsin-related ataxia. Neurology 64:2129–2131PubMedCrossRefGoogle Scholar
  34. 34.
    Shimazaki H, Sakoe K, Niijima K, Nakano I, Takiyama Y (2007) An unusual case of a spasticity-lacking phenotype with a novel SACS mutation. J Neurol Sci 255:87–89PubMedCrossRefGoogle Scholar
  35. 35.
    Stanton M, Pannoni V, Lewis RA, Logigian EL, Naguib D, Shy ME, Cleland J, Herrmann DN (2006) Dispersion of compound muscle action potential in hereditary neuropathies and chronic inflammatory demyelinating polyneuropathy. MuscleNerve 34:417–422Google Scholar
  36. 36.
    Tankisi H, Pugdahl K, Johnsen B, Fuglsang-Fredericksen A (2007) Correlations of nerve conduction measures in axonal and demyelinating polyneuropathies. Clin Neurophysiol 118:2383–2392PubMedCrossRefGoogle Scholar
  37. 37.
    Taoka T, Kin T, Nakagawa H, Hirano M, Sakamoto M, Wada T, Takayama K, Wuttikul C, Iwasaki S, Ueno S, Kichikawa K (2007) Diffusivity and diffusion anisotropy of cerebellar peduncles in cases of spinocerebellar degenerative disease. Neuroimage 37:387–393PubMedCrossRefGoogle Scholar
  38. 38.
    Terracciano A, Casali C, Grieco GS, Orteschi D, Di Giandomenico S, Seminara L, Di Fabio R, Carrozzo R, Simonati A, Stevanin G, Zollino M, Santorelli FM (2009) An inherited large scale rearrangement in SACS associated with spastic ataxia and hearing loss. Neurogenetics 10:151–155PubMedCrossRefGoogle Scholar
  39. 39.
    Vermeer S, Meijer RPP, Pijl BJ, Timmermans J, Cruysberg JRM, Bos MM, Schelhaas HJ, van de Warrenburg BP, Knoers NV, Scheffer H, Kremer B (2008) ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia. Neurogenetics 9:207–214PubMedCrossRefGoogle Scholar
  40. 40.
    Vermeer S, Meijer RPP, Hofste TGJ, Bodmer D, Bosgoed EA, Cremers FP, Kremer BH, Knoers NV, Scheffer H (2009) Design and validation of a conformation sensitive capillary electrophoresis-based mutation scanning system and automated data analysis of the more than 15 kbp-spanning coding sequence of the SACS gene. J Mol Diagn 11:514–523PubMedCrossRefGoogle Scholar
  41. 41.
    Vingolo EM, Di Fabio R, Salvatore S, Grieco G, Bertini E, Leuzzi V, Nesti C, Filla A, Tessa A, Pierelli F, Santorelli FM, Casali C (2011) Myelinated retinal fibers in autosomal recessive spastic ataxia of Charlevoix-Saguenay. Eur J Neurol 18:1187–1190PubMedCrossRefGoogle Scholar
  42. 42.
    Yamamoto Y, Nakamori M, Konaka K, Nagano S, Shimazaki H, Takiyama Y, Sakoda S (2006) Sacsin-related ataxia caused by the novel nonsense mutation Arg4325X. J Neurol 253:1372–1373PubMedCrossRefGoogle Scholar
  43. 43.
    Ying SH, Landman BA, Chowdhury S, Sinofsky AH, Gambini A, Mori S, Zee DS, Prince JL (2009) Orthogonal diffusion-weighted MRI measures distinguish region-specific degeneration in cerebellar ataxia subtypes. J Neurol 256:1939–1942PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • José Gazulla
    • 1
    • 9
    Email author
  • Isabel Benavente
    • 2
  • Ana Carmen Vela
    • 3
  • Miguel Angel Marín
    • 3
  • Luis Emilio Pablo
    • 4
  • Alessandra Tessa
    • 5
  • María Rosario Barrena
    • 6
  • Filippo Maria Santorelli
    • 5
  • Claudia Nesti
    • 5
  • Pedro Modrego
    • 1
  • María Tintoré
    • 7
  • José Berciano
    • 8
  1. 1.Service of NeurologyHospital Universitario Miguel ServetZaragozaSpain
  2. 2.Service of Clinical NeurophysiologyHospital San JorgeHuescaSpain
  3. 3.Service of RadiologyHospital Universitario Miguel ServetZaragozaSpain
  4. 4.Service of OphthalmologyHospital Universitario Miguel ServetZaragozaSpain
  5. 5.Molecular Medicine and NeurogeneticsIRCCS Fondazione Stella Maris. Vial del TirrenoPisaItaly
  6. 6.Service of RadiologyClínica MontecanalZaragozaSpain
  7. 7.Nucleic Acid Chemistry GroupChemistry and Molecular Pharmacology Programme, Institute for Research in Biomedicine of BarcelonaBarcelonaSpain
  8. 8.Department of NeurologyUniversity Hospital Marqués de Valdecilla, University of Cantabria and Centro de Investigación Biomédica en Red de Enfermedades NeurodegenerativasSantanderSpain
  9. 9.ZaragozaSpain

Personalised recommendations