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Bietti Crystalline Dystrophy: for professionals

Overview

PrevalenceEstimated at 1 in 67,000 individuals globally; higher in East Asian populations
InheritanceAutosomal recessive
Genes Involved (OMIM No.)CYP4V2 (#210370)
SymptomsProgressive vision loss, nyctalopia, decreased visual acuity, visual field defects, metamorphopsia, scotomas
Ocular FeaturesCrystalline deposits in retina and cornea, chorioretinal atrophy, pigmentary changes, vascular changes, macular involvement, optic disc pallor or atrophy
Systemic FeaturesElevated serum triglycerides, abnormal cholesterol storage
Key InvestigationsOcular:
Optical Coherence Tomography (OCT)
Fundus Autofluorescence (FAF)
Full-field Electroretinogram (ffERG)
Multifocal Electroretinogram (mfERG)
Fluorescein Angiography (FA)

Systemic:
Lipid profile
ManagementOcular:
Regular Monitoring
Anti-VEGF Therapy
Amsler grid
Lifestyle Modifications

Systemic:
Genetic counselling
Family management, and emotional and social support
Current ResearchStudies on lipid metabolism and retinal degeneration

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Clinical phenotype

Bietti crystalline dystrophy (BCD) is a rare autosomal recessive disorder characterised by yellow-white crystalline deposits in the retina and, occasionally, in the cornea. This condition leads to progressive retinal degeneration, ultimately resulting in significant visual impairment.1,2

Presenting features

Ocular:

  • Visual disturbances: Patients often present with nyctalopia, decreased visual acuity, and visual field defects. These symptoms typically manifest between the second and fourth decades of life.3,4
  • Scotomas: Pericentral and mid-peripheral scotomas are typical, indicating regional rod dysfunction.5,6
  • Metamorphopsia: Straight lines may appear wavy or distorted due to retinal changes.

Fundus

  • Crystalline deposits: Yellow-white refractile crystals scattered in the posterior pole of the retina. Occasionally, crystals may also be seen in the peripheral retina and cornea.1,2
  • Chorioretinal atrophy: Progressive degeneration and atrophy of the retinal pigment epithelium (RPE) and choroid. Areas of atrophy often start in the posterior pole and extend to the mid-peripheral retina.
  • Pigmentary changes: RPE changes and pigmentation, which may mimic retinitis pigmentosa. Bone spicule pigmentation can appear in advanced stages.
  • Vascular changes: Attenuation of retinal vessels. Sclerosis of choroidal vessels.
  • Macular involvement: Progressive macular atrophy leading to central vision loss. Macular oedema may be present in some cases.
  • Optic disc: The optic disc may show signs of pallor or atrophy in advanced stages.

Genetics

Gene: Biallelic mutations in the CYP4V2 gene

  • OMIM No.: #210370
  • Inheritance Pattern: Autosomal Recessive
  • Function: CYP4V2 encodes an enzyme involved in fatty acid metabolism. Mutations result in abnormal lipid processing and crystal formation in ocular tissues.6-8

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Optical Coherence Tomography (OCT):
    • Hyper-reflective dots representing crystalline deposits in the choriocapillaris.9,10
    • Retinal tubulations and hyper-refractive structures in the outer nuclear layer.
    • Degeneration most prominent in the outer retina and photoreceptor layers, but not uniformly distributed.
  2. Fundus Autofluorescence (FAF):
    • Useful in monitoring disease progression over time, with hypoautofluorescence corresponding to areas of RPE atrophy. Retinal crystals do not produce autofluorescence.1
  3. Electrophysiological Testing:
    • Full-field Electroretinogram (ffERG):
      • Varying degrees of rod and cone dysfunction.11,12
      • Reduced amplitudes of scotopic and photopic responses.
      • Can remain normal even in later stages.
    • Multifocal Electroretinogram (mfERG):
      • Detects regional retinal dysfunction, especially in the posterior pole.13
  4. Fluorescein Angiography (FA):
    • Highlights areas of choroidal neovascularisation and subretinal leakage.1

Systemic

  1. Lipid Profile:
    • Elevated serum triglycerides and abnormal cholesterol storage may be observed.

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Diagnosis

Diagnosis is based on clinical findings, including the presence of retinal crystals and chorioretinal atrophy, and is confirmed by genetic testing for mutations in the CYP4V2 gene.

