A very broad and heterogenous group of disorders, cerebellar and brainstem congenital defects (CBCDs) can have a severe impact, yet the genetic basis of many of these disorders is still not fully understood. Professor Enza Maria Valente tells us about her work in investigating the basis of these defects, and its wider impact on the prognosis and management of CBCDs
Sagittal (upper panels) and axial or coronal (lower panels) brain MRIs of distinct CBCDs. First column: Joubert syndrome; second column: Dandy Walker syndrome (upper), cerebellar dysplasia with cysts (lower); third column: primary brainstem malformation; fourth column: ponto-cerebellar hypoplasia.
Understanding the basis of cerebellar defects The underlying basis
of many CBCDs, including Joubert syndrome, ponto-cerebellar hypoplasias and Dandy-Walker syndrome, is still not fully understood. Based at the University of Salerno, Professor Enza Maria Valente is the coordinator of the CBCD project, an ERC-backed initiative pursuing research in this area. “This a very broad and heterogenous group of disorders. Mainly these malformations are not progressive disorders, but relate to defects in the cerebellum and/or in the brainstem arising during embryonic development,” she explains. Some of these disorders can be diagnosed prenatally, through ultrasound scans and/or foetal MRIs, yet much remains to be learned about their genetic basis, as well as their clinical progression and the prognosis for patients. This is of course a major concern for the families affected. “If a disorder is diagnosed prenatally, families may decide to interrupt the pregnancy because they’re uncertain about the prospects of their child improving,” says Professor Valente Many CBCDs share certain core features, such as hypotonia, ataxia, abnormal ocular
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movements and psychomotor delay. It can be difficult to identify the precise nature of the malformation, especially at onset. “This is what makes it complicated to diagnose and classify these patients, because the same clinical presentation may underlie different diseases, and brain imaging is essential to
Multi-disciplinary approach Researchers aim to both investigate the genetic basis of CBCDs, and also improve the way these disorders are managed. The project is following a multidisciplinary approach to this work, combining several study methods across a large cohort of
neurological presentation of CBCDs usually vary in severity, but the core features can be very similar, especially at onset The
reach a correct diagnosis,” outlines Professor Valente. Improving the classification of CBCDs is thus an important part of the project’s research agenda. “Despite the impressive progress made in the past decade, the availability of genetic testing is still relatively limited at the moment, with consequent difficulties in providing an accurate prognosis and genetic counselling to the families,” says Professor Valente. “Also, the management and diagnostic procedures are not always very well-defined, and we have limited knowledge about the pathogenesis of some CBCDs.”
patients with various CBCDs; one workpackage is focused on clinical and neuroimaging. “The main aim of this workpackage is to recruit a large cohort of patients. We then perform a detailed clinical and neuroimaging characterisation of these patients,” says Professor Valente. These patients are divided into sub-groups based on the specific type of malformation, from which Professor Valente and her colleagues will look to build a deeper understanding of CBCDs. “We aim at developing specific correlates between the type of malformation
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