Objective: To provide an updated overview of Parkinson’s disease (PD) associated with E46K mutation carriers in the SNCA gene 20 years after its description, incorporating data from  clinical, imaging, neurophysiological and biomarker studies

Background: The E46K mutation alters alpha-synuclein polarity, causing aggressive autosomal PD with early-onset parkinsonism, autonomic dysfunction, REM disorder, and cognitive decline. Global cases over two decades confirm its dominant inheritance

Method: We conducted a longitudinal analysis of symptomatic and asymptomatic carriers of the E46K mutation. Polysomnographic recordings were assessed. Autonomic dysfunction was examined using cardiac MIBG scintigraphy and non-invasive quantitative measures for hemodynamic function including Valsalva maneuver, deep breathing and tilt table test. Neuroimaging techniques such as MRI and nuclear medicine studies, were employed to assess structural and functional changes.  CSF and serum measurements of α-synuclein, NfL, and GFAP we tested, cognitive function was monitored through serial neuropsychological testing

Results: In some patients, RBD were detected years before motor symptoms and progressively worsening into severe sleep fragmentation and complete loss of REM phases. Two individuals initially met criteria for pure autonomic failure (PAF) before developing PD in their 50s. Myocardial sympathetic denervation was severe and progressively worsened in all symptomatic, particularly in older onset patients. In younger patients, olfactory deficits and RBD preceded cardiac sympathetic denervation. Cognitive impairment emerged approximately 8–9 years after PD diagnosis, with early visuospatial deficits and hallucinations. Variable penetrance was observed, with 2 carriers remaining asymptomatic despite prolonged follow-up. Symptomatic carriers exhibited reduced CSF α-synuclein levels, whereas those who progressed to dementia showed elevated serum NfL and GFAP levels

Conclusion: E46K-related PD represents a continuum between autonomic dysfunction, parkinsonism and LBD, demonstrating unique progression patterns and phenotypic variability. Longitudinal data highlight RBD, autonomic dysfunction, and olfactory deficits as early indicators, supporting their potential role as prodromal biomarkers. Monitoring and studying these cases will help us identify underlying genetic, epigenetic, environmental or pharmacological factors which may be tractable

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-pd-associated-with-the-e46k-mutation-in-the-snca-gene-twenty-years-after/