European Radiology

, Volume 27, Issue 12, pp 5080–5092 | Cite as

Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation

  • Romina Romaniello
  • Filippo Arrigoni
  • Elena Panzeri
  • Andrea Poretti
  • Alessia Micalizzi
  • Andrea Citterio
  • Maria Francesca Bedeschi
  • Angela Berardinelli
  • Raffaella Cusmai
  • Stefano D’Arrigo
  • Alessandro Ferraris
  • Annette Hackenberg
  • Alma Kuechler
  • Margherita Mancardi
  • Sara Nuovo
  • Barbara Oehl-Jaschkowitz
  • Andrea Rossi
  • Sabrina Signorini
  • Frank Tüttelmann
  • Dagmar Wahl
  • Ute Hehr
  • Eugen Boltshauser
  • Maria Teresa Bassi
  • Enza Maria Valente
  • Renato Borgatti



To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations.


Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa.


Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected.


The cerebellar involvement in tubulinopathies shows specific features that may be labelled as ‘tubulin-related CD’. This pattern is unique and differs from other genetic causes of cerebellar dysplasia.

Key Points

Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder.

Cerebellar dysplasia in tubulinopathies shows specific features labelled as ‘tubulin-related CD’.

Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.


Tubulin genes Cerebellum Dysplasia Mutation Neuroimaging 



Cerebellar dysplasia


Cortical cerebellar dysplasia


Cerebellar vermian dysplasia


G Protein-Coupled Receptor 56


Malformations of cortical development


Magnetic resonance imaging




Tubulin, Alpha-1A


Tubulin, Beta-2B


Tubulin, Beta-3


Wingless-Type Mmtv Integration Site Family, Member 1



The authors are grateful to the patients involved in this study and their parents for their kind cooperation. We also acknowledge the PADAPORT project (to RB and EMV) funded by the Pierfranco and Luisa Mariani Foundation. We are also grateful to Dr. Pascal Joset, Institute of Medical Genetics, Zürich, for mutation analysis of one patient.

During the revision process of the manuscript our colleague Andrea Poretti suddenly passed away. Not only was he one of the most important authors of this study, he was first and foremost a dear friend. During the past years his enthusiastic and tireless efforts into the study of cerebellum and brain malformations has influenced all of us deeply. This paper is in memory of Andrea Poretti.

Compliance with ethical standards


The scientific guarantor of this publication is Renato Borgatti.

Conflict of interest

The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.


This study was supported by the Italian Ministry of Health (Grant 5X1000-2012 to RB Grant 5X1000-2014 to RR; Ricerca Finalizzata grant NET-2013-02356160 to RB and EMV), and by the European Research Council (Starting Grant StG260888 to EMV).

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was obtained from all subjects (patients) in this study.

Ethical approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

Some study subjects or cohorts have been previously reported in Romaniello, Arrigoni, Cavallini, et al. [10] and Romaniello, Tonelli, Arrigoni, et al. [11].


• retrospective

• observational

• multicentre study

Supplementary material

330_2017_4945_MOESM1_ESM.docx (27 kb)
Supplementary Table 1 (DOCX 26 kb)
330_2017_4945_MOESM2_ESM.docx (25 kb)
Supplementary Table 2 (DOCX 24 kb)
330_2017_4945_MOESM3_ESM.docx (24 kb)
Supplementary Table 3 (DOCX 23 kb)
330_2017_4945_MOESM4_ESM.docx (52 kb)
Supplementary Figure (DOCX 52 kb)


