Harder-Rauschenberger L, Ip CW.
Mov Disord. 2025 Dec 29. doi: http://10.1002/mds.70172.
Reply
Abstract
We thank Drs Lenka and Jankovic for their response to our review.1 In their letter, the authors expand the discussion of the second-hit hypothesis in dystonia to include peripheral trauma as a trigger in other movement disorders such as parkinsonism and tremor. For both conditions, evidence remains extremely sparse and is largely limited to case reports as previously summarized by the same authors.2 However, although causality is still lacking, parkinsonism has been increasingly associated with systemic inflammatory markers in recent years, making it reasonable to speculate that inflammation after peripheral trauma could trigger or accelerate disease manifestation in individuals already predisposed to parkinsonism. Furthermore, genetic forms of parkinsonism such as LRRK2 exhibit reduced penetrance, and a contribution of extragenetic triggers to disease manifestation is suspected.3 Similarly, reduced penetrance in many genetic dystonias, including DYT-TOR1A–associated dystonia, supports the notion that extragenetic “second hits” may critically shape disease expression.
