Skip to main content

Advertisement

SpringerLink
Log in

Ataxia, Intellectual Disability, and Ocular Apraxia with Cerebellar Cysts: A New Disease?

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

Abstract

Cerebellar cysts are rare findings in pediatric neuroimaging and rather characteristic for dystroglycanopathies and GPR56-related encephalopathy. We aim to report on seven children with cerebellar cysts showing absence of weakness and ruling out mutations within eight dystroglycanopathy genes and GPR56. Data about neurological and ophthalmological features, outcome, and creatine kinase values were collected from clinical histories and follow-up examinations. All MR images were qualitatively evaluated for infra- and supratentorial abnormalities. A SNP 6.0-Array was performed in three children. The POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56 genes were screened in all patients by Sanger sequencing. Seven children from five families were studied. Ataxia, intellectual disability, and language impairment were found in all patients, ocular motor apraxia in five, and severe myopia in three. None of the patients had weakness, only three a minimally increased creatine kinase value. Qualitative neuroimaging evaluation showed cerebellar cysts and dysplasia in the cerebellar hemispheres and vermis in all children. Additional findings were an enlarged fourth ventricle in all children, vermian hypoplasia and brain stem morphological abnormalities in five. The SNP array showed no pathogenetic imbalances in all children evaluated. In all patients, no mutations were found in POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56. The peculiar combination of the same clinical and neuroimaging findings in our patients highly suggests that this phenotype may represent a novel entity, possibly falling within the spectrum of dystroglycanopathies.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Poretti A, Klein A, Boltshauser E. Cerebellar cysts and neuroimaging in congenital muscular dystrophies. In: Boltshauser E, Schmahmann JD, editors. Cerebellar disorders in children. London: Mac Keith Press; 2012. p. 177–83.

    Google Scholar 

  2. Clement E, Mercuri E, Godfrey C, et al. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann Neurol. 2008;64:573–82.

    Article  CAS  PubMed  Google Scholar 

  3. Godfrey C, Clement E, Mein R, et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007;130:2725–35.

    Article  PubMed  Google Scholar 

  4. Mercuri E, Muntoni F. The ever-expanding spectrum of congenital muscular dystrophies. Ann Neurol. 2012;72:9–17.

    Article  PubMed  Google Scholar 

  5. Mercuri E, Messina S, Bruno C, et al. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009;72:1802–9.

    Article  CAS  PubMed  Google Scholar 

  6. Devisme L, Bouchet C, Gonzales M, et al. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain. 2012;135:469–82.

    Article  PubMed  Google Scholar 

  7. Brockington M, Yuva Y, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet. 2001;10:2851–9.

    Article  CAS  PubMed  Google Scholar 

  8. Roscioli T, Kamsteeg EJ, Buysse K, et al. Mutations in ISPD cause Walker–Warburg syndrome and defective glycosylation of alpha-dystroglycan. Nat Genet. 2012;44:581–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Willer T, Lee H, Lommel M, et al. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012;44:575–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Manzini MC, Tambunan DE, Hill RS, et al. Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause of Walker–Warburg syndrome. Am J Hum Genet. 2012;91:541–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Jae LT, Raaben M, Riemersma M, et al. Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry. Science. 2013;340:479–83.

    Article  CAS  PubMed  Google Scholar 

  12. Bahi-Buisson N, Poirier K, Boddaert N, et al. GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. Brain. 2010;133:3194–209.

    Article  PubMed  Google Scholar 

  13. Hopkins B, Sutton VR, Lewis RA, Van den Veyver I, Clark G. Neuroimaging aspects of Aicardi syndrome. Am J Med Genet A. 2008;146A:2871–8.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Steffensen TS, Gilbert-Barness E, Lacson A, Margo CE. Cerebellar migration defects in Aicardi syndrome: an extension of the neuropathological spectrum. Fetal Pediatr Pathol. 2009;28:24–38.

    Article  CAS  PubMed  Google Scholar 

  15. Glamuzina E, Brown R, Hogarth K, et al. Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. J Inherit Metab Dis. 2012;35:459–67.

    Article  PubMed  Google Scholar 

  16. Doherty D, Millen KJ, Barkovich AJ. Midbrain and hindbrain malformations: advances in clinical diagnosis, imaging, and genetics. Lancet Neurol. 2013;12:381–93.

    Article  PubMed  Google Scholar 

  17. Shevell M. Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation, and etiology. Pediatr Clin N Am. 2008;55:1071–84.

    Article  Google Scholar 

  18. Boltshauser E, Poretti A. Nonprogressive congenital ataxia. In: Boltshauser E, Schmahmann JD, editors. Cerebellar disorders in children. London: Mac Keith Press; 2012. p. 135–9.

    Google Scholar 

  19. Poretti A, Boltshauser E. Congenital ataxia (Table 1). In: Boltshauser E, Schmahmann JD, editors. Cerebellar disorders in children. London: Mac Keith Press; 2012. p. 399–400.

    Google Scholar 

  20. Poretti A, Boltshauser E. Ataxia and ocular motor apraxia (Table 7). In: Boltshauser E, Schmahmann JD, editors. Cerebellar disorders in children. London: Mac Keith Press; 2012. p. 406.

    Google Scholar 

  21. Romani M, Micalizzi A, Valente EM. Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet Neurol. 2013;12:894–905.

    Article  PubMed  Google Scholar 

  22. Kondo A, Saito Y, Floricel F, Maegaki Y, Ohno K. Congenital ocular motor apraxia: clinical and neuroradiological findings, and long-term intellectual prognosis. Brain Dev. 2007;29:431–8.

