Objective: Describe the clinical and diagnostic findings of a patient with early-onset Parkinson’s Disease (EOPD) with homozygous variant of unknown significance (VUS) in the SYNJ1 gene and heterozygous VUS in the GBA gene.

Background: A 24 year-old woman born to consanguineous parents of Indian descent presented with gradual onset of slowness of movements starting at age 23. She then developed left hand rest tremor, impaired dexterity, eyelid fluttering with preserved consciousness, and altered speech. She met developmental milestones, graduated college, and had no neuroleptic exposures. Family history was notable for a sister with impaired cognition, generalized slowness, and tremor starting at age 19, who was diagnosed with and treated for Moyamoya disease without improvement.

Method: Her examination was notable for MOCA 20/30, monotone voice, mild dysarthria, intermittent eyelid fluttering and facial dyskinesias with dystonic smile, low-amplitude, high-frequency truncal tremor and intermittent left arm rest tremor and rigidity, bilateral bradykinesia, wide based gait, and impaired tandem.

Results: Serologic testing (e.g., ceruloplasmin, heavy metals, and autoimmune panels) was unremarkable. Neuropsychological testing revealed impaired executive function, attention, language, and visual perception.  Brain MRI/MRA showed mild global atrophy without evidence of vascular abnormalities. A dystonia and parkinsonism panel with reflex to a leukodystrophy panel (GeneDx) identified a homozygous missense VUS in SYNJ1 (encoding synaptojanin 1), c.1375 C>T p.(R459C), and a single heterozygous missense VUS in GBA (encoding glucocerebrosidase), c.882 T>G p.(H294Q). Her SYNJ1 VUS is novel but missense mutations in SYNJ1 have been reported to cause parkinsonism, dystonia, and poor response to levodopa. ¹ Her GBA VUS has conflicting classifications of pathogenicity.² Her tremor is refractory to multiple agents, though mildly responsive to levodopa. Within one year of levodopa initiation, she developed disabling head-bobbing dyskinesias in all ON time.

Conclusion: This is the first reported case of a patient with EOPS and two concurrent variants presenting in a novel and potentially synergistic way with parkinsonism, cognitive impairment, truncal tremor, eyelid fluttering, dystonic smile, and levodopa-responsive tremor with disabling head-bobbing dyskinesias.

References: 1. Quadri M, Fang M, Picillo M, et al. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum Mutat. 2013;34(9):1208-1215. doi:10.1002/humu.22373
2. National Center for Biotechnology Information. ClinVar; [VCV000242810.63], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000242810.63 (accessed Jan. 15, 2025).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-onset-levodopa-responsive-parkinsonism-with-cognitive-impairment-and-head-bobbing-dyskinesias-associated-with-synj1-and-gba-variants-of-unknown-significance/