Tofacitinib improves motor symptoms in parkinsonism associated with a heterozygous NGLY1 variant and autoimmune disease

Introduction: Levodopa-refractory parkinsonism poses a significant diagnostic and therapeutic challenge. Variants in N-glycanase 1 (NGLY1), a key gene in proteostasis, have been associated with movement disorders, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is implicated in neuroinflammation. Case description: We report a 59-year-old woman with parkinsonism and autoimmune polyendocrine syndrome type III, carrying a heterozygous pathogenic NGLY1 variant (p.Arg401Ter). Her motor symptoms were unresponsive to multiple dopaminergic therapies, and a formal levodopa challenge test was negative.Treatment with the JAK inhibitor tofacitinib (5 mg twice daily), initiated for seronegative arthritis, was associated with sustained improvement in rigidity and gait freezing, paralleled by remission of her autoimmune manifestations. Temporary discontinuation of tofacitinib coincided with clinical worsening, followed by recovery upon reintroduction. Discussion: The temporal association between JAK inhibition and motor improvement suggests that modulation of systemic inflammation may influence neurological outcomes in selected patients. A heterozygous NGLY1 variant could act as a disease modifier through neuroimmune dysregulation. Conclusions: This observation highlights a potential link between immune activation and parkinsonian symptoms in patients with systemic autoimmune disease. Immunomodulatory therapy may represent an adjunctive consideration in complex neuroinflammatory presentations, warranting further investigation. LEARNING POINTS: Tofacitinib, a Janus kinase inhibitor, was associated with clinical improvement of parkinsonian symptoms in a patient with systemic autoimmune disease, suggesting a potential modulatory role of inflammation in refractory movement disorders.The presence of a heterozygous N-glycanase 1 variant may contribute to susceptibility or clinical expression of parkinsonism in the setting of immune or inflammatory dysregulation.This case underscores the interplay between immunological and neurodegenerative mechanisms when facing atypical or treatment-refractory neurological presentations.