Skip to main content

Advertisement

SpringerLink
Log in

The Cerebellar Cognitive Affective Syndrome in Ataxia-Telangiectasia

  • Original Paper
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

Ataxia-telangiectasia (AT) is an autosomal recessive, multisystem disease causing cerebellar ataxia, mucocutaneous telangiectasias, immunodeficiency, and malignancies. A pilot study reported cognitive and behavioral manifestations characteristic of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). We set out to test and further define these observations because a more comprehensive understanding of the spectrum of impairments in AT is essential for optimal management. Twenty patients (12 males; 9.86 ± 5.5 years, range 4.3 to 23.2) were grouped by age: AT-I (toddlers and preschoolers, n = 7, 4.3–5.9 years), AT-II (school children, n = 7, 5.9–9.8 years), AT-III (adolescents/young adults, n = 6, 12.6–23.2 years). Standard and experimental tests investigated executive, linguistic, visual-spatial, and affective/social-cognitive domains. Results were compared to standard norms and healthy controls. Cognitive changes in AT-I were limited to mild visual-spatial disorganization. Spatial deficits were greater in AT-II, with low average scores on executive function (auditory working memory), expressive language (vocabulary), academic abilities (math, spelling, reading), social cognition (affect recognition from faces), and emotional/psychological processing. Full Scale IQ scores were low average to borderline impaired. AT-III patients had the greatest level of deficits which were evident particularly in spatial skills, executive function (auditory working memory, sequencing, word/color interference, set-shifting, categorization errors, perseveration), academic achievement, social cognition (affect recognition from faces), and behavioral control. Full Scale IQ scores in this group fell in the impaired range, while language was borderline impaired for comprehension, and low average for expression. Cognitive deficits in AT at a young age are mild and limited to visual-spatial functions. More widespread cognitive difficulties emerge with age and disease progression, impacting executive function, spatial skills, affect, and social cognition. Linguistic processing remains mildly affected. Recognition of the CCAS in children with AT may facilitate therapeutic interventions to improve quality of life.

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.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Boder E, Sedgwick RP. Ataxia-telangiectasia. A familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. A preliminary report on 7 children, an autopsy, and a case history. Univ S Calif Med Bull. 1957;9:15–28.

    Google Scholar 

  2. Boder E. Ataxia-telangiectasia: an overview. In: Gatti RA, Swift M, editors. Ataxia-telangiectasia: genetics, neuropathy, and immunology of a degenerative disease of childhood. New York: Alan R Liss; 1985. p. 1–63.

    Google Scholar 

  3. Gatti R, Perlman S. Ataxia-Telangiectasia. 1999 Mar 19 [Updated 2016 Oct 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26468/

  4. Verhagen MM, Abdo WF, Willemsen MA, Hogervorst FB, Smeets DF, Hiel JA, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology. 2009;73:430–7.

    Article  CAS  PubMed  Google Scholar 

  5. Verhagen MM, Last JI, Hogervorst FBL, Smeets DFCM, Roeleveld N, Verheijen F, et al. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat. 2012;33:561–71.

    Article  CAS  PubMed  Google Scholar 

  6. Taylor AMR, Lam Z, Last JI, Byrd PJ. Ataxia telangiectasia: more variation at clinical and cellular levels. Clin Genet. 2015;87:199–208.

    Article  CAS  PubMed  Google Scholar 

  7. Bottini AR, Gatti RA, Wirenfeldt M, Vinters HV. Heterotopic Purkinje cells in ataxia-telangiectasia. Neuropathology. 2012;32:23–9.

    Article  PubMed  Google Scholar 

  8. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121:561–79.

    Article  PubMed  Google Scholar 

  9. Manto M, Mariën P. Schmahmann’s syndrome—identification of the third cornerstone of clinical ataxiology. Cerebellum Ataxias. 2015;27:2–2.

    Article  Google Scholar 

  10. Levisohn L, Cronin-Golomb A, Schmahmann JD. Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population. Brain. 2000;123:1041–50.

    Article  PubMed  Google Scholar 

  11. Riva D, Giorgi C. The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours. Brain. 2000;123:1051–61.

    Article  PubMed  Google Scholar 

  12. Wibroe M, Cappelen J, Castor C, Clausen N, Grillner P, Gudrunardottir T, et al. Cerebellar mutism syndrome in children with brain tumours of the posterior fossa. BMC Cancer. 2017;17:439.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bolduc ME, Du Plessis AJ, Sullivan N, Khwaja OS, Zhang X, Barnes K, et al. Spectrum of neurodevelopmental disabilities in children with cerebellar malformations. Dev Med Child Neurol. 2011;53:409–16.

