Objective: This study describes a unique case of early-onset Parkinson’s disease (PD) linked to a complex repeat expansion at the FGF14 locus.

Background: While the pure FGF14 (GAA) repeat expansion is a newly identified cause of spinocerebellar ataxia 27B (SCA27B)^1,2, the role of complex (GCA)/(GAA) repeat expansions ((≥300 repeats) as causative mutations in PD remains under-recognized.

Method: We described a patient presenting with typical early-onset PD features. Comprehensive clinical assessments and dopamine transporter imaging (DAT-PET) supported the clinical diagnosis. To investigate a potential genetic etiology, we performed whole-exome sequencing (WES) and targeted long-read sequencing (LRS).

Results: We report a 49-year-old woman with early-onset PD (onset age 37). She presented with right-sided bradykinesia and gait dragging, resting tremor, and sleep disturbances, with reduced left striatal dopamine transporter uptake on DAT-PET. Notably, entacapone initially improved motor symptoms for two hours, but subsequently precipitated severe generalized rigidity, which resolved upon discontinuation. We employed LRS to characterize the FGF14 repeat architecture in a patient with early-onset PD, identifying a complex FGF14 intronic (GCA)/(GAA) repeat expansion (≥300 repeats)³. Sequence analysis demonstrated that the initial segment comprised a (GAA)₂₁-GAG-(GAA)₂₁ motif, featuring a specific (GAG)•(CTC) interruption within the repeat tract. According to the criteria proposed by Zheng et al., the presence of (CTC) or (TCC) interruptions within Segment 1 unequivocally categorizes this allele as a Pattern 1 complex repeat expansion.³ While Pattern 4 is the primary risk factor identified across cohorts, Zheng et al. also observed a significant enrichment of Pattern 1 expansions in certain PD populations (OR=2.56).³ We hypothesize that such (GCA)/(GAA) repeat expansion architectures are prone to forming transcript-level RNA G-quadruplexes (rG4s). Matsuo et al. demonstrated rG4s serve as physical scaffolds accelerating pathological α-synuclein aggregation.⁴ This mechanism may explain her unusual biphasic entacapone response.

Conclusion: Our results suggest that complex (GCA)/(GAA) repeat expansions in FGF14 are a rare cause of early-onset PD. Overall, our study expands the current phenotypic spectrum of FGF14 and underscores the importance of precise genotype-phenotype correlation at this locus.

References: 1.Rafehi H, Read J, Szmulewicz DJ, et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am J Hum Genet. 2023;110(1):105-119. doi:10.1016/j.ajhg.2022.11.015
2.Pellerin D, Danzi MC, Wilke C, et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. New England Journal of Medicine. 2023;388(2):128-141. doi:10.1056/NEJMoa2207406
3.Zheng X, Cen Z, Chen X, et al. A Complex FGF14 (TTC)/(TGC) Repeat Expansion in Parkinson’s Disease. Movement Disorders. n/a(n/a). doi:10.1002/mds.70128
4.Matsuo K, Asamitsu S, Maeda K, et al. RNA G-quadruplexes form scaffolds that promote neuropathological α-synuclein aggregation. Cell. 2024;187(24):6835-6848.e20. doi:10.1016/j.cell.2024.09.037

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MDS Abstracts - https://www.mdsabstracts.org/abstract/complex-fgf14-repeat-expansion-in-early-onset-parkinsons-disease/