DOI: 10.12890/2025_005886
Tofacitinib improves motor symptoms in parkinsonism associated with a heterozygous NGLY1 variant and autoimmune disease
Authors
jorge.alvarez.troncoso@gmail.com
Keywords
Parkinson’s disease, NGLY1 variant, autoimmune polyendocrine syndrome type III (APS-3), tofacitinib, neuroinflammationAbstract
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.
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