    Article  PubMed  Google Scholar 

  14. Bolduc ME, du Plessis AJ, Sullivan N, Guizard N, Zhang X, Robertson RL, et al. Regional cerebellar volumes predict functional outcome in children with cerebellar malformations. Cerebellum. 2012;11:531–42.

    Article  PubMed  Google Scholar 

  15. Brossard-Racine M, du Plessis AJ, Limperopoulos C. Developmental cerebellar cognitive affective syndrome in ex-preterm survivors following cerebellar injury. Cerebellum. 2015;14:151–64.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Boltshauser E, Schmahmann J. Clinical in developmental medicine no. 191-192: Cerebellar disorders in children. London: Mac Keith Press; 2012.

  17. D'Mello AM, Stoodley CJ. Cerebro-cerebellar circuits in autism spectrum disorder. Front Neurosci. 2015;9:408.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hoche F, Frankenberg E, Rambow J, Theis M, Harding JA, Qirshi M, et al. Cognitive phenotype in ataxia-telangiectasia. Pediatr Neurol. 2014;51:297–310.

    Article  PubMed  Google Scholar 

  19. Cabana MD, Crawford TO, Winkelstein JA, Christensen JR, Lederman HM. Consequences of the delayed diagnosis ataxia-telangiectasia. Pediatrics. 1998;102:98–110.

    Article  CAS  PubMed  Google Scholar 

  20. Crawford TO, Mandir AS, Lefton-Greif MA, Goodman SN, Goodman BK, Sengul H, et al. Quantitative neurologic assessment of ataxia-telangiectasia. Neurology. 2000;54:1505–9.

    Article  PubMed  Google Scholar 

  21. Schmahmann JD, Gardner R, MacMore J, Vangel MG. Development of a brief ataxia rating scale (BARS) based on a modified form of the ICARS. Mov Disord. 2009;24:1820–8.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Stoodley CJ. The cerebellum and cognition: evidence from functional imaging studies. Cerebellum. 2012;11:352–65.

    Article  PubMed  Google Scholar 

  23. Stoodley CJ, Valera EM, Schmahmann JD. Functional topography of the cerebellum for motor and cognitive tasks: an fMRI study. NeuroImage. 2012;59:1560–70.

    Article  PubMed  Google Scholar 

  24. Klockgether T, Lüdtke R, Kramer B, Abele M, Bürk K, Schöls L, et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain. 1998;121:589–600.

    Article  PubMed  Google Scholar 

  25. Frankenburg WK. 1930-DENVER II technical manual. Denver: Denver Developmental Materials, Inc; 1996.

    Google Scholar 

  26. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.

    Article  CAS  PubMed  Google Scholar 

  27. Korkman M, Kirk U, Kemp SLNEPSYII. Clinical and interpretative manual. San Antonio: Psychological Corporation; 2007.

    Google Scholar 

  28. Wechsler D. Advanced clinical solutions for WAIS-IV and WMS-IV. San Antonio: Pearson; 2009.

    Google Scholar 

  29. Gioia GA, Isquith PK. Behavior Rating Inventory for Executive Functions. In: Kreutzer JS, DeLuca J, Caplan B, editors. Encyclopedia of clinical neuropsychology. New York: Springer; 2011.

    Google Scholar 

  30. Gurley JR. Behavior Assessment System for Children: Second Edition (BASC-2). In: Goldstein S, Naglieri JA, editors. Encyclopedia of child behavior and development. Boston: Springer; 2011.

    Google Scholar 

  31. ADHD Symptom checklist. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. American Psychiatric Association,Washington, DC 2000.

  32. Gilliam J. GARS-2: Gilliam Autism Rating Scale-Second Edition. Austin: PRO-ED; 2006.

    Google Scholar 

  33. Sparow SS, Cicchetti DV, Balla DA. Vineland Adaptive Behavior Scales, Second Edition (Vineland ™–II). Pearson.

  34. Skuse DH, Mandy WPL, Scourfield J. Measuring autistic traits: heritability, reliability and validity of the Social and Communication Disorders Checklist. Br J Psychiatry. 2005;187:568–72.

    Article  PubMed  Google Scholar 

  35. Wiig EH, Secord W. Test of language competence-expanded edition. In: Level, vol. 1. San Antonio: Pearson; 1988.

    Google Scholar 

  36. Baron-Cohen S, Wheelwright S, Hill J, Raste Y, Plumb I. The “Reading the Mind in the Eyes” Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry. 2001;42:241–51.

