Objective: Early-onset Parkinson’s disease (EOPD) can be linked to different genetic backgrounds than non-EOPD. Therefore, we evaluated 52 patients with EOPD from 4 hospitals in South Korea who did not have PARK gene mutation in previous tests.

Background: Autophagy pathway is being discussed as one of the cause of Parkinson’s disease (PD).

Method: We select multigene panel sequencing including 26 known autophagy related genes (ATG genes) and 25 genes which were possibly associated with the autophagy pathway (ATG associated genes). We analyzed patients by groups: 1) patients having any variants observed in ATG genes (ULK1, ULK2, ATG2A, ATG2B, ATG3, ATG4A, ATG4B, ATG4C, ATG4D, ATG5, BECN1, ATG7, GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B, ATG9A, ATG9B, ATG12, ATG16L1, ATG16L2, RB1CC1, WIPI1, WIPI2, ATG101), 2) patients having variants only in ATG associated genes(CDKN2A, CHMP2B, CHMP4B, DRAM1, LAMP2, LRSAM1, MAP2K7, MAPK9, MTOR, NOS3, PELI3, PIK3C3, PIK3R4, RAB5A, RAB7A, RAB24, SIRT1, SIRT2, TFEB, TP53, ULK3, UVRAG, VAMP3, WDR45, ZFYVE1); and 3) patients who did not have possibly significant variants in our gene panel. The clinical symptoms were also evaluated with onset age, disease duration, UPDRS, H&Y stage, subtype of PD, cognition, and three nonmotor symptoms.

Results: The onset age, UPDRS motor score, H&Y stage, subtype of PD and cognition (MMSE, K-MoCA, CDR) were no significant difference between three groups. However, REM sleep behavior disorders and disease duration showed difference in EOPD having any variants observed in ATG genes than other 2 groups. We found 26 heterozygous variants of uncertain significance in ATG genes among 22 patients (42.3). The variants were found in ATG2B (6/52, 11.5), ATG2A and ATG9B (each 5/52, 9.6), UNK2 (3/52, 5.8), ATG9A (2/52, 3.8), and ULK1, ATG7, ATG12, RB1CC1, and WIPI2 (each 1/52, 1.9). Twenty-five variants of uncertain significant were found in ATG associated genes [ZFYVE1 (4/52), CDKN2A, MAPK9, PIK3R4 (each 3/52), LRSAM1 (2/52), and other 10 genes (each 1/52). Ten patients (19.2) had variants only in ATG-associated genes without ATG gene variants. Variants in most of ATG-related genes were missense variants and 2 variants were nonsense variants.

Conclusion: Multigene panel tests can be effective at identifying rare variants of autophagy gene in patients with EOPD. Further study must be needed to identify the true causal effect of rare variant of autophagy and autophagy related genes in EOPD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-variants-of-autophagy-genes-of-early-onset-parkinsons-disease/