2026 American Academy of Neurology Abstract Website

Valentina Quintana¹, Ignacio Keller Sarmiento², Bernabe Bustos², Lara M. Lange³, Katja Lohmann⁴, Roy Alcalay⁵, Huw Morris⁶, Maria J Marti⁷, Njideka Okubadejo⁸, Azlina Ahmad-Annuar⁹, Shen-Yang Lim⁹, Ai Huey Tan⁹, Tzi Shin Toh⁹, Yi Wen Tay⁹, Tatiana Foroud¹⁰, Kelly Nicole Holohan Nudelman¹⁰, Rauan Kaiyrzhanov⁶, Mie Rizig¹¹, Enza M Valente¹², Zied Landoulsi¹³, Beomseok Jeon¹⁴, Neena Cherayil¹⁵, Zih-Hua Fang¹⁶, Andrew Singleton¹⁷, Joanne Trinh¹⁸, Christine Klein¹⁹, Niccolo Mencacci²
¹Universidad Icesi, ²Northwestern University, ³Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, ⁴Institute of Neurogenetics, University of Lübeck, ⁵Columbia University, ⁶University College London, ⁷Parkinson and Movement Disorders Unit, Hospital Clínic of Barcelona, ⁸College of Medicine, University of Lagos, ⁹University of Malaya, ¹⁰Indiana University School of Medicine, ¹¹UCL Queen square Institute of Neurology, ¹²University of Pavia and IRCCS Mondino Foundation, ¹³Luxembourg Institute of Health, ¹⁴Chung-Ang University Health care system, Hyundae Hospital, ¹⁵Northwestern University Memorial Hospital, ¹⁶German Center for Neurodegenerative Diseases (DZNE), ¹⁷Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, ¹⁸Institute of Neurogenetics, University of Lübeck, Lübeck, Germany, ¹⁹University of Luebeck

Objective:

The aim of this study is to investigate the potential link between AFG3L2 rare pathogenic/likely pathogenic variants with Parkinson’s disease (PD).

Background:

AFG3L2 is a mitochondrial metalloprotease and ATPase. Pathogenic variants have been linked to spinocerebellar ataxia type 28 (SCA28), spastic ataxia type 5 (SPAX5), and optic atrophy type 12 (OPA12). Furthermore, several case reports reported movement disorders, including parkinsonism.

Design/Methods:

We analyzed whole-genome sequencing (WGS) data from the 10th release of the Global Parkinson’s Genetics Program (GP2), clinical exome sequencing (CES) from the 8th GP2 release, and whole-exome (WES) data from the UKBiobank. The dataset included 12,375 WGS-GP2, 3,322 WES-UKBiobank, 10,454 CES-GP2 PD patients and 3,531 WGS-GP2; 101,999 WES-UKBiobank healthy subjects (HS). We prioritized pathogenic or likely pathogenic missense variants based on the ACMG using Franklin and LoF variants with gnomAD minor allele frequency (MAF) <1×10⁻². Burden analyses were performed with UKBiobank adjusting for age, sex, and the first 10 principal components.

Results:

A total of 46 variants met the filtering criteria across all datasets. Three recurrent variants (p.G645S, p.P514S, p.A462V) were identified in a total of 8 PD patients. We identified 11 variant PD carriers in WGS-GP2 (frequency 8 × 10⁻4), 12 in CES-GP2 (freq 1.1 × 10⁻³), 8 in WES-UKBiobank (freq 2.4 × 10⁻³), while no variant carriers were observed in GP2-WGS HS. The burden analyses showed a significant enrichment of missense + LoF rare variants in PD cases compared to HS (Fisher’s exact test, p = 0.014; Wald test, p = 0.007, OR = 2.72, 95% CI: 1.31–5.63; SKAT-O, p < 0.004).

Conclusions:

Our findings suggest that pathogenic variants in AFG3L2 may be associated with PD. Comprehensive clinical characterization of variant carriers, detailed familial segregation analyses, burden tests in other curated cohorts, and functional studies are currently underway to conclusively delineate the contribution of AFG3L2 dysfunction to PD pathogenesis.