Skip to main content

Advertisement

SpringerLink
Log in

Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients

  • Original Article
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

Ataxia with oculomotor apraxia type1 (AOA1, MIM 208920) is a rare autosomal recessive disease caused by mutations in the APTX gene. We screened a cohort of 204 patients with cerebellar ataxia and 52 patients with early-onset isolated chorea. APTX gene mutations were found in 13 ataxic patients (6%). Eleven patients were homozygous for the known p.W279X, p.W279R, and p.P206L mutations. Three novel APTX mutations were identified: c.477delC (p.I159fsX171), c.C541T (p.Q181X), and c.C916T (p.R306X). Expression of mutated proteins in lymphocytes from these patients was greatly decreased. No mutations were identified in subjects with isolated chorea. Two heterozygous APTX sequence variants (p.L248M and p.D185E) were found in six families with ataxic phenotype. Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in five of six mutated subjects. The clinical phenotype was homogeneous, irrespectively of the type and location of the APTX mutation, and it was mainly characterized by early-onset cerebellar signs, sensory neuropathy, cognitive decline, and oculomotor deficits. Three cases had slightly raised alpha-fetoprotein. Our survey describes one of the largest series of AOA1 patients and contributes in defining clinical, molecular, and biochemical characteristics of this rare hereditary neurological condition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Amouri R, Moreira M, Zouari M, El Euch G, Barhoumi C, Kefi M, Belal S, Koenig M, Hentati F (2004) Aprataxin gene mutations in Tunisian families. Neurology 63:928–929

    PubMed  CAS  Google Scholar 

  2. Barbot C, Coutinho P, Chorão R, Ferreira C, Barros J, Fineza I, Dias K, Monteiro J, Guimarães A, Mendonça P, Moreira M, Sequeiros J (2001) Recessive ataxia with ocular apraxia: review of 22 Portoguese patients. Arch Neurol 58:201–205

    Article  PubMed  CAS  Google Scholar 

  3. Clements P, Breslin C, Deeks E, Byrd P, Ju L, Bieganowski P, Brenner C, Moreira M, Taylor A, Caldecott K (2004) The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. DNA Repair (Amst) 3:1493–1502

    Article  CAS  Google Scholar 

  4. Cogan DG (1953) A type of congenital ocular motor apraxia presenting jerky head movements. Am J Ophthalmol 36:433–441

    PubMed  CAS  Google Scholar 

  5. Criscuolo C, Mancini P, Saccà F, De Michele G, Monticelli A, Santoro L, Scarano V, Banfi S, Filla A (2004) Ataxia with oculomotor apraxia type 1 in Southern Italy: late onset and variable phenotype. Neurology 63:2173–2175

    PubMed  CAS  Google Scholar 

  6. D'Arrigo S, Riva D, Bulgheroni S, Chiapparini L, Castellotti B, Gellera C, Pantaleoni C (2008) Ataxia with oculomotor apraxia type 1 (AOA1): clinical and neuropsychological features in 2 new patients and differential diagnosis. J Child Neurol 23:895–900

    Article  PubMed  Google Scholar 

  7. Date H, Onodera O, Tanaka H, Iwabuchi K, Uekawa K, Igarashi S, Koike R, Hiroi T, Yuasa T, Awaya Y, Sakai T, Takahashi T, Nagatomo H, Sekijima Y, Kawachi I, Takiyama Y, Nishizawa M, Fukuhara N, Saito K, Sugano S, Tsuji S (2001) Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat Genet 29:184–188

    Article  PubMed  CAS  Google Scholar 

  8. DiMauro S, Quinzii CM, Hirano M (2007) Mutations in coenzyme Q10 biosynthetic genes. J Clin Invest 117:587–589

    Article  PubMed  CAS  Google Scholar 

  9. Ferrarini M, Squintani G, Cavallaro T, Ferrari S, Rizzuto N, Fabrizi GM (2007) A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: phenotypical and genotypical characterization. J Neurol Sci 260:219–224

