Bietti Crystalline Dystrophy

Bietti Crystalline Dystrophy (BCD) is a rare, inherited eye disease that causes progressive vision loss. It is characterized by the buildup of tiny, yellow or white crystal-like deposits of fatty compounds in the retina (the light-sensitive tissue at the back of the eye) and sometimes in the clear front part of the eye (the cornea). These deposits damage the cells of the retina over time, leading to vision problems. Patients with BCD typically begin to notice symptoms in their teens or twenties, though it can start later. The most common early signs are difficulty seeing in dim light or at night (night blindness) and a gradual loss of side (peripheral) vision. As the disease progresses, central vision may also become blurry or distorted, and color vision can be affected. The rate at which vision declines varies from person to person, but many individuals eventually become legally blind by their fifties or sixties. BCD is a genetic condition passed down from parents to their children. Currently, there is no cure for BCD, but regular eye exams are important to monitor the disease and manage any complications. Low vision aids and specialized services can help patients maximize their remaining sight and maintain their independence. Researchers are actively studying the disease, and clinical trials for potential treatments, such as gene therapy, are ongoing.

Condition category: Retinal Dystrophy

Prevalence: Rare, exact prevalence unknown, but estimated to be higher in East Asian populations.

Inheritance patterns: Autosomal Recessive

Age of onset: Typically during the second to third decade of life (range: early teens to >3rd decade), though onset can occur beyond the third decade.

Clinical overview: Bietti Crystalline Dystrophy (BCD) is a rare, progressive, autosomal recessive tapetoretinal degeneration characterized by the presence of numerous small, glistening yellow-white crystalline lipid deposits in the posterior pole of the retina. These deposits are often accompanied by similar crystals in the corneal limbus, progressive atrophy of the retinal pigment epithelium (RPE) and choriocapillaris, pigment clumping, and sclerosis of the choroidal vessels. Clinically, BCD manifests with symptoms similar to those of retinitis pigmentosa, including progressive night blindness (nyctalopia), visual field loss (such as paracentral or central scotomas), and a gradual reduction in visual acuity. The onset of symptoms typically occurs in the second or third decade of life, and the disease progressively leads to severe visual impairment, often resulting in legal blindness by the fifth or sixth decade. The condition is caused by biallelic mutations in the CYP4V2 gene, which is involved in lipid metabolism. This genetic defect leads to systemic abnormalities in lipid processing, resulting in the characteristic crystalline deposits not only in ocular tissues but also in circulating lymphocytes and fibroblasts. BCD is classified under OMIM #210370 (phenotype) and OMIM *608614 (gene), and its Orphanet number is ORPHA:41751.

Patient and family guide: Bietti Crystalline Dystrophy (BCD) is a rare, inherited eye disease that causes progressive vision loss. It is characterized by the buildup of tiny, yellow or white crystal-like deposits of fatty compounds in the retina (the light-sensitive tissue at the back of the eye) and sometimes in the clear front part of the eye (the cornea). These deposits damage the cells of the retina over time, leading to vision problems. Patients with BCD typically begin to notice symptoms in their teens or twenties, though it can start later. The most common early signs are difficulty seeing in dim light or at night (night blindness) and a gradual loss of side (peripheral) vision. As the disease progresses, central vision may also become blurry or distorted, and color vision can be affected. The rate at which vision declines varies from person to person, but many individuals eventually become legally blind by their fifties or sixties. BCD is a genetic condition passed down from parents to their children. Currently, there is no cure for BCD, but regular eye exams are important to monitor the disease and manage any complications. Low vision aids and specialized services can help patients maximize their remaining sight and maintain their independence. Researchers are actively studying the disease, and clinical trials for potential treatments, such as gene therapy, are ongoing.

