Objective: To characterize the clinical features of PD associated with CYP gene variants (CYP‑iPD) and parkinsonism observed in other neurodegenerative diseases.

Background: Cytochrome P450 (CYP) enzymes play essential roles in cholesterol metabolism (including CYP7A1, CYP7B1, CYP27A1, and CYP51A1) and function as highly conserved housekeeping catalytic enzymes. Variants in several CYP‑encoding genes have been reported in neurodegenerative disorders such as Parkinson’s disease (PD).

Method: We conducted a single‑center observational cohort study at the department of neurology in the Okinawa Islands, Japan. Participants included individuals with idiopathic PD (iPD; n=227), parkinsonism in cerebrotendinous xanthomatosis (PD‑CTX; n=1), and Gaucher disease (PD‑GD; n=2), recruited between April 2024 and March 2026.

iPD diagnoses were established according to the MDS clinical diagnostic criteria, supplemented by MRI, neuromelanin‑sensitive MRI, assessment of white matter hyperintensities (WMH) using the Fazekas scale (periventricular WMH [PVWMH] and deep subcortical WMH [DSWMH]), and dopamine transporter SPECT (DAT‑SPECT).

Targeted gene sequencing using short‑read next‑generation sequencing was performed.

Results: Variants were identified in four families with iPD (CYP7B1, VPS13B, ATP13A2, and APOE ε3, respectively). The PD‑CTX case carried a pathogenic CYP27A1 variant, and two PD‑GD families carried GBA and CYP51A1 variants.

PVWMH, thought to reflect subependymal gliosis and patchy demyelination, and DSWMH, associated with atherosclerosis and axonal loss, were observed at moderate to severe levels in 35.5% and 17.7% of participants, respectively.

The estimated incidence of CYP‑related PD was low (0.21 per 100,000 person‑years). Several families exhibited diffuse CNS involvement, and some relatives developed additional neurological disorders such as spastic paraplegia (SPG5), associated with the same variants.

Conclusion: CYP‑iPD and CYP‑related parkinsonism may present with progressive CNS involvement potentially linked to altered cholesterol metabolism.

Ethical Compliance Statement: This study was approved by the ethics committees of our hospital, the Kazusa DNA Research Institute, Juntendo University, and Kagoshima University. We thank our patient and her family for their generous permission for publication.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/variants-in-cytochrome-p450-encoding-genes-associated-with-parkinsons-disease/