Skip to main content

Advertisement

Log in

Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

A Correction to this article was published on 19 May 2022

This article has been updated

Abstract

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with ocular apraxia type 1 (AOA1) (OMIM: 606,350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with AlphaFold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding, the DNA-repair domain, and the whole 3D structure of APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 years old) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Laurence Newrick, Malcolm Taylor & Marios Hadjivassiliou

Change history

References

  1. Jayadev S, Bird TD. (2013) Hereditary ataxias: overview, Genetics in Medicine. Vol. 15.

  2. Rahmoune H, Boutrid N, Amrane M, Chekkour MC, Bioud B. (2017) Ataxia in children: think about vitamin E deficiency! (comment on: Ataxia in children: early recognition and clinical evaluation). Ital J Pediatr.;43(1).

  3. Brusse E, Maat-Kievit JA, van Swieten JC. (2007) Diagnosis and management of early- and late-onset cerebellar ataxia. Clinical Genetics. Vol. 71.

  4. Fogel BL, Perlman S. (2007) Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurology. Vol. 6

  5. Beaudin M, Matilla-Dueñas A, Soong BW, Pedroso JL, Barsottini OG, Mitoma H, et al. (2019). The classification of autosomal recessive cerebellar ataxias: a consensus statement from the Society for Research on the Cerebellum and Ataxias Task Force. Cerebellum.;18(6).

  6. Incecik F, Herguner O, Mungan N. (2020) Clinical features and molecular genetics of autosomal recessive ataxia in the Turkish population. J Pediatr Neurosci. 15(2).

  7. Guan WJ, Wang JL, Tang BS.  (2012) Recent advance in genetic study of hereditary autosomal recessive cerebellar ataxia. Chinese Journal of Medical Genetics. Vol. 29.

  8. Beaudin M, Dupré N. (2016) Autosomal recessive ataxias. In: Essentials of cerebellum and cerebellar disorders: a primer for graduate students.

  9. Shakkottai VG, Fogel BL. (2013) Clinical neurogenetics: autosomal dominant spinocerebellar ataxia. Neurologic Clinics. Vol. 31.

  10. Stephenson J, Nutma E, van der Valk P, Amor S. (2018) Inflammation in CNS neurodegenerative diseases. Immunology. Vol. 154.

  11. Müller U. (2021) Spinocerebellar ataxias (SCAs) caused by common mutations.  Neurogenetics. Vol. 22.

  12. Mancuso M, Orsucci D, Siciliano G, Bonuccelli U. (2014) The genetics of ataxia: through the labyrinth of the Minotaur, looking for Ariadne’s thread. Journal of Neurology. Vol. 261.

  13. Ataxia-oculomotor apraxia type 1. (2020) In: Definitions.

  14. Arslan EA, Öncel İ, Ceylan AC, Topçu M, Topaloğlu H. (2020) Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel. In: Brain and development.

  15. Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, Gibson T, et al. (2001) The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet. 29(2).

  16. Aicardi J, Barbosa C, Andermann E, Andermann F, Morcos R, Ghanem Q, et al. (1988) Ataxia—ocular motor aprilaxia: a syndrome mimicking ataxia‐telangiectasia. Ann Neurol. 24(4).

  17. Ababneh NA, Al-Kurdi B, Ali D, Abuarqoub D, Barham R, Alzibdeh AM, et al. (2020) Generation and characterization of induced pluripotent stem cell (iPSC) line (JUCTCi002-A) from a patient with ataxia with oculomotor apraxia type 1 (AOA1) harboring a homozygous mutation in the APTX gene. Stem Cell Res. 48.

  18. Séraphin B. (1992) The HIT protein family: a new family of proteins present in prokaryotes, yeast and mammals. Mitochondrial DNA. 3(3).

  19. Zhao D, Huang Z. (2015) Recognition code of ZNF191(243–368) and its interaction with DNA. Bioinorg Chem Appl. 2015.

  20. Russo L, Palmieri M, Caso JV, Abrosca GD, Diana D, Malgieri G, et al. (2015) Towards understanding the molecular recognition process in prokaryotic zinc-finger domain. Eur J Med Chem. 91.

  21. Rass U, Ahel I, West SC. (2007) Actions of aprataxin in multiple DNA repair pathways. J Biol Chem. 282(13).

  22. Seidle HF, Bieganowski P, Brenner C. (2005) Disease-associated mutations inactivate AMP-lysine hydrolase activity of aprataxin. J Biol Chem. 280(22).

  23. Narciso L, Parlanti E, Racaniello M, Simonelli V, Cardinale A, Merlo D, et al. (2016) The response to oxidative DNA damage in neurons: mechanisms and disease. Vol. 2016, Neural Plasticity.

