Expanding the Clinical and Mutational Spectrum of FBXO7-Related Parkinsonism: A Novel Italian Family and Comprehensive Literature Review.

BACKGROUND

Mutations in the FBXO7 gene (PARK15) cause an autosomal recessive, early-onset neurodegenerative disorder typically presenting as Parkinsonian-Pyramidal Syndrome (PPS). Despite its recognition, the high phenotypic variability often delays diagnosis. Here, we report a novel Italian family and synthesize data from all published cases to date, offering an updated clinical and molecular overview of the disease.

METHODS

We performed clinical and molecular characterization of a newly identified family. Furthermore, we conducted a systematic literature review (from 2008 to 2026) to aggregate clinical, genetic, and geographic data of all reported PARK15 cases.

RESULTS

Two siblings presented with a complex phenotype including early-onset parkinsonism, cognitive decline, psychiatric symptoms, and aphasia-type speech disorders. Genetic analyses identified two novel likely pathogenic variants: a missense substitution in the UBL domain (p.Ile74Met) and a frameshift indel (p.Val233GlufsTer8). The literature review (incorporating clinical data from Europe, Asia, and South America) confirms a high prevalence of postural instability (87.5%), bradykinesia (83.3%), and pyramidal signs (~60%). We observed a distinct distribution of variants: missense mutations cluster in the N-terminal UBL and F-box domains, while truncating variants are more common in the C-terminal region.

DISCUSSION: Our findings expand the FBXO7 mutational landscape and underscore the "atypical" clinical markers, such as pyramidal signs and cognitive decline, that distinguish PARK15 from other recessive forms of parkinsonism like PARK2 and PARK6. The dual role of FBXO7 in mitochondrial quality control and proteasomal assembly suggests a broad disruption of cellular homeostasis. These observations refine genotype-phenotype correlations and may guide variant interpretation in routine diagnostic settings.