The First East Asian Patient With Parkinson’s Disease Caused by the A53E SNCA Mutation With Early Progression to Dementia
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Dear Editor,
A 57-year-old Korean woman previously diagnosed with Parkinson’s disease (PD) was referred to our clinic due to visual hallucinations and cognitive decline. The patient initially presented with gait disturbance and clumsiness in her left hand at the age of 55, at which point she showed moderate to severe loss of dopamine transporter availability on an 18F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane positron emission tomography (PET) scan. Levodopa/carbidopa therapy was initiated, which led to the amelioration of her parkinsonian motor symptoms. However, 2 years after the onset of the initial symptoms, she experienced wearing-off phenomena, gait freezing, visual hallucinations, and cognitive decline. Her caregiver reported that she had experienced fluctuations in cognition, excessive daytime sleepiness, and dream-reality confusion. The patient and her family members reported that her father had parkinsonian features that had not been confirmed by a neurologist. A family history of dementia was excluded; however, hyposmia and a history of dream-enacting behavior during sleep were reported. Her Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (motor section) score in the medication ON state was 38, and she was classified as Hoehn and Yahr stage III at a levodopa-equivalent daily dosage of 1,200 mg. Brain magnetic resonance imaging revealed no remarkable findings, whereas 18F-fluorodeoxyglucose PET revealed asymmetric hypometabolism in the right dorsolateral frontal, parietal, lateral temporal, and anterior medial frontal regions without striatal involvement (Figure 1). Her Montreal Cognitive Assessment (MoCA) score was 23, and she had 12 years of education. A comprehensive neuropsychological assessment demonstrated that her level of cognitive performance was compatible with dementia, with impairments in multiple cognitive domains, including frontal/executive, visuospatial, attention, and language functions. Her Clinical Dementia Rating Scale score was estimated to be 1, with a sum of boxes score of 4 and a Beck Depression Inventory score of 17. The cross-cultural smell identification test revealed anosmia, with only two correct answers out of 12 items. The R-R intervals were reduced in the Valsalva and deep groups. Other autonomic function test results were within the normal ranges. The SNCA mutation p.Ala53Glu (c.158C>A, NM000345.3) was detected by whole-exome sequencing, which was confirmed by Sanger sequencing (Supplementary Figure 1 in the online-only Data Supplement). According to the American College of Medical Genetics and Genomics guidelines, this mutation was classified as likely pathogenic (PS3, PM1, PM2, PM5, and PP2). Visual hallucinations were controlled relatively well with a rivastigmine patch at a dose of up to 13.3 mg/24 hours after the discontinuation of pramipexole and rasagiline. Twelve months after the initial visit to our clinic, her parkinsonian motor signs and cognitive function had further deteriorated despite treatment, with a follow-up MoCA score of 17 and a UPDRS Part III score of 65, with Hoehn and Yahr stage IV. She developed mild levodopa-induced dyskinesia at a levodopa-equivalent daily dose of 1,200 mg.
Representative images of neuroimaging examinations. Brain magnetic resonance images showing no notable abnormalities (A-G). FP-CIT PET image indicating moderate to severe depletion of striatal dopaminergic transporters, which was notably more pronounced on the right (H). FDG PET scans revealing right hemisphere asymmetric hypometabolism (I-L) without striatal involvement. FP-CIT PET, 18F-N-(3- fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane positron emission tomography; FDG PET, 18F-fluorodeoxyglucose positron emission tomography.
Since the initial discovery of the p.A53T mutation, several missense mutations in SNCA (p.H50Q, p.E46K, p.G51D, p. A53V, and p.A53E) have been reported to be causative of familial parkinsonism [1-5]. The p.A53E SNCA mutation was discovered most recently in two ethnic groups, a Finnish population and a mixed Dutch, Scottish, and Irish population (Table 1) [5-7]. Our patient represents the third family and the first East Asian patient with this mutation. The p.A53E SNCA mutation was first discovered in a Finnish patient who was clinically diagnosed with Parkinson’s disease with atypical features [5]. The second patient with a p.A53E SNCA mutation, which was discovered by screening patients with PD, was found to share the haplotype of the mutation, indicating that the patients had a common founder [6]. The first non-Finnish family with PD due to the p.A53E mutation was reported in Canada [7]. Patients in this family initially presented with akinetic rigid symptoms that soon progressed to severe spasticity and myoclonic jerks. The first Finnish and Canadian patients showed atypical motor features, while our patient exhibited the typical motor phenotype of asymmetric parkinsonism, with a good response to levodopa without metabolic changes in the striatum visualized on 18F-fluorodeoxyglucose PET. The early development of levodopa-induced dyskinesia in our patient was not unusual; severe dyskinesia has often been reported in PD patients with SNCA mutations [3,4]. Other atypical features, such as myoclonus and spasticity, which are often reported in PD patients with SNCA mutations, were not observed in our patient [1]. While the Finnish patients did not show cognitive decline, the Canadian families exhibited rapid deterioration in cognitive function, as in our patient. Cognitive impairment and psychiatric disturbances have been frequently observed in patients with previously reported SNCA mutations [2,3]. Previously reported cases of early conversion to dementia with impairment in all cognitive domains in patients with an SNCA A53E mutation reported highly abundant alpha-synuclein pathology throughout the cerebral cortex [6,7]. We believe that the cortical hypometabolism observed on 18F-fluorodeoxyglucose PET in our patient reflects the relevant cortical pathology and neurodegeneration.
Summary of previously reported Parkinson’s disease cases with p.A53E mutation
In conclusion, we report the first case of PD with an A53E SNCA mutation in an East Asian individual, characterized by early conversion to dementia. This case highlights the importance for clinicians to consider the A53E SNCA mutation as a potential cause of familial parkinsonism in East Asian populations.
Supplementary Materials
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24118.
Confirmation of the SNCA p.Ala53Glu (c.158C>A, NM000345.3) mutation by Sanger sequencing.
Notes
Ethics Statement
This study was performed in accordance with the tenets of the Declaration of Helsinki after being approved by the Institutional Review Board and Ethics Committee of the Yongin Severance Hospital (9-2024-0012). Informed consent was obtained from the patient.
Conflicts of Interest
The authors have no financial conflicts of interest.
Funding Statement
This research was supported by a grant of the Korea Health Technology R&D Project through the Korean Healthy Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-00265377).
Author Contributions
Conceptualization: Yun Joong Kim. Data curation: Yeo Jun Yoon, Yun Joong Kim. Formal analysis: Jin Ju Kim, Chan Wook Park, Seok Jong Chung, Yun Joong Kim. Funding acquisition: Yun Joong Kim. Investigation: Chan Wook Park, Yun Joong Kim. Methodology: Chan Wook Park, Yun Joong Kim. Project administration: Yun Joong Kim. Resources: Yun Joong Kim. Software: Chan Wook Park, Jin Ju Kim. Supervision: Yun Joong Kim. Validation: Chan Wook Park, Yun Joong Kim. Visualization: Yeo Jun Yoon, Chan Wook Park. Writing—original draft: Yeo Jun Yoon. Writing—review & editing: Jin Ju Kim, Chan Wook Park, Seok Jong Chung, Yun Joong Kim.
Acknowledgements
None