  24. Canugovi C, Misiak M, Ferrarelli LK, Croteau DL, Bohr VA. (2013) The role of DNA repair in brain related disease pathology. DNA Repair (Amst). 12(8).

  25. Martin LJ. (2008) DNA damage and repair: relevance to mechanisms of neurodegeneration. Vol. 67, Journal of Neuropathology and Experimental Neurology.

  26. Hannan MA, Sigut D, Waghray M, Gascon GG. (1994) Ataxia-ocular motor apraxia syndrome: an investigation of cellular radiosensitivity of patients and their families. J Med Genet. 31(12).

  27. Renaud M, Moreira MC, Monga B Ben, Rodriguez D, Debs R, Charles P, et al. (2018) Clinical, biomarker, and molecular delineations and genotype-phenotype correlations of ataxia with oculomotor apraxia type 1. JAMA Neurol. 75(4).

  28. Quiroz Y, Velilla LM, Giraldo M, Lopera F. (2013) Cognitive profiles of frontotemporal dementia and Alzheimer’s disease in a Colombian sample: a preliminary investigation. Alzheimer’s Dement. 9(4S_Part_20)P4–234.

  29. Romenets SR, Acosta‐Baena N, Lopez L, Madrigal L, Street H, Jakimovich L, et al. (2017) [P1–523]: The adherence/retention plan of the Alzheimer’s prevention initiative (API) Colombia Trial. Alzheimer’s Dement. 13(7S_Part_9).

  30. Henao-Arboleda E, Moreno- Carrillo C, Ramos V, Aguirre-Acevedo DC, Pineda D, Lopera F. (2010) Caracterización de síntomas neuropsiquiátricos en pacientes con DCL de tipo amnésico en una población colombiana. Rev Chil Neuropsicol. 5(2).

  31. Romero S, Solano E, Moreno S, Arboleda H, Mohs R, Lopera F, et al. (2013) O2–04–06: Validation of the Alzheimer’s disease assessment scale (ADAS) in Colombia: preliminary results. Alzheimer’s Dement. 9(4S_Part_8).

  32. Mirra SS. (1997) The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging. 18(4 SUPPL.).

  33. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology. 41(4).

  34. Duyckaerts C, Hauw JJ. (1997) Diagnosis and staging of Alzheimer disease. Neurobiol Aging. 18(4 SUPPL.).

  35. Ortiz Zuñiga AM, Simó R, Rodriguez-Gómez O, Hernández C, Rodrigo A, Jamilis L, et al. (2020) Clinical applicability of the specific risk score of dementia in type 2 diabetes in the identification of patients with early cognitive impairment: results of the MOPEAD study in Spain. J Clin Med. 9(9).

  36. Shen J, Sherman M, Souza PE. (2020) Test administration methods and cognitive test scores in older adults with hearing loss. Gerontology. 66(1).

  37. Li H, Durbin R. (2010) Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics.

  38. Li H, Durbin R. (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics.

  39. Burrows M, Wheeler D. (1994) A block-sorting lossless data compression algorithm. Algorithm, data compression.

  40. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, del Angel G, Levy-Moonshine A, et al. (2013) From fastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinforma.

  41. Current protocols in bioinformatics. Current protocols in bioinformatics. 2002.

  42. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res.

  43. Johar AS, Anaya JM, Andrews D, Patel HR, Field M, Goodnow C, et al. (2015) Candidate gene discovery in autoimmunity by using extreme phenotypes, next generation sequencing and whole exome capture. Autoimmunity Reviews.

  44. G. P-F, M.C.S. B, C.A. M, H.R. P, A.S. J, A. C, et al. (2014) Whole exome sequencing of extreme morbid obesity patients: translational implications for obesity and related disorders. Vol. 5, Genes.

  45. Hawi Z, Cummins TDR, Tong J, Arcos-Burgos M, Zhao Q, Matthews N, et al. (2017) Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study. Mol Psychiatry. 22(4).

  46. da Fonseca ACP, Mastronardi C, Johar A, Arcos-Burgos M, Paz-Filho G. (2017) Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies. Journal of Diabetes and its Complications.

  47. Paz-Filho G, Boguszewski MCS, Mastronardi CA, Patel HR, Johar AS, Chuah A, et al. (2014) Whole exome sequencing of extreme morbid obesity patients: translational implications for obesity and related disorders. Genes (Basel).

  48. Johar A, Sarmiento-Monroy JC, Rojas-Villarraga A, Silva-Lara MF, Patel HR, Mantilla RD, et al. (2016) Definition of mutations in polyautoimmunity. J Autoimmun. 72.

  49. Wong ML, Arcos-Burgos M, Liu S, Vélez JI, Yu C, Baune BT, et al. (2017) The PHF21B gene is associated with major depression and modulates the stress response. Mol Psychiatry. 22(7).