  1. 1.
    Poretti A, Boltshauser E, Huisman TA (2016) Cerebellar and Brainstem malformations. Neuroimaging Clin N Am 26:341–357CrossRefPubMedGoogle Scholar
  2. 2.
    Patel S, Barkovich AJ (2002) Analysis and classification of cerebellar malformations. AJNR Am J Neuroradiol 23:1074–1087PubMedGoogle Scholar
  3. 3.
    Demaerel P (2002) Abnormalities of cerebellar foliation and fissuration: classification, neurogenetics and clinicoradiological correlations. Neuroradiology 44:639–646CrossRefPubMedGoogle Scholar
  4. 4.
    Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB (2012) A developmental and genetic classification for malformations of cortical development: update 2012. Brain 135:1348–1369CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bosemani T, Orman G, Boltshauser E, Tekes A, Huisman TA, Poretti A (2015) Congenital abnormalities of the posterior fossa. Radiographics 35:200–220CrossRefPubMedGoogle Scholar
  6. 6.
    Bahi-Buisson N, Poirier K, Fourniol F et al (2014) The wide spectrum of tubulinopathies: what are the key features for the diagnosis? Brain 137:1676–1700CrossRefPubMedGoogle Scholar
  7. 7.
    Kumar RA, Pilz DT, Babatz TD et al (2010) TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins. Hum Mol Genet 19:2817–2827CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Oegema R, Cushion TD, Phelps IG et al (2015) Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes. Hum Mol Genet 24:5313–5325CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Richards S, Aziz N, Bale S, Bick D et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Romaniello R, Arrigoni F, Cavallini A et al (2014) Brain malformations and mutations in α- and β-tubulin genes: a review of the literature and description of two new cases. Dev Med Child Neurol 56:354–360CrossRefPubMedGoogle Scholar
  11. 11.
    Romaniello R, Tonelli A, Arrigoni F et al (2012) A novel mutation in the β-tubulin gene TUBB2B associated with complex malformation of cortical development and deficits in axonal guidance. Dev Med Child Neurol 54:765–776CrossRefPubMedGoogle Scholar
  12. 12.
    Keays DA, Tian G, Poirier K (2007) Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128:45–57CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zanni G, Colafati GS, Barresi S (2013) Description of a novel TUBA1A mutation in Arg-390 associated with asymmetrical polymicrogyria and mid-hindbrain dysgenesis. Eur J Paediatr Neurol 17:361–365CrossRefPubMedGoogle Scholar
  14. 14.
    Jaglin XH, Poirier K, Saillour Y et al (2009) Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat Genet 41:746–752CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cushion TD, Dobyns WB, Mullins JG (2013) Overlapping cortical malformations and mutations in TUBB2B and TUBA1A. Brain 136:536–548CrossRefPubMedGoogle Scholar
  16. 16.
    Cederquist GY, Luchniak A, Tischfield MA et al (2012) An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation. Hum Mol Genet 21:5484–5499CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tischfield MA, Baris HN, Wu C et al (2010) Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 140:74–87CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Alby C, Malan V, Boutaud L et al (2016) Clinical, genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation. Birth Defects Res A Clin Mol Teratol 106:36–46CrossRefPubMedGoogle Scholar
  19. 19.
    Romaniello R, Arrigoni F, Bassi MT, Borgatti R (2015) Mutations in α- and β-tubulin encoding genes: implications in brain malformations. Brain Dev 37:273–280, ReviewCrossRefPubMedGoogle Scholar
  20. 20.
    Bahi-Buisson N, Cavallin M. Tubulinopathies Overview (2016) In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2016.18Google Scholar
  21. 21.
    Saywell V, Cioni JM, Ango F (2014) Developmental gene expression profile of axon guidance cues in Purkinje cells during cerebellar circuit formation. Cerebellum 13:307–317CrossRefPubMedGoogle Scholar
  22. 22.
    Bilimoria PM, Bonni A (2013) Molecular control of axon branching. Neuroscientist 19:16–24CrossRefPubMedGoogle Scholar
  23. 23.
    Barallobre MJ, Pascual M, Del Río JA, Soriano E (2005) The Netrin family of guidance factors: emphasis on Netrin-1 signalling. Brain Res Rev 49:22–47CrossRefPubMedGoogle Scholar
  24. 24.
    Buel GR, Rush J, Ballif BA (2010) Fyn promotes phosphorylation of collapsin response mediator protein 1 at tyrosine 504, a novel, isoform-specific regulatory site. J Cell Biochem 111:20–28CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lin PC, Chan PM, Hall C, Manser E (2011) Collapsin response mediator proteins (CRMPs) are a new class of microtubule-associated protein (MAP) that selectively interacts with assembled microtubules via a taxol-sensitive binding interaction. J Biol Chem 286:41466–41478CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Moreno-Flores MT, Martín-Aparicio E, Avila J, Díaz-Nido J, Wandosell F (2002) Ephrin-B1 promotes dendrite outgrowth on cerebellar granule neurons. Mol Cell Neurosci 20:429–446CrossRefPubMedGoogle Scholar
  27. 27.
    Qu C, Dwyer T, Shao Q, Yang T, Huang H, Liu G (2013) Direct binding of TUBB3 with DCC couples netrin-1 signaling to intracellular microtubule dynamics in axon outgrowth and guidance. J Cell Sci 126:3070–3081CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Breuss M, Morandell J, Nimpf S et al (2015) The Expression of Tubb2b Undergoes a Developmental Transition in Murine Cortical Neurons. J Comp Neurol 523:2161–2186CrossRefPubMedGoogle Scholar
  29. 29.
    Fallet-Bianco C, Laquerrière A, Poirier K et al (2014) Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly. Acta Neuropathol Commun 2:69CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tischfield MA, Cederquist GY, Gupta ML Jr, Engle EC (2011) Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations. Curr Opin Genet Dev 21:286–294CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Aldinger KA, Mendelsohn NJ, Chung BH et al (2016) Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations. J Med Genet 53:427–430CrossRefPubMedGoogle Scholar