Symptoms and clinical features: The clinical presentation of Bietti Crystalline Dystrophy (BCD) typically begins in the second or third decade of life, though onset can vary. Early symptoms predominantly include progressive nyctalopia (night blindness) and a gradual reduction in visual acuity. Patients may also begin to experience visual field loss, which can manifest as peripheral field loss (ring, paracentral, or central scotoma). At this stage, the characteristic small, glistening yellow-white crystalline deposits are visible scattered throughout the posterior pole of the retina, and sometimes in the corneal limbus. As the disease progresses to the intermediate stages, the visual deficits become more pronounced. The reduction in visual acuity continues, and the visual field loss expands. Impairment of color vision may also become apparent, particularly if atrophic lesions encroach on the fovea or if cystoid macular edema develops. The crystalline deposits in the retina may begin to diminish or disappear in areas where severe chorioretinal atrophy has occurred, while remaining visible in areas that are still mildly degenerated. In the advanced stages of BCD, patients typically experience profound vision loss, often resulting in legal blindness by the fifth or sixth decade of life. The visual acuity can range from severely reduced to hand motion only, although central vision can sometimes be spared even in severe cases. The fundus appearance in late stages is characterized by extensive atrophy of the retinal pigment epithelium and choriocapillaris, pigment clumping, and sclerosis of the choroidal vessels, with few or no crystalline deposits remaining in the severely atrophic areas.

Molecular pathology: The pathophysiology of Bietti Crystalline Dystrophy involves biallelic pathogenic variations in the CYP4V2 gene, which encodes a member of the cytochrome P450 family of enzymes. The CYP4V2 enzyme is known to play a role in fatty acid and steroid metabolism. Dysfunctional lipid metabolism resulting from CYP4V2 mutations leads to the systemic accumulation of fatty acids and the formation of complex lipid deposits in crystalline form. These lipid inclusions are found intracellularly in the retina, cornea, and conjunctiva, as well as systemically in circulating lymphocytes and skin fibroblasts. The accumulation of these crystalline lipid deposits in the retinal pigment epithelium (RPE) and choriocapillaris is associated with progressive atrophy of these layers, pigment clumping, and sclerosis of the choroidal vessels. The exact mechanism by which these lipid deposits lead to cellular toxicity and subsequent chorioretinal degeneration remains to be fully elucidated, but it ultimately results in the progressive loss of photoreceptor function and visual impairment characteristic of the disease.

Genetics: Bietti Crystalline Dystrophy is inherited in an autosomal recessive pattern. The condition is caused by biallelic pathogenic variants in the CYP4V2 gene, located on chromosome 4q35. Carrier testing and genetic counseling are recommended for at-risk relatives. The CYP4V2 gene is the only known causative gene for BCD. Numerous mutations have been identified, including the most common pathogenic variant in individuals of Chinese ancestry, c.802-8_810delinsGC. Other reported variants include c.1091-2A>G and c.332T>C (p.Ile111Thr), the latter of which has only been reported in European individuals. Genotype-phenotype correlations suggest that individuals who are homozygous or compound heterozygous for the c.802-8_810delinsGC variant tend to have an earlier age of onset and more severe disease based on electrophysiologic testing. The c.332T>C variant may be associated with an unusual central and paracentral corneal distribution of crystalline deposits, potentially indicating a dose-dependent phenotype. However, the high degree of clinical variability in BCD, even among individuals with the same CYP4V2 pathogenic variants, suggests the influence of other genetic or environmental modifying factors.

