Sidransky Syndrome-GBA1-Related Parkinson's Disease and Its Targeted Therapies

Sidransky syndrome represents a distinct variant of Parkinson's disease (PD) that is linked to pathogenic variants in the glucocerebrosidase (GBA1) gene. This disorder exhibits an earlier onset, a more severe course, and a higher dementia prevalence compared to idiopathic PD. While the pathogenesis remains debated between loss-of-function and gain-of-function mechanisms, targeted therapies are emerging. Pharmacological chaperones (PCs), like high-dose Ambroxol, aim to mitigate enzyme misfolding-a primary driver of this disorder-rather than addressing metabolic deficiencies seen in Gaucher disease. Despite failed trials of substrate reduction therapies, current clinical trials with Ambroxol and other PCs highlight promising avenues for disease modification. This commentary advocates for increased awareness of Sidransky syndrome to advance diagnostic strategies, promote genetic testing, and refine targeted treatments, with the potential to transform care for GBA1-related PD and prodromal stages of the disease.