Bietti Crystalline Dystrophy

Key Points at a Glance

Key Points of This Disease

• An autosomal recessive chorioretinal dystrophy caused by biallelic mutations in the CYP4V2 gene.
• Yellow-white crystalline deposits appear in the retina, and 25-50% of patients also have crystals at the corneal limbus.
• Patients notice night blindness and vision loss in their 20s-30s, with progressive expansion of chorioretinal atrophy.
• High incidence in East Asians (Chinese, Japanese, Korean)
• Can cause complications such as choroidal neovascularization, cystoid macular edema, and macular hole
• Currently no curative treatment; management focuses on complication control and follow-up
• Clinical trials of gene replacement therapy using AAV2 vector are ongoing

1. What is Bietti crystalline dystrophy?

Bietti crystalline dystrophy (BCD) is an autosomal recessive chorioretinal dystrophy caused by biallelic mutations in the CYP4V2 gene ¹⁾. It was first reported in 1937 by Italian ophthalmologist G.B. Bietti in three patients ¹⁾.

CYP4V2 encodes an enzyme belonging to the cytochrome P450 family, and more than 100 mutations have been identified to date ¹⁾. The prevalence of BCD is high in East Asians (Chinese, Japanese, Korean), and gene frequency analysis estimates it at approximately 1 in 67,000 ¹⁾.

Visual impairment often begins in the 20s to 40s. Some patients progress to severe visual impairment and legal blindness in their 50s to 60s.

2. Main symptoms and clinical findings

Subjective symptoms

The initial symptoms of BCD are often noticed in the 20s to 30s ¹⁾.

• Night blindness (nyctalopia): Impaired vision in dark environments due to rod dysfunction is often the initial symptom
• Progressive vision loss: Gradually worsens with progression of chorioretinal atrophy
• Visual field defects: May cause peripheral visual field constriction and central scotoma
• Color vision abnormalities: May be observed in advanced cases

The rate of symptom progression varies greatly between eyes and among individuals ¹⁾.

Clinical Findings

The fundus findings of BCD are classified into three stages according to the Yuzawa classification ¹⁾.

Early Stage

Retinal crystals: Numerous yellowish-white crystalline deposits are observed in the posterior pole.

RPE changes: Mild RPE irregularity and depigmentation are scattered.

Choroid: No obvious atrophy is observed.

Intermediate Stage

Crystal expansion: The deposition area extends to the equator.

RPE atrophy: Geographic RPE atrophy appears in the posterior pole.

Choroidal sclerosis: Choroidal vessels become sclerotic and narrowed.

Advanced Stage

Extensive atrophy: Chorioretinal atrophy extends from the posterior pole beyond the equator.

Crystal reduction: Crystals decrease and disappear as atrophy progresses.

Exposure of large choroidal vessels: Large vessels become visible due to severe atrophy of the RPE and choriocapillaris.

In the advanced stage, a characteristic finding is the decrease in crystals as atrophy progresses, and this trend has been confirmed in a 13-year long-term follow-up ⁶⁾.

Yellow-white crystals may be observed in the subepithelial and anterior stroma of the corneal limbus, seen in 25–50% of patients ¹⁾. It is reported to be more frequent in patients of Nordic descent. Similar crystal deposits have also been reported in the lens ¹⁾.

In consanguineous families, crystal deposits in the cornea and retina have been reported not only in affected individuals but also in family members ⁵⁾. Additionally, systemic lipid metabolism abnormalities such as elevated serum cholesterol, LDL, and triglycerides may be present ⁵⁾.

Q Are corneal crystals seen in all BCD patients?

A

Corneal crystals are not present in all cases; reports indicate they are found in 25–50% of patients ¹⁾. Since CYP4V2 expression in the cornea is limited, BCD cannot be ruled out even without corneal crystals. Diagnosis is primarily based on retinal findings and genetic testing.

3. Causes and Risk Factors

CYP4V2 Gene Mutation

The causative gene for BCD is CYP4V2 (chromosome 4q35), identified by Li et al. in 2004 ¹⁾. CYP4V2 encodes cytochrome P450 family 4 subfamily V member 2, which is involved in the ω-hydroxylation of fatty acids ¹⁾. More than 100 mutations have been reported to date ¹⁾.

The most frequent mutation in Asian populations is c.802-8_810delinsGC, accounting for a high proportion of patients in Japan, China, and Korea ¹⁾³⁾. In Brazilian patients, a novel mutation c.1169G>T (p.Arg390Leu) has been identified, and a mutation at the same site, c.1169G>A (p.Arg390His), has also been reported ³⁾⁴⁾.