Diagnostic evaluation: Diagnosis of Bietti Crystalline Dystrophy (BCD) is primarily based on ophthalmic evaluation revealing numerous small glistening yellow-white crystalline deposits in the retina, with or without similar deposits in the cornea. These findings are accompanied by retinal pigment epithelium (RPE) atrophy, pigment clumping, and choroidal vessel sclerosis. Corneal crystals, typically isolated in the subepithelial and anterior stroma of the peripheral cornea, are detected in up to 50% of patients and appear more frequently in those of northern European descent. Clinical diagnostic workup includes spectral domain optical coherence tomography (OCT), which is valuable for identifying hyper-reflective dots representing crystalline deposits, primarily residing in the RPE-choriocapillaris complex. OCT also reveals outer retinal degeneration and other reflective spots such as retinal tubulation. Full-field electroretinography (ffERG) shows varying degrees of rod and cone dysfunction, ranging from normal to severely reduced amplitudes, though it is more likely to be abnormal in mid- to late-stage disease. Multifocal ERG (mfERG) can detect regional areas of abnormal retinal function earlier in the disease course. Fundus autofluorescence (FAF) is useful for monitoring disease extent and progression, with regions of RPE atrophy showing decreased autofluorescence. Visual field testing typically reveals progressive peripheral field loss (ring, paracentral, or central scotoma). If clinical features are equivocal, the diagnosis can be confirmed through molecular genetic testing to identify biallelic pathogenic variants in the CYP4V2 gene. Differential diagnosis includes other crystalline retinopathies such as retinitis pigmentosa, primary hyperoxaluria, cystinosis, and drug toxicity (e.g., tamoxifen, talc).

Differential diagnosis: Differential diagnosis of Bietti crystalline dystrophy includes: (1) Cystinosis — crystalline deposits in cornea and conjunctiva, systemic disease, CTNS mutations. (2) Oxalosis — crystalline retinopathy with renal failure, calcium oxalate deposits. (3) Tamoxifen retinopathy — crystalline macular deposits, medication history. (4) Talc retinopathy — intravenous drug use history, refractile deposits in small vessels. (5) Sjögren-Larsson syndrome — crystalline macular deposits with ichthyosis and spastic diplegia. (6) Primary hyperoxaluria — crystalline retinopathy with renal stones and renal failure.

Natural history: The onset of Bietti Crystalline Dystrophy typically occurs during the second or third decade of life, though it can range from the early teens to beyond the third decade. The presenting symptoms, rate of disease progression, and disease severity are highly variable, even among individuals of the same age, within the same family, and with the same genetic variants. The disease is characterized by a progressive reduction in visual acuity, nyctalopia (night blindness), and visual field loss. In the early or milder stages, affected individuals may retain sufficient vision to drive. However, as the disease progresses, the loss of peripheral visual field and/or central acuity typically results in legal blindness by the fifth or sixth decade of life. Interestingly, the crystalline deposits in the retina have been observed to diminish or even disappear in areas of severe chorioretinal atrophy as the disease advances to later stages. Central vision can sometimes be spared even in persons with severe disease, though loss of central visual acuity often reflects atrophy or degenerative changes close to or including the fovea.

Management and treatment research: ### Current management and supportive care There is currently no cure for Bietti crystalline dystrophy (BCD). Care focuses on monitoring vision and retinal health, managing complications when possible, and supporting independence as vision changes. - Regular follow-up with an ophthalmologist, ideally a retina specialist, can help monitor retinal changes and remaining vision. Visit schedules are individualized. - Some people develop potentially treatable complications, including cystoid macular edema (fluid buildup in the central retina), macular holes, or choroidal neovascularization (CNV). CNV involves abnormal blood vessels growing beneath the retina. - CNV may be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) medicines. These injections can reduce leakage from abnormal blood vessels. - Low-vision rehabilitation can help people make the most of remaining vision. Services may include magnifiers, electronic visual aids, lighting recommendations, orientation and mobility training, and workplace or school accommodations. - Genetic testing can identify disease-causing variants in **CYP4V2**, the gene most commonly associated with autosomal recessive BCD. Genetic counseling can help families understand inheritance, testing options for relatives, and family-planning considerations. ### Approved therapies No gene therapy or other disease-modifying treatment is currently approved specifically for Bietti crystalline dystrophy. ### Investigational gene therapies Several gene-based treatments are being studied in BCD. These treatments remain investigational and have not been established as safe or effective for routine clinical use. - **VGR-R01** is an adeno-associated virus (AAV) gene-augmentation therapy designed to deliver a functional copy of **CYP4V2** to retinal cells. - A Phase 3 study in China is ongoing but not recruiting (**NCT06699108**). - A Phase 1 safety and tolerability study is active but not recruiting (**NCT05694598**). - A Phase 1/2 study evaluating treatment of the other eye after initial dosing is not yet recruiting (**NCT07586306**). - **ZVS101e** is being studied in BCD in several clinical trials. - A Phase 3 efficacy and safety study is active but not recruiting (**NCT06743646**). - A Phase 1/2 safety and efficacy study is active but not recruiting (**NCT05832684**). - Another study is not yet recruiting (**NCT07653971**). - An extended-treatment compassionate administration program is enrolling by invitation only (**NCT07307469**). - **NGGT001** is being evaluated for Bietti crystalline corneoretinal dystrophy, a term also used for BCD in some research settings. - An early-phase safety and efficacy study is active but not recruiting (**NCT06302608**). - A Phase 1/2 safety and efficacy study is active but not recruiting (**NCT06706427**). ### Considering clinical trials Eligibility for a BCD clinical trial may depend on genetic test results, retinal structure, remaining vision, age, location, and prior treatments. Recruitment status may change, and some studies may be limited to specific sites or invitation-only participation. A retina specialist can help review whether a study may be appropriate and discuss potential risks, possible benefits, follow-up requirements, and travel considerations.

