Cerebellar Genetic Diseases: Diagnostic and Monitoring

A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (10 June 2022) | Viewed by 20151

Special Issue Editor


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Guest Editor
Department of Developmental Neurology, Fondazione IRCCS, Istituto Neurologico "C. Besta," Via Celoria 11, 20133 Milan, Italy
Interests: pediatric neurology; cerebellar diseases; genetic syndromes; neurodevelopmental disorders

Special Issue Information

Dear Colleagues,

Pediatric genetic ataxias are typically thought of as rare diseases, but looking closely they appear to comprise a large number of conditions, some of which are relatively common. When approaching the matter from an etiopathological point of view, the first important differentiation should be made between malformative congenital conditions and neurodegenerative diseases. This categorization is made on genetic and radiological bases, since molecular defects lying in genes that are mainly implicated in central nervous system development lead to congenital abnormalities, while mutations in genes coding for proteins implicated in cerebellar functioning and metabolism determine an unceasing postnatal insult, thus causing cerebellar deterioration. The correct diagnosis of these diseases is pivotal to address patients to plan clinical management and therapeutic strategies, and to provide adequate genetic counselling to family members.

Prof. Dr. Stefano D'Arrigo
Guest Editor

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Keywords

  • cerebellum
  • ataxia
  • cerebellar hypoplasia
  • cerebellar atrophy

Published Papers (5 papers)

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Research

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13 pages, 1362 KiB  
Article
A Clinical-Based Diagnostic Approach to Cerebellar Atrophy in Children
by Claudia Ciaccio, Chiara Pantaleoni, Franco Taroni, Daniela Di Bella, Stefania Magri, Eleonora Lamantea, Daniele Ghezzi, Enza Maria Valente, Vincenzo Nigro and Stefano D’Arrigo
Appl. Sci. 2021, 11(5), 2333; https://doi.org/10.3390/app11052333 - 05 Mar 2021
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Abstract
Background: Cerebellar atrophy is a neuroradiological definition that categorizes conditions heterogeneous for clinical findings, disease course, and genetic defect. Most of the papers proposing a diagnostic workup for pediatric ataxias are based on neuroradiology or on the literature and experimental knowledge, with a [...] Read more.
Background: Cerebellar atrophy is a neuroradiological definition that categorizes conditions heterogeneous for clinical findings, disease course, and genetic defect. Most of the papers proposing a diagnostic workup for pediatric ataxias are based on neuroradiology or on the literature and experimental knowledge, with a poor participation of clinics in the process of disease definition. Our study aims to offer a different perspective on the way we approach cerebellar atrophy in developmental age, building a clinical-based diagnostic workup to guide molecular diagnosis. Methods: we recruited 52 patients with pediatric-onset cerebellar atrophy and definite disease categorization. Children underwent brain MRI, neurophysiological exams, metabolic investigations, and muscle biopsy with respiratory chain complex study. Single-gene sequencing, next-generation sequencing NGS panels, whole-exome sequencing (WES), and disease-specific techniques have been used to reach genetic confirmation. Results: Brain MRI is the main method of diagnosis, followed by tests on muscle biopsy and peripheral nervous system study. Other exams (e.g., metabolic investigations or evoked potentials) may be useful to narrow the list of diagnostic possibilities. Conclusions: We propose a diagnostic approach to cerebellar atrophy in children based on clinical findings, and support the evidence that a precise phenotypic definition may lead to the formulation of a definite diagnosis or otherwise guide the back phenotyping process derived from large molecular data. Full article
(This article belongs to the Special Issue Cerebellar Genetic Diseases: Diagnostic and Monitoring)
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Review

