# A Clinical-Based Diagnostic Approach to Cerebellar Atrophy in Children
## 1 Introduction  
Cerebellar Atrophy (CA) is a neuroradiological definition for an arborized cerebellum with progressive and irreversible volume reduction, where neurons have been lost following a neurodegenerative process [1, 2, 3]. Numerous diseases, which especially in children may have a genetic cause, share such a brain-imaging pattern. When addressing cerebellar genetic diseases in childhood, it is relatively easy to formulate a diagnosis in the case of cerebellar malformations, for which an extensive categorization conceived by [PERSON] in 2009 serves as an accurate guide [4]. The diagnostic process is more challenging for cerebellar atrophy, as the radiological patterns are often overlapping, tend to evolve over time, and it is often not possible reach an etiopathologicaldefinition based solely on brain Magnetic Resonance Imaging (MRI) findings. The most complete and recent classification of cerebellar degenerative patterns was published by [PERSON] and colleagues and it is essentially based on neuroimaging [3]. CA can affect the vermis, the hemispheres, or both, but most of the time the vermis is more severely affected [2]. A peculiar hypo-atrophic pattern, where atrophy is superimposed on hypoplasia, characterizes diseases caused by genes responsible for cerebellar integrity and trophism; these genes are not primarily implicated in embryonic brain development, but the detrimental insult is early and severe, causing in utero damage mimicking malformative disease. This is mainly typical of Congenital Disorders of Glycoslation (CDG) and Pontocerebellar Hypoplasias (PCH), where the severity of the atrophy may or may not evolve [2; 4]. Despite the miscellaneous MRI patterns and the variety of the genetic pathways involved, the clinical presentation can be very similar among patients. Initially, developmental stages may be normally achieved, but unbalance and incoordination with gait, stance, and sitting problems emerge in most children as a major sign of cerebellar involvement. Many pediatric patients also show a reduced muscular tone, even in the absence of pyramidal or peripheral nervous system involvement, confirming the role of the cerebellum in tone maintenance. Nystagmus, saccadic intrusion, and impaired pursuit are frequently found, as well as dysarthria and orobuccal dyspraxia. Finally, a global developmental delay is often present, confirming the cerebellum's role in cognition (reviewed by [PERSON] et al. [5]). Beyond cerebellar involvement, children with CA may present signs of the impairment of other neurological or extra-neurological systems. Brain MRI can reveal the concomitant atrophy of supratentorial regions, more typically in ravaging disorders with severe and progressive disability, as in the case of Neuronal Ceroid Lipofuscinois (NCL); white matter (WM) abnormalities may be found, and that is the case of the Hypomyelinating Leukodystrophies (HLD) with cerebellar involvement, but also in some DNA repair defect disorders [2; 6]. This latter group of diseases typically show extrapyramidal system deterioration and Peripheral Nervous System (PNS) involvement (axonal neuropathy). The concurrent presence of cerebellar and pyramidal signs is instead more common in some Spinocerebellar Ataxias (SCA) or metabolic/mitochondrial disorders [6; 7]. Retinopathy can be present, but it is not immediately attributable to a specific disorder, although it may hint at SCA or mitochondrial diseases [8; 9]. Given the unspecific clinical presentation, overlapping radiological patterns, and shared comorbidities, the diagnosis of children with CA is often challenging. In more recent years, the progress of next-generation sequencing (NGS)-based techniques has significantly increased the diagnostic yield of pediatric ataxias. However, the broader the analysis is, the more variants are detected and need interpretation, and only a definite knowledge of the clinical presentation may help in reaching a molecular diagnosis.