Copyright information

© European Society of Radiology 2017

Authors and Affiliations

  • Romina Romaniello
    • 1
  • Filippo Arrigoni
    • 2
  • Elena Panzeri
    • 3
  • Andrea Poretti
    • 4
    • 5
  • Alessia Micalizzi
    • 6
    • 7
  • Andrea Citterio
    • 3
  • Maria Francesca Bedeschi
    • 8
  • Angela Berardinelli
    • 9
  • Raffaella Cusmai
    • 10
  • Stefano D’Arrigo
    • 11
  • Alessandro Ferraris
    • 12
  • Annette Hackenberg
    • 13
  • Alma Kuechler
    • 14
  • Margherita Mancardi
    • 15
  • Sara Nuovo
    • 6
    • 16
  • Barbara Oehl-Jaschkowitz
    • 17
  • Andrea Rossi
    • 18
  • Sabrina Signorini
    • 9
  • Frank Tüttelmann
    • 19
  • Dagmar Wahl
    • 20
  • Ute Hehr
    • 21
  • Eugen Boltshauser
    • 22
  • Maria Teresa Bassi
    • 3
  • Enza Maria Valente
    • 6
    • 23
  • Renato Borgatti
    • 1
  1. 1.Neuropsychiatry and Neurorehabilitation Unit, Scientific InstituteIRCCS Eugenio MedeaBosisio PariniItaly
  2. 2.Neuroimaging Laboratory, Scientific InstituteIRCCS Eugenio MedeaBosisio PariniItaly
  3. 3.Laboratory of Molecular Biology, Scientific InstituteIRCCS Eugenio MedeaBosisio PariniItaly
  4. 4.Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological ScienceThe Johns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Department of NeurogeneticsKennedy Krieger InstituteBaltimoreUSA
  6. 6.Neurogenetics UnitIRCCS Fondazione Santa LuciaRomeItaly
  7. 7.Department of Biological and Environmental SciencesUniversity of MessinaMessinaItaly
  8. 8.Clinical Genetics UnitFondazione IRCCS Ca’ Granda, Ospedale Maggiore PoliclinicoMilanItaly
  9. 9.Unit of Child Neurology and PsychiatryIRCCS “C. Mondino” FoundationPaviaItaly
  10. 10.Neurology Unit, Bambino Gesù Children’s HospitalIRCCSRomeItaly
  11. 11.Developmental Neurology DivisionIRCCS Fondazione Istituto Neurologico C. BestaMilanItaly
  12. 12.Mendel LaboratoryIRCCS Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
  13. 13.Universitäts, Kinderspital Zürich, EleonorenstiftungZürichSwitzerland
  14. 14.Institut für Humangenetik EssenUniversität Duisburg-EssenEssenGermany
  15. 15.Unit of Child Neuropsychiatry Giannina Gaslini InstituteGenoaItaly
  16. 16.Department of Medicine and SurgeryUniversity of SalernoSalernoItaly
  17. 17.Practice of Human GeneticsHomburg (Saar)Germany
  18. 18.Neuroradiology UnitGiannina Gaslini InstituteGenoaItaly
  19. 19.Institute of Human GeneticsUniversity of MünsterMünsterGermany
  20. 20.Private Practice for Human GeneticsAugsburgGermany
  21. 21.Department of Human GeneticsUniversity of RegensburgRegensburgGermany
  22. 22.Department of Pediatric NeurologyUniversity Children’s HospitalZurichSwitzerland
  23. 23.Department of Molecular MedicineUniversity of PaviaPaviaItaly

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