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16 pages, 4861 KiB  
Review
Neuroimaging of Pediatric Cerebellum in Inherited Neurodegenerative Diseases
by Luisa Chiapparini and Marco Moscatelli
Appl. Sci. 2021, 11(18), 8522; https://doi.org/10.3390/app11188522 - 14 Sep 2021
Cited by 1 | Viewed by 6876
Abstract
In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar [...] Read more.
In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar atrophy or cerebellar atrophy associated with other cerebellar or supratentorial abnormalities. Neuroradiological progression is often observed. In congenital disorders of glycosylation (CDG), for example, MRI may be normal, may demonstrate mild cerebellar atrophy or, in the advanced stages of the disease, marked atrophy of the cerebellar hemispheres and vermis associated with the abnormal signal intensity of the cerebellar cortex and white matter and brainstem hypotrophy. In spinal cerebellar ataxias (SCAs), very rare in the pediatric population, MRI may demonstrate isolated cerebellar atrophy or cerebellar and brainstem atrophy. MRI shows characteristic findings in other diseases, strongly suggesting a distinct disorder, such as neuroaxonal dystrophy, ARSACS, ataxia-telangiectasia, or precise mitochondrial diseases. An example of neurodegenerative disorder with prenatal onset is pontocerebellar hypoplasia (PCH). PCH represents a group of neurodegenerative disorders characterized by microcephaly, early cerebellar hypoplasia, and variable atrophy of the cerebellum and ventral pons, genetically divided into several subtypes. Cerebellar hypoplasia visible on MRI is often the first sign that suggests the clinical diagnosis. In most cases, the PCH subtype may demonstrate a characteristic pattern distinguishable at MRI. Selective involvement of the cerebellum, sometimes accompanied by brainstem or supratentorial abnormalities in different combinations, may help restrict the differential diagnosis and may address the specific molecular screening. Full article
(This article belongs to the Special Issue Cerebellar Genetic Diseases: Diagnostic and Monitoring)
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15 pages, 289 KiB  
Review
Clinical, Cognitive and Behavioural Assessment in Children with Cerebellar Disorder
by Stefano D’Arrigo, Carmela Loiacono, Claudia Ciaccio, Chiara Pantaleoni, Flavia Faccio, Matilde Taddei and Sara Bulgheroni
Appl. Sci. 2021, 11(2), 544; https://doi.org/10.3390/app11020544 - 08 Jan 2021
Cited by 1 | Viewed by 2640
Abstract
Cerebellar disorders are characterised clinically by specific signs and symptoms, often associated with neurodevelopmental disorder. While the clinical signs of cerebellar disorders are clearly recognisable in adults and have a precise anatomo-functional correlation, in children the semiotics are less clear and vary with [...] Read more.
Cerebellar disorders are characterised clinically by specific signs and symptoms, often associated with neurodevelopmental disorder. While the clinical signs of cerebellar disorders are clearly recognisable in adults and have a precise anatomo-functional correlation, in children the semiotics are less clear and vary with age because of the particular nature of the cerebellum’s maturation. Unlike other structures of the central nervous system, this begins at a later stage of foetal development and extends over a longer period of time, even after birth. As a result, the typical signs of cerebellar dysfunction will only become evident when the cerebellar functions have become integrated into the complex circuits of the central nervous system. This means that poor motor coordination in the very early years of life may not necessarily correlate with cerebellar dysfunction, and this may also be encountered in healthy children. The cerebellum’s role in cognitive and emotional functions relies on its structure and the complexity of its connections. Cognitive and behavioral impairment in cerebellar disorders can be the results of acquired lesions or the action of genetic and environmental risk factors, to which the cerebellum is particularly vulnerable considering its pattern of development. In the pathological setting, early evidence of cerebellar damage may be very vague, due, partly, to spontaneous compensation phenomena and the vicarious role of the connecting structures (an expression of the brain’s plasticity). Careful clinical assessment will nonetheless enable appropriate instrumental procedures to be arranged. It is common knowledge that the contribution of neuroimaging is crucial for diagnosis of cerebellar conditions, and neurophysiological investigations can also have a significant role. The ultimate goal of clinicians is to combine clinical data and instrumental findings to formulate a precise diagnostic hypothesis, and thus request a specific genetic test in order to confirm their findings, wherever possible. Full article
(This article belongs to the Special Issue Cerebellar Genetic Diseases: Diagnostic and Monitoring)
16 pages, 1598 KiB  
Review
Overview of the Cerebellar Function in Anticipatory Postural Adjustments and of the Compensatory Mechanisms Developing in Neural Dysfunctions
by Silvia Maria Marchese, Veronica Farinelli, Francesco Bolzoni, Roberto Esposti and Paolo Cavallari
Appl. Sci. 2020, 10(15), 5088; https://doi.org/10.3390/app10155088 - 24 Jul 2020
Cited by 4 | Viewed by 4939
Abstract
This review aims to highlight the important contribution of the cerebellum in the Anticipatory Postural Adjustments (APAs). These are unconscious muscular activities, accompanying every voluntary movement, which are crucial for optimizing motor performance by contrasting any destabilization of the whole body and of [...] Read more.
This review aims to highlight the important contribution of the cerebellum in the Anticipatory Postural Adjustments (APAs). These are unconscious muscular activities, accompanying every voluntary movement, which are crucial for optimizing motor performance by contrasting any destabilization of the whole body and of each single segment. Moreover, APAs are deeply involved in initiating the displacement of the center of mass in whole-body reaching movements or when starting gait. Here we present literature that illustrates how the peculiar abilities of the cerebellum i) to predict, and contrast in advance, the upcoming mechanical events; ii) to adapt motor outputs to the mechanical context, and iii) to control the temporal relationship between task-relevant events, are all exploited in the APA control. Moreover, recent papers are discussed which underline the key role of cerebellum ontogenesis in the correct maturation of APAs. Finally, on the basis of a survey of animal and human studies about cortical and subcortical compensatory processes that follow brain lesions, we propose a candidate neural network that could compensate for cerebellar deficits and suggest how to verify such a hypothesis. Full article
(This article belongs to the Special Issue Cerebellar Genetic Diseases: Diagnostic and Monitoring)
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9 pages, 2136 KiB  
Brief Report
Phenotypic Definition and Genotype-Phenotype Correlates in PMPCA-Related Disease
by Valentina Serpieri, Tommaso Biagini, Concetta Mazzotta, Rosa Pasquariello, Anna Rubegni, Filippo Santorelli, Gerardo Ongari, Silvia Cerri, Tommaso Mazza, Roberta Battini and Enza Maria Valente
Appl. Sci. 2021, 11(2), 748; https://doi.org/10.3390/app11020748 - 14 Jan 2021
Cited by 1 | Viewed by 2016
Abstract
Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two [...] Read more.
Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two unrelated patients. Methods: We report a second Italian patient carrying novel PMPCA variants (p.Trp278Leu; p.Arg362Gly). Molecular modeling, dynamics simulation, RT-qPCR, and Western blotting were performed to predict the pathogenic impact of variants in the two Italian patients and attempt genotype-phenotype correlates. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. However, blood lactate, muscle biopsy, and MRI spectroscopy were normal. PMPCA protein levels were significantly higher than controls despite normal cDNA levels. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. Conclusion: We confirm the expansion of PMPCA phenotypic spectrum including an intermediate phenotype of progressive encephalopathy without systemic involvement. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition. Full article
(This article belongs to the Special Issue Cerebellar Genetic Diseases: Diagnostic and Monitoring)
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