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Differential Diagnoses

  • Primary hyperoxaluria
  • Cystinosis
  • Sjögren-Larsson syndrome
  • Drug toxicity

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Management

  • Regular monitoring: Annual ophthalmic examinations to monitor disease progression and detect CNV early.
  • Anti-VEGF therapy: Intravitreal injections (e.g., bevacizumab, ranibizumab) are effective for treating CNV.1
  • Patient education: Use of Amsler grid for self-monitoring of visual distortion.
  • Lifestyle modifications: Encouraging protective measures against light exposure and maintaining regular follow-up appointments.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive comprehensive management of their condition (genetic testing and genetic counselling) and to have the opportunity to participate in clinical research.

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Current research

Ongoing studies aim to better understand the pathophysiology of BCD, focusing on lipid metabolism and its role in retinal degeneration.

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Further information and support

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References

  1. Vargas M, Mitchell A, Yang P, et al. Bietti Crystalline Dystrophy. 2012 Apr 12 [Updated 2019 Feb 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK91457/
  2. Lee KY, Koh AH, Aung T, Yong VH, Yeung K, Ang CL, Vithana EN. Characterization of Bietti crystalline dystrophy patients with CYP4V2 mutations. Invest Ophthalmol Vis Sci. 2005;46:3812-6.
  3. 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.
  4. Xiao X, Mai G, Li S, Guo X, Zhang Q. Identification of CYP4V2 mutation in 21 families and overview of mutation spectrum in Bietti crystalline corneoretinal dystrophy. Biochem Biophys Res Commun. 2011;409:181-6.
  5. 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.
  6. Zhang X, Xu K, Dong B, Peng X, Li Q, Jiang F, Xie Y, Tian L, Li Y. Comprehensive screening of CYP4V2 in a cohort of Chinese patients with Bietti crystalline dystrophy. Mol Vis. 2018;24:700-11.
  7. García-García GP, López-Garrido MP, Martínez-Rubio M, Moya-Moya MA, Belmonte-Martínez J, Escribano J. Genotype-phenotype analysis of Bietti crystalline dystrophy in a family with the CYP4V2 Ile111Thr mutation. Cornea. 2013;32:1002-8.
  8. 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.
  9. Zweifel SA, Engelbert M, Laud K, Margolis R, Spaide RF, Freund KB. Outer retinal tubulation: a novel optical coherence tomography finding. Arch Ophthalmol. 2009;127:1596-602.
  10. Kojima H, Otani A, Ogino K, Nakagawa S, Makiyama Y, Kurimoto M, Guo C, Yoshimura N. Outer retinal circular structures in patients with Bietti crystalline retinopathy. Br J Ophthalmol. 2012;96:390-3.
  11. Usui T, Tanimoto N, Takagi M, Hasegawa S, Abe H. Rod and cone a-waves in three cases of Bietti crystalline chorioretinal dystrophy. Am J Ophthalmol. 2001;132:395-402.
  12. Lockhart CM, Smith TB, Yang P, Naidu M, Rettie AE, Nath A, Weleber R, Kelly EJ. Longitudinal characterisation of function and structure of Bietti crystalline dystrophy: report on a novel homozygous mutation in CYP4V2. Br J Ophthalmol. 2018;102:187-94.
  13. Halford S, Liew G, Mackay DS, Sergouniotis PI, Holt R, Broadgate S, Volpi EV, Ocaka L, Pobson AG, Holder GE, Moore AT, Michaelides M, Webster AR. Detailed phenotypic and genotypic characterization of Bietti crystalline dystrophy. Ophthalmology. 2014;121:1174-84.

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Updated on June 3, 2024
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