Heterozygous FBXO7 as potential genetic modifiers in early-onset Parkinson’s disease with levodopa responsive non-motor features

• FBXO7 may play a role as a gene modifier in early-onset Parkinson’s disease • Heterozygous variants may contribute to a non-motor-predominant phenotype • FBXO7 carriers exhibit significant levodopa-responsive autonomic features • Parasympathetic vagal nuclei alterations may underlie central autonomic dysfunction To report a retrospective clinical series of four patients diagnosed with early-onset Parkinson’s disease (EOPD) carrying heterozygous variants of uncertain significance (VUSs) in the FBXO 7 gene. FBXO 7 encodes an F-box-domain-containing protein involved in the mitophagy process, and mutations in this gene have been associated with PARK15, an atypical form of Parkinson’s disease (PD) with an autosomal recessive inheritance pattern. Patients were identified using the Mayo Clinic Data Explorer . All the cases with a heterozygous FBXO 7 variant and a clinical diagnosis of EOPD evaluated at Mayo Clinic between 2017 and 2024 were included. Clinical features, genetic testing, imaging, and treatment data were obtained retrospectively from medical records review. Motor symptoms were assessed using the UPDRS part-III score, and non-motor symptoms were assessed using the NMSS score. Four patients met the inclusion criteria. All exhibited a non-motor predominant phenotype, with significant autonomic features either as an early presentation or as a preeminent component. These features manifested with a broad spectrum of symptoms including sialorrhea, constipation, urinary urgency, orthostatic intolerance and altered heat sensitivity. DaT-scan imaging, available in three of the four cases, was consistent with a PD diagnosis. All patients responded well to levodopa treatment, showing substantial improvement in both motor and non-motor symptoms (NMSS). FBXO 7 may play a role as a phenotypic gene modifier and contribute to the development of EOPD characterized by levodopa-responsive, non-motor-predominant features in heterozygous variant carriers. Specifically, these features appear to be associated with central autonomic dysfunction, particularly affecting the parasympathetic vagal nuclei.