    Article  CAS  PubMed  Google Scholar 

  37. Coull GJ, Leekam SR, Bennet M. Simplifying second-order belief attribution: what facilitates children’s performance on measures of conceptual understanding? Soc Dev. 2006;15:548–63.

    Article  Google Scholar 

  38. Hughes C, Adlam A, Happé F, Jackson J, Taylor A, Caspi A. Good test—retest reliability for standard and advanced false-belief tasks across a wide range of abilities. J Child Psychol Psychiatry. 2000;41:483–90.

    Article  CAS  PubMed  Google Scholar 

  39. Wimmer H, Perner J. Beliefs about beliefs: representation and constraining function of wrong beliefs in young children's understanding of deception. Cognition. 1983;13:103–28.

    Article  CAS  PubMed  Google Scholar 

  40. Wellman HM, Cross D, Watson J. Meta-analysis of theory-of-mind development: the truth about false belief. Child Dev. 2001;72:655–84.

    Article  CAS  PubMed  Google Scholar 

  41. Sullivan K, Zaitchik D, Tager-Flusberg H. Preschoolers can attribute second-order beliefs. Dev Psychol. 1994;30:395–402.

    Article  Google Scholar 

  42. Auyeung B, Wheelwright S, Allison C, Atkinson M, Samarawickrema N, Baron-Cohen S. The children’s empathy quotient and systemizing quotient: sex differences in typical development and in autism spectrum conditions. J Autism Dev Disord. 2009;39:1509–21.

    Article  PubMed  Google Scholar 

  43. Schmahmann JD, Weilburg JB, Sherman JC. The neuropsychiatry of the cerebellum—insights from the clinic. Cerebellum. 2007;6:254–67.

    Article  PubMed  Google Scholar 

  44. Hoche F, Guell X, Sherman JC, Vangel MG, Schmahmann JD. Cerebellar contribution to social cognition. Cerebellum. 2016;15:732–43.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Toomela A. Drawing development: stages in the representation of a cube and a cylinder. Child Dev. 1999;70:1141–50.

    Article  Google Scholar 

  46. Meyers JE, Meyers KR. Rey complex figure test and recognition trial: professional manual. PAR, Inc.

  47. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76.

    Article  CAS  PubMed  Google Scholar 

  48. Sang L, Qin W, Liu Y, Han W, Zhang Y, Jiang T, et al. Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures. Neuroimage. 2012;61:1213–25.

    Article  PubMed  Google Scholar 

  49. Volkow ND, Tomasi D, Wang GJ, Studentsova Y, Margus B, Crawford TO. Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives. Brain. 2014;137:1753–61.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Osterrieth PA. The challenge of copying a complex figure. Arch Psychologie. 1944;30:205–353.

    Google Scholar 

  51. Shin MS, Park SY, Park SR, Seol SH, Kwon JS. Clinical and empirical applications of the Rey-Osterrieth Complex Figure Test. Nat Protoc. 2006;1:892–9.

    Article  PubMed  Google Scholar 

  52. Hoche F, Guell X, Vangel MG, Sherman JC, Schmahmann JD. The cerebellar cognitive affective/Schmahmann syndrome scale. Brain. 2017;141:248–70.

    Article  PubMed Central  Google Scholar 

  53. Schmahmann JD, Pandya DN. Anatomical investigation of projections to the basis pontis from posterior parietal association cortices in rhesus monkey. J Comp Neurol. 1989;289:53–73.

    Article  CAS  PubMed  Google Scholar 

  54. Schmahmann JD, Pandya DN. The cerebrocerebellar system. Int Rev Neurobiol. 1997;41:31–60.

    Article  CAS  PubMed  Google Scholar 

  55. Schmahmann JD, Pandya DN. Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function. Neurosci Lett. 1995;199:175–8.

    Article  CAS  PubMed  Google Scholar 

  56. Middleton FA, Strick PL. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science. 1994;266:458–61.

    Article  CAS  PubMed  Google Scholar 

  57. Guillot A, Collet C, editors. The neurophysiological foundations of mental and motor imagery. New York: Oxford University Press; 2010.

    Google Scholar 

  58. Cengiz B, Boran HE. The role of the cerebellum in motor imagery. Neurosci Lett. 2016;617:156–9.

    Article  CAS  PubMed  Google Scholar 

  59. Gerardin E, Sirigu A, Lehericy S, Poline JB, Gaymard B, Marsault C, et al. Partially overlapping neural networks for real and imagined hand movements. Cereb Cortex. 2000;10:1093–104.

