Case Report: Deep brain stimulation in SYNJ1-related early-onset parkinsonism

Deep brain stimulation (DBS) is established for levodopa-responsive Parkinson's disease (PD), but the outcomes of DBS in rare genetic early-onset parkinsonism remain incompletely defined. While its efficacy is documented in monogenic forms of parkinsonism (e.g., LRRK2, Parkin, PINK1, and SNCA), clinical data regarding the safety and efficacy of DBS in carriers of the SYNJ1 mutation remain scarce.

We report two patients with SYNJ1-related early-onset parkinsonism treated with bilateral DBS and place their outcomes in a single-center gene-listed EOPD DBS cohort. Case 1 carried a novel homozygous SYNJ1 c.1969A > G (p. Thr657Ala) missense variant and 46, XY disorder of sex development; GPi-DBS enabled the levodopa equivalent daily dose (LEDD) reduction from 775 to 300 mg/day, with improved dyskinesia and sleep, although motor fluctuations and neuropsychiatric symptoms persisted. Case 2 carried a SYNJ1 c.1627 + 13 T > A intronic variant; subthalamic nucleus deep brain stimulation (STN-DBS) reduced the LEDD from 955 to 605 mg/day and Unified Parkinson's Disease Rating Scale (UPDRS-III) score from 51 to 32 at 1.5-year follow-up. In the contextual cohort, the median LEDD reduction after DBS was 35.2%. These observations support DBS as a feasible symptomatic strategy in selected genetic early-onset Parkinson's disease (EOPD) while emphasizing genotype-specific uncertainty.

These cases illustrate heterogeneous clinical responses to DBS in patients with early-onset parkinsonism carrying SYNJ1 variants. DBS may provide symptomatic benefit in carefully selected patients, but the small sample size and variant-level uncertainty preclude conclusions regarding genotype-specific efficacy.