  50. Senior AW, Evans R, Jumper J, Kirkpatrick J, Sifre L, Green T, et al. (2020) AlphaFold. Nature. 577(7792).

  51. Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. (2021) Highly accurate protein structure prediction with AlphaFold. Nature. 596(7873).

  52. Hofmann K, Bucher P. (1995) The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factors. Vol. 20, Trends in Biochemical Sciences.

  53. Doğan B, Najafabadi HS. (2018) Computational methods for analysis of the DNA-binding preferences of Cys2His2 zinc-finger proteins. In: Methods in molecular biology.

  54. Yoon G, Caldecott KW. (2018) Nonsyndromic cerebellar ataxias associated with disorders of DNA single-strand break repair. In: Handbook of clinical neurology.

  55. Çaǧlayan M, Prasad R, Krasich R, Longley MJ, Kadoda K, Tsuda M, et al. (2017) Complementation of aprataxin deficiency by base excision repair enzymes in mitochondrial extracts. Nucleic Acids Res. 45(17).

  56. Jiang B, Glover JNM, Weinfeld M. (2017) Neurological disorders associated with DNA strand-break processing enzymes. Mechanisms of Ageing and Development. Vol. 161.

  57. Akbari M, Sykora P, Bohr VA. (2015) Slow mitochondrial repair of 5′-AMP renders mtDNA susceptible to damage in APTX deficient cells. Sci Rep. 5.

  58. Criscuolo C, Mancini P, Saccà F, De Michele G, Monticelli A, Santoro L, et al. (2004) Ataxia with oculomotor apraxia type 1 in Southern Italy: late onset and variable phenotype. Neurology. 63(11).

  59. 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(1–2).

  60. Barbot C, Coutinho P, Chorao R, Ferreira C, Barros J, Fineza I, et al. (2001) Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch Neurol. 58(2).

  61. Tallaksen CME, Dietrichs E. (2004) The genetics of movement disorders: spinocerebellar degenerations. Tidsskr den Nor Laegeforening. 124(17).

  62. Perlman S, Bay J-O, Uhrhammer N, Gatti RA. (2010) Ataxia telangiectasia and variants. In: The cerebellum and its disorders.

  63. Perlman S, Becker-Catania S, Gatti RA. (2003) Ataxia-telangiectasia: diagnosis and treatment. Semin Pediatr Neurol. 10(3).

  64. Uhrhammer N, Bay J, Perlman S, Gatti R. (2011) Ataxia-telangiectasia and variants. Atlas Genet Cytogenet Oncol Haematol. (4).

  65. Scoles DR, Pulst SM. (2018) Spinocerebellar ataxia type 2. In: Advances in experimental medicine and biology.

  66. Egorova PA, Bezprozvanny IB. (2019) Molecular mechanisms and therapeutics for spinocerebellar ataxia type 2.  Neurotherapeutics. Vol. 16.

  67. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. (2019) STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47(D1).

  68. Li M, Lu LY, Yang CY, Wang S, Yu X. (2013) The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response. Genes Dev. 27(16).

  69. Le Ber I, Moreira MC, Rivaud-Péchoux S, Chamayou C, Ochsner F, Kuntzer T, et al. (2003) Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. Brain. 126(12).

  70. Shahwan A, Byrd PJ, Taylor AMR, Nestor T, Ryan S, King MD. (2006) Atypical presentation of ataxia-oculomotor apraxia type 1. Dev Med Child Neurol. 48(6).

  71. Paucar M, Alonso I, Eriksson M, Beniaminov S, Coutinho P, Svenningsson P. (2015) Novel APTX mutation in a Hispanic subject affected by ataxia with oculomotor apraxia type 1. Mov Disord Clin Pract. 2(1).

  72. Le Ber I, Bouslam N, Rivaud-Péchoux S, Guimarães J, Benomar A, Chamayou C, et al. (2004) Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain. 127(4).

  73. Bomont P, Watanabe M, Gershoni-Barush R, Shizuka M, Tanaka M, Sugano J, et al. (2000) Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33–34, and with hearing impairment and optic atrophy to 6p21–23. Eur J Hum Genet. 8(12).

  74. Kesper K, Horvath R, Zühlke C, Klockgether T. (2007) Two cases of ataxia with oculomotor apraxia type 1 (AOA1) without muscle coenzyme Q10 deficiency. Aktuelle Neurol. 34(S 2).

  75. Le Ber I, Dubourg O, Benoist JF, Jardel C, Mochel F, Koenig M, et al. (2007) Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. Neurology. 68(4).

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mauricio Arcos-Burgos.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aguillon, D., Vasquez, D., Madrigal, L. et al. Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings. Mol Neurobiol 59, 3845–3858 (2022). https://doi.org/10.1007/s12035-022-02821-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-02821-7

Keywords

Navigation