Bietti’s crystalline dystrophy (BCD) is a rare inherited retinal degenerative disease characterized by progressive night blindness, visual field constriction, and crystalline deposits in the retina and cornea. The disease is caused by mutations in CYP4V2, a gene involved in fatty acid metabolism. Traditionally, BCD has been viewed primarily as an ocular disorder. However, as CYP4V2-targeted gene therapies move into clinical exploration, a new question has become increasingly important: does BCD also involve measurable systemic metabolic changes, and could blood-based markers help monitor disease status and treatment-related metabolic safety?
A new study by researchers from the Eye and ENT Hospital of Fudan University, Shanghai Proton and Heavy Ion Center, and collaborators provides fresh evidence from plasma metabolomics. Using a family-controlled design, the team enrolled 36 genetically confirmed patients with BCD and 49 unaffected first-degree relatives as controls. This design helped reduce the confounding effects of genetic background and shared environmental differences, which can be especially important in rare inherited diseases. Through untargeted liquid chromatography–tandem mass spectrometry-based metabolomic profiling, the researchers found that BCD is associated not only with retinal degeneration, but also with systemic lipid metabolic rewiring, energy-related metabolic stress, and compensatory network changes.
“BCD has often been understood as a retinal degenerative disease, but CYP4V2 itself is involved in fatty acid metabolism, so we wanted to re-examine the disease from a systemic metabolic perspective,” said Prof. Shenghai Zhang of Fudan University. “The family-controlled design helped us reduce the interference of genetic background and shared environmental factors, making the metabolic signals associated with BCD clearer. Our findings suggest that, in the future, assessment of disease progression and gene therapy safety may need to consider not only traditional ophthalmic measures, but also the patient’s systemic metabolic status.”
Metabolomic profiling revealed a clearly distinct plasma lipid signature in BCD patients relative to their unaffected relatives, a separation validated by orthogonal partial least-squares discriminant analysis. The metabolic differences were driven by the disease itself rather than age, sex, or genotype, with over half of all detected lipid features significantly altered across multiple lipid classes. Importantly, lipids annotated as known CYP4V2 substrates accumulated significantly more than non-substrate lipids, supporting the idea that the circulating lipidome reflects the systemic consequences of CYP4V2 enzymatic dysfunction.
The metabolic changes extended beyond lipid accumulation. The researchers also observed secondary disturbances in amino acid and purine metabolism. Branched-chain and aromatic amino acids were systematically depleted, while purine-related metabolites such as AMP, xanthine, and hypoxanthine were elevated, pointing to possible energy stress and accelerated nucleotide catabolism in patients with BCD. Network analysis further revealed an upregulation of metabolites related to the pentose phosphate pathway. In particular, sedoheptulose 7-phosphate shifted from a peripheral node in controls to a highly connected “super-hub” in patients with BCD. Because the pentose phosphate pathway is closely linked to NADPH production and antioxidant defense, this network shift may represent a compensatory response to lipid accumulation and oxidative metabolic stress. However, this interpretation remains a mechanism-based inference from cross-sectional metabolomic and network analyses, and will require targeted flux analysis, isotope tracing, and CYP4V2-knockout cellular or animal models for further validation.
Beyond mapping disease biology, the study identified a candidate blood-based biomarker panel with potential translational value. Individually, AMP and TG (34:1) each showed strong discriminatory performance, with area under the receiver operating characteristic curve (AUC) values of 0.877 and 0.860 respectively; the combined AMP–TG (34:1) panel reached an AUC of 0.957 (95% confidence interval of 0.922–0.993), with bootstrap validation confirming stable performance. The pairing is biologically grounded: AMP reflects cellular energy stress, while TG (34:1) represents systemic lipid accumulation, making the panel biologically interpretable as well as statistically discriminative. This panel carries particular clinical relevance as CYP4V2-directed gene therapies advance into clinical development. Hyperlipidemia has been documented as a treatment-emergent adverse event in prior gene therapy studies, and some BCD patients already present with elevated baseline triglyceride levels. If validated in larger and longitudinal cohorts, blood-based metabolic markers could complement conventional ophthalmic outcome measures, helping support disease-state monitoring, pretreatment risk stratification, and surveillance of systemic metabolic safety during therapeutic intervention.
Overall, this study expands the view of BCD from a retinal disorder to an inherited eye disease accompanied by systemic metabolic rewiring. It suggests that CYP4V2 deficiency may drive specific lipid accumulation, secondary disturbances in amino acid and purine metabolism, and compensatory metabolic network changes. The AMP–TG (34:1) panel offers a candidate blood-based tool for future disease monitoring and gene therapy safety assessment. For this rare retinal degeneration, the findings suggest that understanding disease progression and therapeutic response may require looking not only at the eye, but also at systemic metabolism.
Article information:
Systemic lipid rewiring and compensatory metabolic networks in Bietti’s crystalline dystrophy
Read the full article: https://doi.org/10.1016/j.edisc.2026.100057
About Eye Discovery
Eye Discovery is an open-access, peer-reviewed international academic journal, with ISSN 3117-4167. It is published quarterly by Elsevier and serves as the official journal of Eye & ENT Hospital of Fudan University, China.
Eye Discovery is dedicated to creating a high-end platform for ophthalmologists, scientists, and scholars worldwide to focus on innovative achievements in ophthalmology and interdisciplinary fields, and to promote academic dissemination and exchange.
Website: https://www.sciencedirect.com/journal/eye-discovery
Submit: https://www.editorialmanager.com/edisc/Default.aspx
From 2026 to 2028, the article processing charge ( APC ) will be waived.
Eye Discovery
Observational study
People
Systemic lipid rewiring and compensatory metabolic networks in Bietti’s crystalline dystrophy
18-Aug-2026