Background: Classically, dystonia is attributed to dysfunctional basal ganglia, but recent evidence points to disturbances within a wider inter-connecting network, i.e. the cerebello-thalamo-basal ganglia pathway. Analogously, we hypothesized that abnormal (mal)adaptive plasticity within the cerebello-thalamo-basal ganglia pathway could also explain the frequent presence of dystonic features in young patients with Early Onset Ataxia (EOA). In children with EOA, the prevalence and pathogenesis of comorbid dystonia is still unclear. We reasoned that the identification of co-expressed genes involved in EOA, AOA (Adult Onset Ataxia) and dystonia could elucidate shared biological pathways.
Methods:  In a historic cohort of 36 well-phenotyped EOA children,¹ we retrospectively determined the prevalence of comorbid dystonia. Furthermore, we determined gene co-expression by GeneNetwork* and PANTHER software.²
Results: In pediatric EOA, the prevalence of comorbid dystonic features was 67% (24/36), as assessed by 2 (mean) of 6 movement disorder experts. GeneNetwork* analysis revealed a 9-fold overrepresentation of co-expressed genes involved in GABA receptor activity (in EOA and AOA) and an 11-fold overrepresentation of genes for tricarboxylic acid, involved in ATP production and GABA synthesis (in EOA, AOA and dystonia).
Conclusion: In EOA, the prevalence of comorbid dystonic features seems relatively high (EOA 67% vs AOA 14-54%). Our gene co-expression data suggest that hampered mitochondrial energy production and GABA synthesis (the neurotransmitter of Purkinje cells) may contribute to the pathogenesis of comorbid dystonia in EOA patients. In EOA, these results may support a direct (metabolic) and indirect (maladaptive network plasticity) pathway underlying comorbid dystonia.