Outlook: The prognosis for Bietti Crystalline Dystrophy is generally poor regarding long-term visual outcomes, as there is currently no known cure for the disease. The progressive loss of peripheral visual field and central visual acuity typically results in legal blindness by the fifth or sixth decade of life. However, the rate of progression and severity of visual impairment can vary widely among affected individuals, and central vision may be spared until the late stages of the disease in some cases. Quality of life is significantly impacted as the disease progresses, affecting the ability to perform daily activities such as driving, reading, and navigating in low light. Supportive management, including referral to low vision specialists and the use of visual aids, is crucial for helping patients maximize their remaining vision and maintain independence. Regular monitoring is also necessary to manage potential complications such as choroidal neovascularization or macular edema, which can further compromise vision.

Epidemiology: Bietti Crystalline Dystrophy is generally considered a rare disease, but it may be underdiagnosed. It is estimated to account for up to 3% of individuals initially diagnosed with retinitis pigmentosa (RP) and approximately 10% of those with autosomal recessive RP. Based on the worldwide prevalence of RP, the prevalence of BCD is estimated to be up to 1 in 67,000 individuals. The condition appears to be more common in people of East Asian descent, particularly among Chinese and Japanese populations. However, individuals of European, Middle Eastern, African, and North and South American origin have also been reported. Corneal deposits may be more common in patients of northern European background compared to those of Asian descent.

Selected references: 1. Bietti G. Ueber familiaeres Vorkommen von 'Retinitis punctata albescens' (verbunden mit 'Dystrophia marginalis cristallinea corneae'), Glitzern des Glaskoerpers und anderen degenerativen Augenveraenderungen. Klin Monatsbl Augenheilkd. 1937;99:737-757. 2. Lin J, Nishiguchi KM, Nakamura M, Dryja TP, Berson EL, Miyake Y. Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy. J Med Genet. 2005;42(6):e38. PMID: 15937078 3. Lee J, Jiao X, Hejtmancik JF, et al. The metabolism of fatty acids in human Bietti crystalline dystrophy. Invest Ophthalmol Vis Sci. 2001;42(8):1707-14. PMID: 11431433 4. Garcia-Garcia GP, Martinez-Rubio M, Moya-Moya MA, Perez-Santonja JJ, Escribano J. Current perspectives in Bietti crystalline dystrophy. Clin Ophthalmol. 2019;13:1379-99. PMID: 31440026 5. Wang J, Zhang J, Yu S, et al. Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial. Sig Transduct Target Ther. 2024;9:95. PMID: 38632258 6. Vargas M, Mitchell A, Yang P, Weleber R. Bietti Crystalline Dystrophy. GeneReviews. 2012. PMID: 23152994 7. Mataftsi A, Zografos L, Mermoud A, Munier FL. Bietti's crystalline corneoretinal dystrophy: a cross-sectional study. Graefes Arch Clin Exp Ophthalmol. 2004;242(6):459-65. PMID: 15150686