Risk Factors

• Ethnic background: Higher incidence in East Asians (Chinese, Japanese, Korean) ¹⁾
• Consanguineous marriage: As an autosomal recessive disorder, consanguinity increases the risk of homozygous mutations ⁵⁾
• Family history: Carrier testing is recommended if there are affected first-degree relatives.

About Genetic Counseling

If diagnosed with BCD, genetic counseling for family members is available. Genetic testing to determine carrier status can also be performed. Please consult your doctor or genetic counselor when considering family planning.

Q How is BCD inherited?

A

BCD is inherited in an autosomal recessive pattern. If both parents are carriers of a CYP4V2 mutation, there is a 25% chance that a child will develop the disease. If only one parent is a carrier, the child will not develop the disease, but there is a 50% chance that the child will be a carrier.

4. Diagnosis and Testing Methods

Fundus Examination

The basis of diagnosis is the identification of characteristic findings on fundus examination. The triad of yellowish-white crystalline deposits in the retina, RPE atrophy, and choroidal vascular sclerosis is observed ¹⁾. Crystals at the corneal limbus also aid in diagnosis.

Imaging Tests

Multimodal imaging is useful for evaluating BCD ¹⁾.

Test Method	Main Evaluation Items	Characteristic Findings
Optical Coherence Tomography (OCT)	Retinal Structure	Hyperreflective dots, ORT
Optical Coherence Tomography Angiography (OCTA)	Choroidal Vessels	Decreased capillary density
FAF	RPE function	Hyper/hypoautofluorescence pattern

• OCT (Optical Coherence Tomography): Depicts hyperreflective dots (corresponding to crystals) within the retina, outer retinal tubulation (ORT), and disruption or loss of the ellipsoid zone (EZ)¹⁾. In advanced cases, thinning of the outer retina becomes prominent.
• OCTA (Optical Coherence Tomography Angiography): Can quantitatively evaluate decreased blood flow density in the choriocapillaris¹⁾.
• Fundus Autofluorescence (FAF): Shows hypoautofluorescence in areas of RPE atrophy and a hyperautofluorescent ring at the border of atrophy, useful for assessing progression of atrophy¹⁾.
• AOSLO (Adaptive Optics Scanning Laser Ophthalmoscopy): Can visualize crystal deposits at the cellular level and has revealed the presence of cyst-like structures not captured by conventional OCT³⁾.

Electroretinography (ERG)

Electroretinography is essential for evaluating rod and cone function. In BCD, the amplitudes of a-waves and b-waves under scotopic (rod system) and photopic (cone system) conditions are reduced¹⁾⁵⁾.

Genetic Testing

When clinical findings are unclear, sequencing of CYP4V2 can provide a definitive diagnosis¹⁾⁴⁾.

Differential Diagnosis

• Retinitis pigmentosa
• Cystinosis
• Primary hyperoxaluria
• Drug-induced crystalline retinopathy (tamoxifen, canthaxanthin, etc.)

5. Standard Treatment

Currently, there is no established curative treatment for BCD ¹⁾. The mainstay of treatment is management of complications and monitoring of progression. Regular ophthalmic examinations at least once a year are recommended.

Management of Complications

Choroidal Neovascularization

Treatment: Intravitreal injection of anti-VEGF agents is effective ¹⁾.

Pediatric case: A report described a favorable outcome in a 15-year-old boy after a single injection of ranibizumab ²⁾. This was the first pediatric anti-VEGF treatment for BCD-associated MNV ²⁾.

Cystoid Macular Edema

Treatment: Carbonic anhydrase inhibitors (oral acetazolamide, topical dorzolamide) are used ¹⁾.

Mechanism: This is non-vascular edema, thought to involve Müller cell dysfunction ¹⁾.

Macular Hole

Characteristics: A rare complication; a report described development of an asymptomatic full-thickness macular hole during 13 years of follow-up ⁶⁾.

Treatment strategy: If asymptomatic and the fovea is preserved, surgical indication should be carefully considered ⁶⁾.

Importance of Follow-up

BCD is a slowly progressive disease, but complications such as choroidal neovascularization and macular edema can cause relatively rapid vision loss. Continue regular check-ups and seek early medical attention if symptoms change.

Low Vision Care

For patients with progressive visual impairment, referral to a low vision specialist and use of assistive devices are important.

Q If choroidal neovascularization (MNV) is found, how is it treated?

