Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation
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.
• 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.
KeywordsTubulin genes Cerebellum Dysplasia Mutation Neuroimaging
Cortical cerebellar dysplasia
Cerebellar vermian dysplasia
G Protein-Coupled Receptor 56
Malformations of cortical development
Magnetic resonance imaging
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.
Written informed consent was obtained from all subjects (patients) in this study.
Institutional Review Board approval was obtained.
Study subjects or cohorts overlap
• multicentre study
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