    Article  PubMed  CAS  Google Scholar 

  10. Fogel B, Perlman S (2007) Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol 6:245–257

    Article  PubMed  CAS  Google Scholar 

  11. Fukuhara N, Nakajima T, Sakajiri K, Matsubara N, Fujita M (1995) Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): a new disease. J Neurol Sci 133:140–151

    Article  PubMed  CAS  Google Scholar 

  12. Gellera C, Castellotti B, Mariotti C, Mineri R, Seveso V, Didonato S, Taroni F (2007) Frataxin gene point mutations in Italian Friedreich ataxia patients. Neurogenetics 8:289–299

    Article  PubMed  CAS  Google Scholar 

  13. Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH, Gatti R, Date H, Onodera O, Taucher-Scholz G, Lavin MF (2004) Aprataxin, a novel protein that protects against genotoxic stress. Hum Mol Genet 13:1081–1093

    Article  PubMed  CAS  Google Scholar 

  14. Habeck M, Zuhlke C, Bentele KH, Unkelbach S, Kress W, Burk K, Schwinger E, Hellenbroich Y (2004) Aprataxin mutations are a rare cause of early onset ataxia in Germany. J Neurol 251:591–594

    Article  PubMed  CAS  Google Scholar 

  15. Harris JL, Jakob B, Taucher-Scholz G, Dianov GL, Becherel OJ, Lavin MF (2009) Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage. Hum Mol Genet 18:4102–4117

    Article  PubMed  CAS  Google Scholar 

  16. Hirano M, Yamamoto A, Mori T, Lan L, Iwamoto TA, Aoki M, Shimada K, Furiya Y, Kariya S, Asai H, Yasui A, Nishiwaki T, Imoto K, Kobayashi N, Kiriyama T, Nagata T, Konishi N, Itoyama Y, Ueno S (2007) DNA single-strand break repair is impaired in aprataxin-related ataxia. Ann Neurol 61:162–174

    Article  PubMed  CAS  Google Scholar 

  17. Inoue N, Izumi K, Mawater S, Shida K, Kuroiwa Y (1971) Congenital ocular motor apraxia and cerebellar degeneration. Report of two cases. Jpn J Clin Neurol 11:855–861

    Google Scholar 

  18. Koike R, Tanaka H, Tsuji S (1998) Early onset ataxia associated with hypoalbuminemia. Neurol Med 48:237–242

    Google Scholar 

  19. Le Ber I, Brice A, Durr A (2005) New autosomal recessive cerebellar ataxias with oculomotor apraxia. Curr Neurol Neurosci Rep 5:411–417

    Article  PubMed  Google Scholar 

  20. Le Ber I, Dubourg O, Benoist JF, Jardel C, Mochel F, Koenig M, Brice A, Lombes A, Durr A (2007) Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. Neurology 68:295–297

    Article  PubMed  Google Scholar 

  21. Le Ber I, Moreira MC, Rivaud-Pechoux S, Chamayou C, Ochsner F, Kuntzer T, Tardieu M, Said G, Habert MO, Demarquay G, Tannier C, Beis JM, Brice A, Koenig M, Durr A (2003) Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. Brain 126:2761–2772

    Article  PubMed  Google Scholar 

  22. Mahajnah M, Basel-Vanagaite L, Inbar D, Kornreich L, Weitz R, Straussberg R (2005) Familial cognitive impairment with ataxia with oculomotor apraxia. J Child Neurol 20:523–525

    PubMed  Google Scholar 

  23. Moreira MC, Barbot C, Tachi N, Kozuka N, Mendonca P, Barros J, Coutinho P, Sequeiros J, Koenig M (2001) Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. Am J Hum Genet 68:501–508

    Article  PubMed  CAS  Google Scholar 

  24. Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, Gibson T, Mendonca P, Costa M, Barros J, Yanagisawa T, Watanabe M, Ikeda Y, Aoki M, Nagata T, Coutinho P, Sequeiros J, Koenig M (2001) The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet 29:189–193

