Misdiagnosis and Underdiagnosis

• What is BCD often misdiagnosed as?
• Suggestions on how to improve correct diagnosis of BCD
• Doctors’ View
• From the Literature
• Patients’ Experience

What is BCD often misdiagnosed as?

BCD is sometimes described as “sparkling retina” by eye doctors due to the presence of yellow or yellow-white, refractile/shiny crystals and/or complex lipid deposits in the retina (and in some cases also in the cornea).¹ This is a key characteristic of BCD. However, not all BCD patients have this clinical manifestation. In addition, BCD shares similar clinical phenotypes with some other retinal diseases and may be misdiagnosed as: ^{2 3 4 5}

1. Retinitis pigmentosa (RP). The clinical symptoms and findings on visual field testing, electrophysiologic studies, and degeneration of the retinal pigment epithelium (RPE)/choroid in Bietti Crystalline Dystrophy (BCD) are similar to those of other forms of retinal degeneration that fall under the category of retinitis pigmentosa (RP) and allied disorders. In addition, the crystalline deposits in the retina may not be obvious, especially in early- and advanced-stage BCD patients. Therefore, even doctors who have experience in diagnosing BCD may sometimes still misdiagnose BCD.
2. Choroideremia. BCD and choroideremia share the symptom of progressive chorioretinal degeneration. ⁶
3. Other retinal diseases which also have refractile crystal-like deposits in the retina, for example:
   1. Stargardt Disease (SD) group 3
   2. dominant forms of RPE65
   3. RDS – PRPH2 form of retinitis pigmentosa
   4. Other Crystalline Retinopathies. Crystalline deposits in the retina is not unique to BCD and may be associated with the following:
      • Primary hyperoxaluria type 1 and type 2
      • Cystinosis, particularly the more benign adolescent presentation
      • Sjögren-Larsson syndrome
      • Infectious Crystalline Keratopathy
      • Drug toxicity (e.g., tamoxifen, the anesthetic methoxyflurane, the oral tanning agent canthaxanthine)
      • Drug abuse (talc retinopathy)
4. Late-Onset Retinal Degeneration (LORD)
5. Some BCD patients reported that they were advised by the doctors that they do not have an eye disease at all and the crystals or abnormal appearance in their retinae are due to:
   • Pollution, or
   • Unhealthy diet

Suggestions on how to improve correct diagnosis of BCD

1. Diagnosis: See BCD Diagnosis for discussions on BCD symptoms, clinical findings and various imaging techniques (fundus photograph, FAF, OCT, etc.) used in diagnosing BCD. For example, researchers suggest using infrared imaging technique to enhance observation of retinal crystals in BCD. ^{7 8} In particular, hyperreflective appearance on near-infrared reflectance (NIR) imaging has been reported to yield 100% sensitivity and 100% specificity in diagnosing BCD among patients with chorioretinal dystrophy accompanied by crystalline-like deposits; ⁹
2. Refer to specialists: Refer suspected BCD patients to retinal specialists who have seen BCD patients. We have compiled a global list of doctors who have seen BCD patients, see BCD Doctors; and/or
3. Genetic testing: Identification of biallelic mutations in the CYP4V2 gene by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive. Indeed, molecular genetic testing such as next-generation sequencing (NGS) is an invaluable tool for an accurate clinical diagnosis of inherited retinal diseases, including BCD. ^{10 11 12} To date, more than 100 mutations in the CYP4V2 gene has been identified among BCD patients.¹³

Doctors’ View:

From the Literature:

Patients’ Experience: