Long-term efficiency of pallidal DBS and the role of Levodopa treatment in DYT-GNAL and 18p deletion syndrome associated dystonia: an observational study and review of literature.

Abstract

Dystonia due to loss-of-function variants in the GNAL gene in DYT-GNAL and 18p-deletion (18pdel) syndrome has been reported to respond well to pallidal deep brain stimulation (GPi-DBS) occasionally, but long-term data is scarce. GNAL is implicated in dopamine receptor function, which may explain anecdotal reports of hypokinesia in DYT-GNAL and 18pdel-associated dystonia, a phenomenon that has not yet been systematically reviewed. We retrospectively evaluated a cohort of three patients with GNAL variants treated with GPi-DBS, documenting individual long-term outcomes spanning up to 25 years. Dystonia severity was assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Burke - Fahn - Marsden Dystonia Rating Scale (BFMDRS). We also documented bradykinetic symptoms and levodopa response. A literature review was added focusing on DBS outcomes and the effects of levodopa in DYT-GNAL and 18pdel-associated dystonia. In our patients, TWSTRS severity subscale I was reduced by 63% in early (≤ 12months; 20.7 to 7.7 points) and 81% in late follow-up (> 12months; 20.7 to 4 points) after GPi-DBS χ. BFMDRS decreased by 67% and 44%; each with a Kendall's coefficient of 0.78, indicating a high degree of concordance in improvement trajectories. Two patients exhibited bradykinesia, which was levodopa-responsive in one. GPi-DBS responses have been reported for another ten DYT-GNAL and two 18pdel-patients. Bradykinesia prompted levodopa challenges in 15 patients, resulting in improvement in five. Long-term follow-up data from three DYT-GNAL patients treated with DBS showed sustained improvement in dystonia, particularly in cervical symptoms. Bradykinesia may be an inherent clinical feature of GNAL-related dystonia, warranting further investigation.