Objective: To report phenotype variability in a family with SNCA duplication associated Parkinsonism.

Background: Pathogenic variants in SNCA, the gene coding for α-synuclein, cause familial Parkinson’s Disease (PD). SNCA multiplications causing overexpression of wild-type α-synuclein are more common than missense or deletion mutations.[1] SNCA triplications typically present earlier (mean age of onset 34.5 years) and have rapid, severe clinic courses. SNCA duplications usually have more insidious courses and may be indistinguishable from idiopathic PD (mean age of onset 46.9 years). Duplication heterozygotes have varied inter- and intra-familial phenotypes and penetrance.[2] Here the phenotypes within a kindred with pathogenic SNCA duplication are described.

Method: The proband’s genetic testing was performed via the Invitae Hereditary Parkinson Disease and Parkinsonism Panel in 2021. Patient information was abstracted via chart review.

Results: The proband developed left hand tremor and bradykinesia at age 52, with several years of antecedent anxiety and RBD. He was diagnosed with PD at 52. Dysautonomia (orthostatic hypotension with syncope, constipation, and urinary incontinence), psychosis, dementia, and motor fluctuations appeared within 5 years of diagnosis. The proband’s sister developed slowed walking, left-sided bradykinesia, and constipation at age 57, diagnosed as PD. 6 years after diagnosis, she developed anxiety, constipation, mild orthostatism, and RBD but no neuropsychiatric symptoms. Family history is notable for a Parkinsonian syndrome in the proband’s maternal grandfather, maternal grand uncle, and maternal grand uncle’s two daughters. The family describes their ancestry as English and Scandinavian. Heterozygous duplication of the entire coding sequence of the SNCA gene was found in the proband.

Conclusion: Two siblings presented at similar ages with typical PD symptoms. Within 5 years of diagnosis, their phenotypes diverged, characterized by marked psychosis, autonomic failure, and dementia in the proband. This juxtaposition shows the phenotypic variability in SNCA duplications, even within kindreds. Physicians should consider genetic etiologies in patients presenting with Parkinsonism and a suggestive family history. Phenotypic variability within kindreds occurs and mild or typical phenotypes should not dissuade the consideration of genetic counseling and subsequent genetic testing.

References: 1. Guadagnolo D, Piane M, Torrisi MR, Pizzuti A and Petrucci S (2021)Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings. Front. Neurol. 12:648588.doi: 10.3389/fneur.2021.648588
2. Book A, Guella I, Candido T, Brice A, Hattori N, Jeon B, Farrer MJ and the SNCA Multiplication Investigators of the GEoPD Consortium (2018) A Meta-Analysis of α-Synuclein Multiplication in Familial Parkinsonism. Front. Neurol. 9:1021. doi: 10.3389/fneur.2018.01021

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-presentation-of-snca-duplication-parkinsonism-in-a-family-kindred/