    Article  PubMed  CAS  Google Scholar 

  25. Mosesso P, Piane M, Palitti F, Pepe G, Penna S, Chessa L (2005) The novel human gene aprataxin is directly involved in DNA single-strand-break repair. Cell Mol Life Sci 62:485–491

    Article  PubMed  CAS  Google Scholar 

  26. Onodera O (2006) Spinocerebellar ataxia with ocular motor apraxia and DNA repair. Neuropathology 26:361–367

    Article  PubMed  Google Scholar 

  27. Quinzii CM, Kattah AG, Naini A, Akman HO, Mootha VK, DiMauro S, Hirano M (2005) Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology 64:539–541

    Article  PubMed  CAS  Google Scholar 

  28. Quinzii CM, Lopez LC, Naini A, DiMauro S, Hirano M (2008) Human CoQ10 deficiencies. Biofactors 32:113–118

    Article  PubMed  CAS  Google Scholar 

  29. Reynolds JJ, El-Khamisy SF, Katyal S, Clements P, McKinnon PJ, Caldecott KW (2009) Defective DNA ligation during short-patch single-strand break repair in ataxia oculomotor apraxia 1. Mol Cell Biol 29:1354–1362

    Article  PubMed  CAS  Google Scholar 

  30. Sekijima Y, Hashimoto T, Onodera O, Date H, Okano T, Naito K, Tsuji S, Ikeda S (2003) Severe generalized dystonia as a presentation of a patient with aprataxin gene mutation. Mov Disord 18:1198–1200

    Article  PubMed  Google Scholar 

  31. Shahwan A, Byrd PJ, Taylor AM, Nestor T, Ryan S, King MD (2006) Atypical presentation of ataxia-oculomotor apraxia type 1. Dev Med Child Neurol 48:529–532

    Article  PubMed  Google Scholar 

  32. Taroni F, DiDonato S (2004) Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci 5:641–655

    Article  PubMed  CAS  Google Scholar 

  33. Taroni F, Verderio E, Dworzak F, Willems P, Cavadini P, DiDonato S (1993) Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet 4:314–320

    Article  PubMed  CAS  Google Scholar 

  34. Tranchant C, Fleury M, Moreira MC, Koenig M, Warter JM (2003) Phenotypic variability of aprataxin gene mutations. Neurology 60:868–870

    PubMed  CAS  Google Scholar 

  35. Tsao CY, Paulson G (2005) Type 1 ataxia with oculomotor apraxia with aprataxin gene mutations in two American children. J Child Neurol 20:619–620

    PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Mrs. Simona Allievi for cell culture and biochemical analyses and to Dr. Floriano Girotti for referring a patient. Study partially supported by Italian Minister of Health (R.C. 2008–2009).

Author information

Authors and Affiliations

  1. SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133, Milan, Italy

    Barbara Castellotti, Caterina Mariotti, Marco Rimoldi, Roberto Fancellu, Massimo Plumari, Sara Caimi, Daniela Di Bella, Stefano Di Donato, Franco Taroni & Cinzia Gellera

  2. Child Neurology Department, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133, Milan, Italy

    Graziella Uziel, Nardo Nardocci, Isabella Moroni & Giovanna Zorzi

  3. SOSD Central and Peripheral Degenerative Neuropathies, Department of Clinical Neurosciences, Fondazione-IRCCS, Istituto Neurologico “Carlo Besta”, via Celoria11, 20133, Milan, Italy

    Davide Pareyson

Authors
  1. Barbara Castellotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caterina Mariotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Rimoldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberto Fancellu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Massimo Plumari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Caimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Graziella Uziel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nardo Nardocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Isabella Moroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giovanna Zorzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Davide Pareyson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Daniela Di Bella
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Stefano Di Donato
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Franco Taroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Cinzia Gellera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Caterina Mariotti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castellotti, B., Mariotti, C., Rimoldi, M. et al. Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients. Neurogenetics 12, 193–201 (2011). https://doi.org/10.1007/s10048-011-0281-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-011-0281-x

Keywords

Search

Navigation