Autosomal Dominant Parkinson's Disease Caused by <scp><i>SNCA</i></scp> p.<scp>E46K</scp> Mutation in a Family with Russian Ancestry

Several SNCA point mutations have been associated with Parkinson's disease (PD) and atypical parkinsonism, each showing high phenotypic variability.1-6 The p.E46K mutation was reported in only two distinct families with PD: one Basque and the other Bolivian, both having Spanish ancestry.3, 7 In the current study, we describe a family with PD linked to the SNCA p.E46K mutation. We assessed SNCA mRNA transcripts and α-synuclein levels in blood from the proband, his father, PD patients, and controls (methods detailed in the Supplementary Appendix and Supplementary Tables S1 and S2). We identified the pathogenic heterozygous p.E46K SNCA mutation in the patient (III-1), confirmed by Sanger sequencing (Fig. 1), which was absent in his neurologically healthy father. The family history revealed a clear pattern of autosomal-dominant inheritance. The proband's mother developed PD symptoms at age 37 years and, at 39, was hospitalized, because of severe hallucinations, in a psychiatric ward, where she passed away from an unknown cause. The patient's grandmother also had PD and passed away at the age of 63. The maternal lineage is ethnically Russian, originating from the Pskovia region. The patient's father carried the wild-type of the mutation and had no neurological condition by the age of 75. The proband also has a healthy daughter who did not consent to participate in the study. The carrier of p.E46K, a 45-year-old male, exhibited early-onset PD at age 20 years, initially characterized by bradykinesia and right-arm dexterity loss. By age 25, he was diagnosed with PD demonstrating a favorable response from levodopa therapy. After 11 years of PD progression, the patient received bilateral subthalamic nucleus deep brain stimulation and initially had a positive response. Currently, he has dopamine dysregulation syndrome and experiences fluctuations with extended time off. He was prescribed a daily dosage equivalent to 850 mg of levodopa. Regarding the non-motor symptoms, the patient presented with chronic constipation, rapid eye movement sleep behavior disorder, decreased sense of smell, anxiety, and depression. More recently, he has developed dementia and experienced mild nocturnal hallucinations. Fluorodeoxyglucose-positron emission tomography /computed tomography demonstrated glucose hypometabolism in bilateral parietal, occipital, and posterior cingulate cortices (Supplementary Fig. S1). In our study, SNCA-112-mRNA levels in the p.E46K-SNCA-PD patient's CD45+ cells (6.618 [6.421-13.070]) were elevated, compared with PD patients (0.518 [0.001–6.455], P = 0.042) and controls (0.196 [0.001–3.818], P = 0.036), but not significantly different from the proband's father (2.463 [1.470–2.822], P = 0.3) (Supplementary Fig. S2; Supplementary Table S3). α-Synuclein levels showed no significant variation across groups (Supplementary Fig. S3). In conclusion, we report a family of Russian ancestry with early-onset autosomal-dominant PD caused by a p.E46K-SNCA mutation. To the best of our knowledge, this is the third family reported worldwide and the first family of non-Spanish ancestry. In the patient with p.E46K mutation, we demonstrated disruption of alpha-synuclein transcript SNCA-112 level, but no effect on level of α-synuclein. It would be of importance to replicate our findings in other patients bearing the same mutation and to further understand the impact of p.E46K on α-synuclein translation and evaluate its levels using other approaches. We thank the participants for contributing to this study. K.S. is supported by Parkinson Canada Movement Disorders Clinical Fellowship. Z.G.O. is supported by the Fonds de recherche du Québec-Santé (FRQS) Chercheurs-boursiers award, in collaboration with Parkinson Quebec, and is a William Dawson Scholar. Z.G.O. received consultancy fees from Lysosomal Therapeutics (LTI), Idorsia, Prevail Therapeutics, Inceptions Sciences (now Ventus), Ono Therapeutics, Bial Biotech, Bial, Handl Therapeutics, UCB, Capsida, Denali Lighthouse, Guidepoint, and Deerfield. Other authors have nothing to disclose. (1) Research project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C. Review and critique. (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and critique. K.S.: 1A, 1B, 1C, 2A, 2B, 3A. I.M.: 1A, 1B, 1C, 2B, 2C, 3B. A.Z.: 1C, 2C, 3B. M.S.: 1C, 2C, 3B. M.B.: 1C, 2C, 3B. T.S.: 1C, 2C, 3B. E.Y.: 1C, 2C, 3B. J.A.: 1C, 2C, 3B. F.A.: 1C, 2C, 3B. Z.G.O.: 1B, 1C, 2C, 3B. A.E.: 1A, 1B, 2A, 2C, 3A, 3B. S.P.: 1A, 1B, 2A, 2C, 3A, 3B. All data relevant to this study are included within the article and the accompanying supplementary files. Data S1. Supplementary Appendix. Figure S1. FDG-PET images show glucose hypometabolism in bilateral parietal, occipital, and posterior cingulate cortices. Additionally, mild glucose hypometabolism is observed in the left temporal cortex. Figure S2. SNCA-112 mRNA level in CD45+ peripheral blood cells from E46K-SNCA-PD patient and patient's father, PD patients, and controls. * - P < 0.05 after multiple correction. The y-axis is presented on a logarithmic scale. PD, Parkinson's disease. Figure S3. Relative alpha-synuclein level in CD45+ peripheral blood cells from the E46K-SNCA-PD patient, proband's father, PD patients, and individuals of the control group. (A – Western blot analysis; B, C – quantification of the results as the ratio of alpha-synuclein to GAPDH and total protein, respectively). The E46K-SNCA-PD patient and the proband's father's samples were measured in quadruple, others in duplicate. The y-axis is presented on a logarithmic scale. Table S1. Clinical characteristic of PD patients and controls. Table S2. Primer sequences for estimation of SNCA-140, −126, −112 mRNA levels in studied groups. Table S3. SNCA-112, -126, -140 mRNA levels in CD45+ peripheral blood cells from the p.E46K SNCA PD patient and the proband's father, PD patients, and controls. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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