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Clinical and imaging findings in Parkinson disease associated with the A53E SNCA mutation.

ABSTRACT: OBJECTIVE:To describe the clinical features and brain imaging findings of autosomal dominant Parkinson disease (PD) associated with a recently reported mutation in SNCA. METHODS:A Finnish family with PD in 3 successive generations, in accordance with an autosomal dominant inheritance pattern, was identified. We examined 2 available members of the family, the female proband and her daughter (both with early-onset PD), clinically and using dopamine transporter imaging ([(123)I]FP-CIT SPECT). A possible causative genetic defect was investigated by molecular genetic analyses. RESULTS:A heterozygous c.158C>A (p.A53E) point mutation in SNCA was revealed in both patients. The patients presented with PD clinically characterized by severe bradykinesia but with very little tremor and early onset of levodopa-induced dyskinesia. No cognitive decline or dysautonomic features have emerged during more than 5 years of follow-up. Both patients presented with a severe striatal binding defect in dopamine transporter SPECT imaging. CONCLUSIONS:The results of this observational study add evidence to the suggestion that the p.A53E mutation in SNCA is indeed pathogenic and results in autosomal dominant PD. Bradykinesia and early onset of levodopa-induced dyskinesia are the characteristic clinical features associated with the A53E mutation, but the patients did not exhibit dementia or dysautonomia. The [(123)I]FP-CIT SPECT findings indicated a profound, symmetric dopaminergic defect, in contrast to those observed in patients with idiopathic PD.

SUBMITTER: Martikainen MH

PROVIDER: S-EPMC4811387 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Clinical and imaging findings in Parkinson disease associated with the A53E SNCA mutation.

Martikainen Mika H MH Päivärinta Markku M Hietala Marja M Kaasinen Valtteri V

Neurology. Genetics 20151015 4

<h4>Objective</h4>To describe the clinical features and brain imaging findings of autosomal dominant Parkinson disease (PD) associated with a recently reported mutation in SNCA.<h4>Methods</h4>A Finnish family with PD in 3 successive generations, in accordance with an autosomal dominant inheritance pattern, was identified. We examined 2 available members of the family, the female proband and her daughter (both with early-onset PD), clinically and using dopamine transporter imaging ([(123)I]FP-CI ...[more]

PMID: 27066564

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Project description:Objective: In the province of Brescia, Italy, historical neurotoxic metal exposure has occurred for several decades. This study aimed to explore the role of metal exposure and genetics on Parkinson's Disease (PD) and Parkinsonism. Methods: Cases were enrolled from four local clinics for movement disorders. Randomly selected controls non-affected by neurological or psychiatric conditions were enrolled from the same health centers keeping a similar gender ratio and age distribution as for cases. Data on sociodemographic variables, clinical onset and life habits were collected besides accurate occupational and residential history. Blood samples were collected from all participants for genotyping of target polymorphisms in genes linked to PD and/or metal transport. Results: A total number of 432 cases and 444 controls were enrolled in the study, with average age of 71 years (72.2 for cases and 70 for controls). The average age at diagnosis was 65.9 years (SD 9.9). Among the potential risk factors, family history of PD or Parkinsonism showed the strongest association with the diseases (OR = 4.2, 95% CI 2.3, 7.6 on PD; OR = 4.3, 95% CI 1.9, 9.5 for Parkinsonism), followed by polymorphism rs356219 in the alpha-synuclein (SNCA) gene (OR = 2.03, 95% CI 1.3, 3.3 for CC vs. TT on PD; OR = 2.5, 95% CI 1.1, 5.3 for CC vs. TT on Parkinsonism), exposure to metals (OR = 2.4;, 95% CI 1.3, 4.2 on PD), being born in a farm (OR = 1.8; 95% CI 1.1, 2.8 on PD; OR = 2.6; 95% CI 1.4, 4.9 on Parkinsonism) and being born in the province of Brescia (OR = 1.7; 95% CI 1.0, 2.9 on PD). Conditional OR of having PD depending by SNCA polymorphism and metal exposure highlights higher risk of PD among CC SNCA carriers and being exposed to metals. However, the interaction term was not statistically significant. Conclusions: Lifetime exposure to metals and genetic variation in SNCA gene are relevant determinants of PD and Parkinsonism in the highly industrialized area of Brescia, Italy. The lack of evidence of statistical interaction between environmental and genetic factors may be due to the low frequencies of subjects representing the exposure categories and the polymorphism variants and does not rule out the biological interaction.

Project description:ImportanceCognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.ObjectiveTo determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.Design, setting, and participantsWe studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.Main outcomes and measuresNine variables derived from 7 psychometric tests.ResultsThe APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.Conclusions and relevanceOur data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

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Clinical and imaging findings in Parkinson disease associated with the A53E SNCA mutation.

Publications

Clinical and imaging findings in Parkinson disease associated with the A53E SNCA mutation.

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