Misdiagnosis and Underdiagnosis

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. 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:

“I believe BCD is underdiagnosed.”
Prof Dr med Francis Munier
Switzerland

“I believe that BCD is commoner than thought due to misdiagnosis.”
K. Gregory-Evans MD PhD FRCS FRCOphth FRCSC
Professor of Ophthalmology
Canada

“It is very probable that many BCD cases are missed and misdiagnosed.”
Juan Carlos Zenteno, MD, PhD
Mexico

From the Literature:

In five out of the above six BCD patients initial diagnosis was RP, and an accurate diagnosis was only made when patients presented to our clinic.”14
“Progressive vision loss and degeneration of the retinal pigment epithelium (RPE)/choroid are the symptoms similar to most forms of retinal degeneration that are categorized under RP. Due to similar clinical phenotypes, many advance cases of BCD have been misdiagnosed as RP.” “Based on the genetic findings it seems that the patient might be in advanced stages of BCD. There might have been misdiagnoses as RP, due to few phenotypic symptoms like severe visual loss, extensive chorioretinal atrophy, pigment deposition and minimal crystals.”15
“In fact, we can consider other differential diagnosis such as retinitis punctata albescens, fundus albipunctatus, retinitis pigmentosa, Stargardt’s disease, autosomal dominant crystaline dystrophy, etc.”16
“Some patients manifested the typical phenotype of BCD characterized by yellowish-white crystalline deposits throughout the fundus. However, some patients in advanced stage were easily misdiagnosed as other inherited retinal degeneration because the crystalline deposits diminished or even disappeared.”17

Patients’ Experience:

“I am a 51-year-old female and it was at 24, during my first pregnancy, when I began to notice symptoms of BCD. It was difficult for my eyes to adjust from bright light to low light and there were small spots of central vision missing in my right eye. I was initially diagnosed with Stargardt’s disease and it took over a year of traveling to see many specialists before I was correctly diagnosed with Bietti’s Crystalline Dystrophy. At that time, the prognosis was that I would be blind within 5 years. That was 27 years ago – BCD remains untreatable today and is widely misdiagnosed.”
Laurel, a BCD patient from the US

“My name is Steve and I was diagnosed of a blind spot 23 years ago. The blind spot was in my left eye. And not knowing what really the blind spot was, since it wasn’t affecting my vision at the time, I kind of let it go. 10 years went by, 13 years went by, and it progressively got worse until it reached my center vision, and I was no longer able to see out of my left eye. In the meantime, I had gone to six ophthalmologists, and none of them really knew what I had. They knew I had some kind of retina degenerative disease. And it wasn’t until I did some research and I found a doctor at Cleveland Clinic, that I finally realized that I had what’s called BCD, Bietti Crystalline Dystrophy.
Imagine how many of the 285 million people in the world with partial or loss of vision who were also misdiagnosed that could also have BCD when not know it.”
Steve, a BCD patient from the US

“My journey of BCD diagnosis was quite long and puzzling. I was told that I have unique eyes for almost a decade by two optometrists at yearly eye exams. During one eye exam, I was asked whether I was exposed to a lot of pollution where I grew up. I didn’t think so and my optometrist was also not sure why at my 20’s, I would have drusen-like deposits on my retina. After urges from one optometrist, I finally made an appointment with a retina specialist and he assured me that I am fine but asked me to look up Stargardt disease. I guess he hinted me that I may have Stargardt? However, I quickly moved on with my life and forgot about everything. The mystery started to unfold a few years ago when I started to have trouble driving or even walking at night. My new optometrist prescribed new glasses for me, which only made me dizzy. Another new optometrist suspected BCD but he was not sure. I felt scared and my world started to shatter. I had to wait for a month to see another visual function specialist my optometrist recommended. Each day in fear and uncertainty seemed too long but I tried very hard to hold back my tears and hoped for the best. At the doctor visit, bright lights were shined into my eyes, hard lenses were glued to my eyes and then I was left in a pitch-black room. Finally, I was told I may have BCD but he has never seen anything like that. One thing he confirmed is that my visual function is abnormal. Now I know I really have unique eyes but this time, I can no longer be calm and optimistic. The ophthalmologist they recommended is very popular and I couldn’t make an appointment until 3 months later. The other ophthalmologist I visited in between finally told me that I have typical representation of BCD. He was sure of my diagnosis even before I got my gene test results. Now I am even more puzzled that if it’s so obvious to him, how come I was not diagnosed sooner by any of the other doctors in the past decade? Indeed, the gene test confirmed I have BCD. I sincerely hope that with more awareness of BCD, no one would go through the same exhausting, fearful and long journey as I did.”
A BCD patient from the US

