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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
Neuro

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Tubulin genes Cerebellum Dysplasia Mutation Neuroimaging 

Abbreviations

CD

Cerebellar dysplasia

CCD

Cortical cerebellar dysplasia

CVD

Cerebellar vermian dysplasia

GPR56

G Protein-Coupled Receptor 56

MCDs

Malformations of cortical development

MRI

Magnetic resonance imaging

PMG

Polymicrogyria

TUBA1A

Tubulin, Alpha-1A

TUBB2B

Tubulin, Beta-2B

TUBB3

Tubulin, Beta-3

WNT1

Wingless-Type Mmtv Integration Site Family, Member 1

Notes

Acknowledgements

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

Guarantor

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.

Funding

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].

Methodology

• 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)

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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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