    Article  CAS  PubMed  Google Scholar 

  60. Desmond JE, Gabrieli JD, Wagner AD, Ginier BL, Glover GH. Lobular patterns of cerebellar activation in verbal working- memory and finger-tapping tasks as revealed by functional MRI. J Neurosci. 1997;17:9675–85.

    Article  CAS  PubMed  Google Scholar 

  61. Fiez JA. Cerebellar contributions to cognition. Neuron. 1996;16:13–5.

    Article  CAS  PubMed  Google Scholar 

  62. Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. NeuroImage. 2009;33:489–501.

    Article  Google Scholar 

  63. Guell X, Gabrieli JDE, Schmahmann JD. Triple representation of language, working memory, social and emotion processing in the cerebellum: convergent evidence from task and seed-based resting-state fMRI analyses in a single large cohort. NeuroImage. 2018 Feb 1. https://doi.org/10.1016/j.neuroimage.2018.01.082.

  64. Adolphs R. Processing of emotional and social information by the human amygdala. In: Gazzaniga MS, editor. The new cognitive neurosciences III. 3rd ed. Massachusetts: MIT Press; 2004. p. 1005–16.

    Google Scholar 

  65. Schmahmann JD. From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp. 1996;4:174–98.

    Article  CAS  PubMed  Google Scholar 

  66. Schmahmann JD, Pandya DN. Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. J Neurosci. 1997;17:438–58.

    Article  CAS  PubMed  Google Scholar 

  67. Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413–34.

    Article  CAS  PubMed  Google Scholar 

  68. Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD, Blatt GJ, et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012;11:777–807.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Frith CD, Friston KJ, Liddle PF, Frackowiak RS. PET imaging and cognition in schizophrenia. J R Soc Med. 1992;85:222–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Schmahmann JD. The role of the cerebellum in affect and psychosis. J Neurolinguistics. 2000;13:189–214.

    Article  Google Scholar 

  71. Schmahmann JD. The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Neuropsychol Rev. 2010;20:236–60.

    Article  PubMed  Google Scholar 

  72. Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003 Sep 10;23(23):8432–44.

    Article  CAS  PubMed  Google Scholar 

  73. Buckner RL, Krienen FM, Castellanos A, Diaz JC, Yeo BT. The organization of the human cerebellum estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:2322–45.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Worth PF, Srinivasan V, Smith A, et al. Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia. Mov Disord. 2013;28:524–8.

    Article  CAS  PubMed  Google Scholar 

  75. Alterman N, Fattal-Valevski A, Moyal L, et al. Ataxia-telangiectasia: mild neurological presentation despite null ATM mutation and severe cellular phenotype. Am J Med Genet. 2007;143A:1827–34.

    Article  CAS  PubMed  Google Scholar 

  76. Jiang D, Zhang Y, Hart RP, Chen J, Herrup K, Li J. Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency. Brain. 2015;138:3520–36.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the assistance throughout the project of Jason MacMore, Marygrace Neal, and Xavier Guell.

Funding

This study was supported in part by the Ataxia Telangiectasia Children’s Project, the National Ataxia Foundation, NIH 5R01NS080816-03, and the MINDlink Foundation.

Author information

Authors and Affiliations

  1. Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 100 Cambridge Street, Suite 2000, Boston, MA, 02114, USA

    Franziska Hoche & Jeremy D. Schmahmann

  2. Psychology Assessment Center, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Maureen P. Daly & Janet C. Sherman

  3. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Yogesh K. Chutake

  4. Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Eve Valera

Authors
  1. Franziska Hoche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maureen P. Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yogesh K. Chutake
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eve Valera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Janet C. Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeremy D. Schmahmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy D. Schmahmann.

Ethics declarations

Conflict of Interest

Dr. Schmahmann consults for Bayer, Biogen, Biohaven, Cadent and Pfizer, and receives royalties for book publications from Elsevier, Oxford, MacKeith, and Springer. The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOC 157 kb)

ESM 2

(DOC 73 kb)

ESM 3

(DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hoche, F., Daly, M.P., Chutake, Y.K. et al. The Cerebellar Cognitive Affective Syndrome in Ataxia-Telangiectasia. Cerebellum 18, 225–244 (2019). https://doi.org/10.1007/s12311-018-0983-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-018-0983-9

Keywords

Search

Navigation