“Hi. I am 30 years old and I live in London although I am not from here. I am Eastern European and I am a BCD patient. In fact I was only officially diagnosed yesterday although I have known for a while now that this is going to be most likely outcome when they took my blood sample for the test in about a year ago. And the way I received the diagnosis was a relief. It is better knowing what I have for certain than not knowing.
At first I experienced some symptoms about three years ago at which point I went to a number of doctors who had not seen this before and they had no idea what this could possibly be. And they kept sending me from one doctor to another until I found someone who did.”
A BCD patient from UK

Disclaimer: The information herein are for general information purpose only and may be inaccurate, incomplete and outdated. Nothing herein shall be construed as medical advice or diagnosis. Consult your doctor for medical advice and diagnosis.
1 Roth, B., Weng, C. (2019). Spotlight Case: Two Sparkling Retinas. American Society of Retina Specialists. 
https://www.asrs.org/education/spotlight-case-two-sparkling-retinas
2 Bietti Crystalline Dystrophy, Mauricio Vargas, MD, PhD, Amanda Mitchell, MS, CGC, Paul Yang, MD, PhD, and Richard Weleber, MD, DABMG, FACMG. GeneReviews ®
https://www.ncbi.nlm.nih.gov/books/NBK91457/
3 Bietti’s Crystalline Dystrophy, EyeWiki, American Academy of Ophthalmology, Eric Zhang, Stephen C. Dryden, M.D.,
https://eyewiki.aao.org/Bietti%27s_Crystalline_Dystrophy
4 Crystalline retinopathy: Unifying pathogenic pathways of disease, Jaclyn L.Kovach MD, HacerIsildak, MD, David Sarraf, MD, Surv Ophthalmol. 2019 Jan – Feb;64(1):1-29.
5 Ophthalmologists with experience in diagnosing inherited retinal diseases, including BCD
6 Katagiri S, Hayashi T, Gekka T, Tsuneoka H. (2017). A novel homozygous CYP4V2 variant (p.S121Y) associated with a choroideremia-like phenotype. Ophthalmic Genet;38(3):286–287.
7 Yanagi Y, Tamaki Y, Fukushima H. (2003). Fine retinal crystalline deposits observed by confocal scanning laser ophthalmoscopic examination using infrared light. British Journal of Ophthalmology;87:509-510.
8 Brar VS, Benson WH. (2015). Infrared imaging enhances retinal crystals in Bietti's crystalline dystrophy. Clin Ophthalmol;9:645-8.
9 Oishi A, Oishi M, Miyata M, et al. (2018). Multimodal imaging for differential diagnosis of Bietti crystalline dystrophy. Ophthalmol Retina;2(10):1071–1077
10 Beryozkin A, Shevha E, Kimchii A, et al. (2015). Whole exome sequencing reveals mutations in known retinal disease genes in 33 out of 68 Israeli families with inherited retinopathies. Sci Rep;(5):13187.
11 Wang F, Wang H, Tuan HF, et al. Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet. 2014;133(3):331–345. 
12 Jinda W, Taylor TD, Suzuki Y, et al. (2017). Whole exome sequencing in eight Thai patients with leber congenital amaurosis reveals mutations in the CTNNA1 and CYP4V2 genes. Invest Ophthalmol Vis Sci;58(4):2413–2420. 
13 García-García, G. P., Martínez-Rubio, M., Moya-Moya, M. A., Pérez-Santonja, J. J., & Escribano, J. (2019). Current perspectives in Bietti crystalline dystrophy. Clinical ophthalmology, 13:1379–1399.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679682/table/T0002/?report=objectonly
14 Mataftsi A, Zografos L, Millá E, Secrétan M, Munier FL.(2004). Bietti’s crystalline corneoretinal dystrophy: a cross-sectional study. Retina;24:416–426.
15 Arpita, G., et al. Molecular diagnosis of inherited retinal diseases with non-specific clinical phenotypes using whole exome sequencing. (2016) Bioinfo Proteom Img Anal 2(2): 125- 127.
16 Tabatabaei A, Soleimani M, Moghimi S, Kiarudi MY. (2009). A case of Bietti crystalline dystrophy with preserved visual acuity and extinguished electroretinogram: a case report. Cases J. ;2:7100.
17 Guo Tong, Jia Ruixuan, Chen Ningning, Yang Liping (2019). Clinical manifestation and gene mutation of Bietti crystalline corneoretinal dystrophy. Chin J Exp Ophthalmol, 2019,37(9): 730-735.
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