# A Clinical-Based Diagnostic Approach to Cerebellar Atrophy in Children
## 4 Discussion
Ataxia or other signs of cerebellar dysfunction may not be present at onset and emerge over time; most children who reach sufficient motor skills develop truncal or appendicular ataxia, as well as oculomotor functions are impaired in the majority of cases. Oculomotor abnormalities and arbocusucal dyspraxia are common but not disease-specific, although strabismus is almost uniformly found in CDG. Muscular hypotoria affects more than a half of children at any age and may be the sign of a cerebellar and early pyramidal involvement; in younger children, the sign may disappear with age and evolve into ataxia or, in some cases, turn into spasticity. Our clinical data confirm that a combined pyramidal and extrapyramidal dysfunction is a clue of DNA repair disorders [7]. This latter disease group is also the one most frequently complicated by epilepsy, suggesting that DNA repair disorders must always be considered in children with ataxia, epilepsy, and microcephaly (also a recurrent finding). Unless we have a definite suspicion based on brain MRI and clinical evaluation, we need the help of neurophysiology and laboratory tests to narrow the field of differential diagnosis. Abnormalities in EEG are often found in children with mitochondrial/metabolic disorders, even in the absence of seizures, as an effect of global metabolic dysfunction on brain activity. Alterations in ERG are generally considered a sign of mitochondrial diseases or some specific SCA, mainly SCA7 [9; 10; 11; 12; 13], but they do not seem to recur in particular groups of diseases in our cohort, and the same happens for visual and auditory evoked potentials. VEP may give a strong clue to diagnosis, for example revealing signs of optic nerve involvement in Wolfram Syndrome. In such studies though, the poor collaboration of younger and severely disabled children must be considered. SEP appears helpful, showing a dysfunction in the somatosensory system functioning, at different levels, in those disorders known to possibly have such features (ARSACS, DNA repair defects, FRDA, NBIA, Wolfram syndrome); unexpectedly, neither of the two SCA children who underwent the exam had SEP abnormalities. PNS involvement sometimes complicates the clinical presentation and course of children. In our cohort, EMG and NCS data were helpful to guide genetic analyses, in some cases focusing on a very specific disorder. Patients with NCS abnormalities were affected by ARSACS, Charcot-Marie-Tooth 2Z (CMT2Z), DNA repair disorders, FRDA, and mitochondrial diseases; EMG was altered in the same disorders, plus NBIA and PCH. The highest recurrence of PNS involvement was found in children with DNA repair defects: this demonstrates that, even if EMG is quite an invasive exam to perform in a child, it must be considered as it may lead to diagnosis. Notably, the _PNKP_ gene was recently described to cause a large spectrum of phenotypes, ranging from congenital macroccephaly to adult-onset ataxia [14]; we suggest that in children where ataxia is associated with at least two of the following three features--microcephaly, seizures, and neuropathy--_PNKP_ sequencing should be considered, especially in the presence of supportive elements such as AFP/cholesterol/albumin alterations or signs of extrap pyramidal system involvement. The role of muscle biopsy in the diagnostic process of pediatric ataxias is already recognized and biochemical studies on muscle samples were found to be helpful in a range from 5.5% up to 23% of children [8; 15; 16; 17]. In our cohort, a definite alteration was found in 24% of children, thus confirming the role of the exam in the diagnostic process of pediatric-onset CA. Lastly, the study proves the effectiveness of a laboratory investigations for conditions that may present with CA in the phenotype (and therefore genotype) definition (results summarized in Table 11). Abnormalities of serum AA, urinary AO, T-IEF, cholesterol, albumin, and AFP were found in a proportion of patients and in such cases unambiguously defined the disease group.