    Article  PubMed  Google Scholar 

  23. Sargent MA, Poskitt KJ, Jan JE. Congenital ocular motor apraxia: imaging findings. AJNR Am J Neuroradiol. 1997;18:1915–22.

    CAS  PubMed  Google Scholar 

  24. Poretti A, Huisman TA, Scheer I, Boltshauser E. Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol. 2011;32:1459–63.

    Article  CAS  PubMed  Google Scholar 

  25. Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366:636–46.

    Article  CAS  PubMed  Google Scholar 

  26. Cirak S, Foley AR, Herrmann R, et al. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain. 2013;136:269–81.

    Article  PubMed  Google Scholar 

  27. Quattrocchi CC, Zanni G, Napolitano A, et al. Conventional magnetic resonance imaging and diffusion tensor imaging studies in children with novel GPR56 mutations: further delineation of a cobblestone-like phenotype. Neurogenetics. 2013;14:77–83.

    Article  PubMed  Google Scholar 

  28. Louhichi N, Triki C, Quijano-Roy S, et al. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. Neurogenetics. 2004;5:27–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Topaloglu H, Brockington M, Yuva Y, et al. FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology. 2003;60:988–92.

    Article  CAS  PubMed  Google Scholar 

  30. Mercuri E, Topaloglu H, Brockington M, et al. Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations. Arch Neurol. 2006;63:251–7.

    Article  PubMed  Google Scholar 

  31. Yis U, Uyanik G, Heck PB, et al. Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker–Warburg phenotype. Neuromuscul Disord. 2011;21:20–30.

    Article  PubMed  Google Scholar 

  32. Aida N, Yagishita A, Takada K, Katsumata Y. Cerebellar MR in Fukuyama congenital muscular dystrophy: polymicrogyria with cystic lesions. AJNR Am J Neuroradiol. 1994;15:1755–9.

    CAS  PubMed  Google Scholar 

  33. Aida N, Tamagawa K, Takada K, et al. Brain MR in Fukuyama congenital muscular dystrophy. AJNR Am J Neuroradiol. 1996;17:605–13.

    CAS  PubMed  Google Scholar 

  34. Messina S, Tortorella G, Concolino D, et al. Congenital muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia, and epilepsy. Neurology. 2009;73:1599–601.

    Article  CAS  PubMed  Google Scholar 

  35. Barkovich AJ. Neuroimaging manifestations and classification of congenital muscular dystrophies. AJNR Am J Neuroradiol. 1998;19:1389–96.

    CAS  PubMed  Google Scholar 

  36. Lefeber DJ, Schonberger J, Morava E, et al. Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. Am J Hum Genet. 2009;85:76–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Barone R, Aiello C, Race V, et al. DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Ann Neurol. 2012;72:550–8.

    Article  CAS  PubMed  Google Scholar 

  38. Radmanesh F, Caglayan AO, Silhavy JL, et al. Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities. Am J Hum Genet. 2013;92:468–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Stevens E, Carss KJ, Cirak S, et al. Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of alpha-dystroglycan. Am J Hum Genet. 2013;92:354–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Buysse K, Riemersma M, Powell G, et al. Missense mutations in beta-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome. Hum Mol Genet. 2013;22:1746–54.

    Article  CAS  PubMed  Google Scholar 

  41. Carss KJ, Stevens E, Foley AR, et al. Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb–girdle muscular dystrophies associated with hypoglycosylation of alpha-dystroglycan. Am J Hum Genet. 2013;93:29–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the patients and their families for their cooperation.

Grant/Financial Support

This work was partly supported by the Anna Müller Grocholski Foundation, Zurich, Switzerland (grant to AP), the European Research Council (ERC starting grant #260888 to EMV), and the Italian Ministry of Health (Ricerca Corrente 2013, Ricerca Finalizzata Malattie Rare 2008 to EMV).

Disclosure

All coauthors do not report conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Pediatric Neurology, University Children’s Hospital of Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland

    Andrea Poretti, Andrea Klein & Eugen Boltshauser

  2. Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Andrea Poretti & Thierry A. G. M. Huisman

  3. Department of Pediatrics, University Hospital RWTH, Aachen, Germany

    Martin Häusler

  4. Department of Pediatrics, DRK Kliniken Berlin Westend, Berlin, Germany

    Arpad von Moers

  5. Pediatric Neurology, Children’s Hospital, Landshut, Germany

    Bastian Baumgartner

  6. Institute of Human Genetics, University Hospital RWTH, Aachen, Germany

    Klaus Zerres

  7. Laboratory of Molecular Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy

    Chiara Aiello, Ginevra Zanni & Enrico Bertini

  8. IRCCS Stella Maris Institute, Pisa, Italy

    Francesca Moro & Filippo M. Santorelli

  9. Institute of Neuropathology, RWTH University, Aachen, Germany

    Joachim Weis

  10. Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza Institute, San Giovanni Rotondo, Italy

    Enza Maria Valente

  11. Department of Medicine and Surgery, University of Salerno, Salerno, Italy

    Enza Maria Valente

Authors
  1. Andrea Poretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Häusler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arpad von Moers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bastian Baumgartner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Klaus Zerres
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chiara Aiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesca Moro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ginevra Zanni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Filippo M. Santorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thierry A. G. M. Huisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Joachim Weis
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Enza Maria Valente
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Enrico Bertini
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Eugen Boltshauser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eugen Boltshauser.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Poretti, A., Häusler, M., von Moers, A. et al. Ataxia, Intellectual Disability, and Ocular Apraxia with Cerebellar Cysts: A New Disease?. Cerebellum 13, 79–88 (2014). https://doi.org/10.1007/s12311-013-0521-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-013-0521-8

Keywords

Search

Navigation