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Neurology and Psychiatry Get Closer Again: Lessons From Dystonia

Review of: Mencacci NE et al. Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders. Brain 2020;143(9):2771–2787. At the time when neurology and psychiatry evolved into two different disciplines, dystonia was classified as “motor neurosis” and considered alongside functional conditions. After the brilliant intuition of Marsden that dystonia was a motor disorder resulting from basal ganglia dysfunction, the progressive discovery of dozens of genes causative of dystonia has definitely pushed the condition into the domain of “neurological” disorders. Still, many patients with what we (artificially) define isolated dystonia demonstrate associated psychiatric features, often preceding the motor onset and therefore suggesting that they share a common neurobiology. In their recent work, Mencacci and colleagues applied a comprehensive system biology approach primarily using transcriptome analyses to explore (1) which brain cells are most relevant to several genes causing prominent dystonia without structural or degenerative abnormalities and including those associated with different phenotypes of isolated, associated, and paroxysmal dystonia; (2) whether these genes converge toward shared cellular pathways; and (3) if a common genetic architecture between monogenic dystonia and psychiatric disorders exists. After the exploration of the cellular specificity of single dystonia genes across a broad range of brain regions, Mencacci and colleagues used multiple statistical iterations on tissue-specific transcriptomic data derived from human adult brains to generate co-expression networks, which consider gene expression correlations and represent a means to identify concealed functional relationships between genes of interest. Thus, Mencacci and colleagues first demonstrated that dystonia genes are significantly enriched in adult nigral neurons and striatal medium spiny neurons, the results being robust across species. Moreover, they identified four coexpression networks derived from substantia nigra, putamen, frontal cortex, and white matter, which were significantly enriched for dystonia genes as well as for genes associated with synaptic transmission and neurodevelopment. Finally, they observed that significant enrichment of depression-, obsessive-compulsive disorderand schizophrenia-heritability was observed within 2 dystoniaenriched networks. Because the phenotypes associated with the coexpressed genes range from isolated to complex dystonia syndromes, the current evidence would challenge the clinical classification of dystonia, as grouping patients solely on their phenotype might not mirror the molecular structure of the disease. As such, a conceptual shift that points to the identification of dystonia biotypes, irrespective of the clinical manifestations, now seems advisable as it might successfully pave the way toward novel therapeutic approaches targeting shared pathophysiological mechanisms rather than just clinical symptoms. Interestingly, the convergence with genes implicated with synaptic transmission and neurodevelopment reinforces the hypothesis of dystonia resulting from synaptic dysfunction or being a neurodevelopmental disorder. Unfortunately, the co-expression networks were generated through transcriptome data of adult brains, preventing the recognition of potentially critical developmental windows. Moreover, because this approach can be utilized only with recognized genes, novel genetic discoveries will possibly detect functional convergence in other brain regions relevant to dystonia (ie, cerebellum). Finally, this work highlights shared biological contributions to dystonia and psychiatric disorders. If, on the one hand, it supports the need to transform the current model of care of dystonia into a multidisciplinary model, on the other hand, it would raise the alternative argument of dystonia representing a downstream clinical manifestation of a primary psychiatric disorder. This interpretation would similarly undermine the validity of any of these clinically defined, neurologic or psychiatric diseases as discrete neurobiological entities and would call for an effort to move toward a molecular taxonomy of neuropsychiatric disorders.