A

Intravitreal injection of anti-VEGF drugs is the standard treatment, and efficacy has been reported not only in adults but also in pediatric cases ²⁾. Early detection through regular monitoring with OCT/OCTA is important.

6. Pathophysiology and Detailed Pathogenesis

CYP4V2 has fatty acid ω-hydroxylase activity, producing dicarboxylic acids by hydroxylating the terminal carbon of saturated medium-chain fatty acids ¹⁾. It is also involved in the conversion of fatty acid precursors to n-3 polyunsaturated fatty acids (n-3 PUFAs) ¹⁾.

When CYP4V2 mutations reduce these enzyme activities, abnormalities occur in lipid binding, elongation, and desaturation ¹⁾. As a result, cholesterol and cholesterol esters accumulate in the cells of the retina, cornea, and conjunctiva, depositing as crystals ¹⁾.

The CYP4V2 gene is highly expressed in the RPE, but also in the heart, brain, lung, liver, kidney, and lymphocytes ¹⁾. Since lipid inclusions have been confirmed in skin fibroblasts and lymphocytes, it is suggested that systemic lipid metabolism abnormalities may exist ¹⁾. However, the clinical phenotype is limited to the eyes.

AI-based 3D protein structure analysis of CYP4V2 variants shows that mutations cause structural changes in the heme-binding site, leading to loss of enzyme function ³⁾.

7. Latest Research and Future Perspectives

For patients: Please read carefully

The following content is currently at the research stage or in clinical trials, and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

Gene Replacement Therapy

For BCD, gene therapy using subretinal injection of an AAV vector carrying the human CYP4V2 gene is being studied ¹⁾.

Wang et al. evaluated the safety and efficacy of subretinal injection of a recombinant AAV2/8-CYP4V2 vector in a first-in-human clinical trial with 12 participants. No treatment-related serious toxicity was reported, and 77.8% of treated eyes showed improvement in BCVA by day 180 ¹⁾.

Multiple clinical trials are currently underway, with NCT04722107 and NCT05694598 registered ³⁾. Basic research using animal models (mice, zebrafish) and iPSCs is also being conducted in parallel ¹⁾.

Advanced Imaging Diagnostics

Kumar et al. (2025) discovered cyst-like structures in the BCD retina using deep phenotyping with AOSLO (adaptive optics scanning laser ophthalmoscopy), which were not detectable by conventional OCT ³⁾. These structures are independent of crystal deposits and may represent a novel degenerative finding specific to BCD.

The combination of AI-based 3D protein structure prediction and AOSLO for genotype-phenotype analysis is an approach that may contribute to improved clinical diagnostic accuracy and the development of biomarkers for disease progression ³⁾.

Q When will gene therapy become available?

A

As of 2025, multiple clinical trials are ongoing, and early results are promising ³⁾. However, the timing for availability as a general treatment has not been determined. Please consult your physician for the latest information.

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8. References

1. Saatci AO, Ata F, Çetin GO, Kayabaşı M. Diagnostic and Management Strategies of Bietti Crystalline Dystrophy: Current Perspectives. Clin Ophthalmol. 2023;17:953-967.
2. Kayabaşı M, Ata F, Saatci AO. Unilateral macular neovascularization formation during the follow-up of a 15-year-old boy with Bietti crystalline dystrophy and the successful treatment outcome with a single intravitreal ranibizumab injection. GMS Ophthalmol Cases. 2023;13:Doc06.
3. Kumar A, Sun YJ, Rasmussen DK, et al. Enhanced genotype-phenotype analysis using multimodal adaptive optics and 3D protein structure in Bietti Crystalline Dystrophy. Am J Ophthalmol Case Rep. 2025;38:102312.
4. da Palma MM, Motta FL, Salles MV, et al. Expanding the Phenotypic and Genotypic Spectrum of Bietti Crystalline Dystrophy. Genes. 2021;12(5):713.
5. Garli M, Aydin Kurna S. A case of Bietti crystalline dystrophy with clinical, electrophysiological, and imaging findings. North Clin Istanb. 2021;8(5):521-524.
6. Saatci AO, Kayabaşı M, Avci R. Asymptomatic Unilateral Full-Thickness Macular Hole in a Patient with Bietti Crystalline Dystrophy During 13-Year Follow-up with Optical Coherence Tomography. Turk J Ophthalmol. 2022;52:212-215.
7. Wang J, Zhang J, Yu S, et al. Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial. Signal Transduct Target Ther. 2024;9:1-10.
8. 日本眼科学会. 網膜色素変性診療ガイドライン. 日眼会誌.