Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation


Sanaz Khosravani, Gang Chen, Laurie J Ozelius, and Kristina Simonyan. 2021. “Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation.” Neurobiology of Disease, 148 (105223).
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Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation


Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in the prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine-learning classification of 95.2% of unaffected relatives together with patients rather than healthy controls substantiated these neural alterations as the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine-learning categorization of 28.6% of unaffected relative as patients indicated their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials.
Last updated on 01/07/2021