Freezing of Gait as a Complication of Pallidal Deep Brain Stimulation in DYT- KMT2B Patients with Evidence of Striatonigral Degeneration

TL;DR

This study reports that freezing of gait often occurs in DYT-KMT2B dystonia patients after GPi-DBS, possibly due to striatonigral degeneration, highlighting the need for long-term monitoring and alternative treatments.

Contribution

It provides the first detailed characterization of FOG as a complication of GPi-DBS in DYT-KMT2B patients and links it to striatonigral degeneration.

Findings

FOG developed in all patients post-DBS

DaTscan showed bilateral striatal dopaminergic denervation in most cases

FOG was refractory to dopaminergic treatment in most patients

Abstract

Background: Mutations in KMT2B are a recognized cause of early-onset complex dystonia, with deep brain stimulation (DBS) of the internal globus pallidus (GPi-DBS) being an effective treatment. However, gait impairment, particularly freezing of gait (FOG), remains a significant challenge in DYT-KMT2B patients post-DBS. Objectives: To characterize the emergence of FOG in DYT-KMT2B patients treated with GPi-DBS and explore potential underlying mechanisms, including striatonigral degeneration. Methods: Five patients (four females) with KMT2B-related dystonia and protein-truncating variants (PTVs) were retrospectively analyzed. Clinical progression, response to GPi-DBS, and the presence of FOG were documented. Dopaminergic function was assessed using DaTscan (SPECT for ^123I-ioflupane) in four patients. Results: FOG developed in all patients, with onset ranging from 1 to 15.5 years post-DBS. DaTscan abnormalities, indicative of bilateral striatal dopaminergic denervation, were observed in four cases. Prior to DBS, all patients exhibited dystonia unresponsive to L-dopa, and post-DBS, FOG remained refractory to dopaminergic treatment in most cases. Despite initial improvements in gait post-DBS, only one patient maintained independent ambulation at the last follow-up. Conclusions: FOG is an emerging complication in DYT-KMT2B patients with PTVs undergoing GPi-DBS, potentially linked to underlying striatonigral degeneration. The findings suggest a need for long-term motor surveillance and consideration of alternative therapeutic strategies, including dopaminergic trials, in this patient population. Further studies are required to elucidate the precise mechanisms driving DBS-related hypokinetic gait disturbances in DYT-KMT2B dystonia.