Objective: In children with Early Onset Ataxia (EOA), we aimed to determine the prevalence of comorbid dystonia and to explore the pathogenesis by the shared genetic background.

Background: Recent publications in patients with cervical dystonia have indicated cerebellar Purkinje cell pathology. In pediatric EOA patients with developing cerebello-thalamo-basal ganglia motor networks, we hypothesized that the association between ataxia and dystonia could be particularly strong due to additional (mal)adaptive plasticity. In EOA children, however, the prevalence and etiology of comorbid dystonia is still unknown. We reasoned that exploration of co-expression between genes involved in EOA, AOA and dystonia disorders could provide pathophysiologic insight in shared biological pathways.

Methods: In a historic cohort of 36 well-phenotyped EOA children by 6 internationally recognized movement disorder specialists (ref 1), we retrospectively determined the prevalence of comorbid dystonia. As previously published, we determined gene co-expression by GeneNetwork* and PANTHER software (ref 2).

Results: In pediatric EOA, the prevalence of comorbid dystonic features was 67% (24/36), detected by 1-6 (mean 2) movement disorder experts. Network analysis of genes co-expressed with shared EOA and AOA genes revealed a 9 fold overrepresentation of genes involved in GABA receptor activity and subsequent network analysis of shared EOA, AOA and dystonia genes revealed an 11 fold overrepresentation of genes involved in Tricarboxylic acid (TCA), necessary for mitochondrial ATP production and GABA synthesis (the neurotransmitter of cerebellar Purkinje cells).

Conclusions: In pediatric EOA, the prevalence of comorbid dystonic features appears particularly high (EOA 67% vs AOA 14-54%), potentially due to maladaptive plasticity. Our genetic data suggest that hampered mitochondrial energy production and GABA synthesis may provide a shared disease mechanism for comorbid dystonia with EOA and AOA. These results in EOA children could support a direct (metabolic) and indirect (maladaptive plasticity) association between cerebellar Purkinje cell pathology and dystonia.

References: 1. Lawerman TL, Brandsma R, van Geffen JT, Lunsing RJ, Burger H, Tijssen MA, de Vries JJ, de Koning TJ and Sival DA. Reliability of phenotypic early-onset ataxia assessment. DMCN 2016;58(1):70-6. 2. Nibbeling E, Delnooz CS, de Koning TJ, Sinke RJ, Jinnah HA, Tijssen MAJ, Verbeek DS. Using the shared genetics of dystonia and ataxia to unravel their pathogenesis. Neurosci & Biobehav Rev 2017; 75: 22-39. *http://129.125.135.180:8080/GeneNetwork/cytoscape.html.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/comorbid-pediatric-early-onset-ataxia-and-dystonia-is-the-cerebellum-involved/