Pratik Bikkannavar

Speciality Trainee, Royal Free London NHS Foundation Trust

Introduction and Clinical Presentation:

Bietti’s crystalline corneoretinal dystrophy (BCCD) is a rare heritable disease first described in a case-series of three patients in 1937 (1). Since then, BCCD has been reported worldwide in a range of ethnic groups, although it is known to be particularly prevalent in the Japanese and Chinese populations. In its early stages BCCD is often asymptomatic, and may only be picked up as an incidental finding in patients that have undergone slit-lamp fundoscopy. The disease typically becomes symptomatic at 20 to 40 years of age, with affected patients reporting impaired night-vision, constriction of the visual-fields, and a decline in visual acuity, sometimes with colour-vision impairment. Both eyes are typically affected, although often asymmetrically (2,3).

Aetiology and Pathophysiology:

BCCD is caused by more than a hundred known autosomal-recessively inherited mutations in CYP4V2, a gene that codes for a particular enzyme belonging to the cytochrome P450 family of enzymes. This enzyme is expressed in a range of tissues within the body, including the retinal pigment epithelium (RPE) and the cornea, and it is thought to play a role in the metabolism of fatty-acids. The mutations implicated in BCCD are thought to cause a derangement in physiological lipid-metabolic pathways, leading to chorioretinal atrophy, retinal and corneal deposition of crystalline lipoid material, and subsequent photoreceptor- loss (3,4). In keeping with the enzyme’s wide distribution in bodily tissues, deposition in the form of cellular inclusions in other bodily tissues has also been documented in BCCD, however only that in the retina and the cornea has been found to alter the tissue-function sufficiently to be of clinical relevance (5).

Diagnosis:

With a dystrophic disease simultaneously involving both the retina and the cornea being rare, the diagnosis of BCCD is primarily based on clinical findings, the main differential diagnoses being other crystalline retinopathies. On slit-lamp examination, small and well- distributed yellowish crystalline deposits in the retina are characteristic of early-stage BCCD, with the pathology starting in the posterior pole of the retina and over time involving more peripheral areas of retina. As the disease progresses, RPE-atrophy, pigmentary changes, and sclerosis of the choroidal vessels are all known to manifest, with an associated decrease in the prominence of the crystalline deposits over time. Corneal involvement is only present in approximately a third of cases, and is in the form of crystalline deposits that are mainly seen in the anterior layers of the peripheral cornea. A small minority of patients is also known to have crystalline deposition in the lens.

Fundus autofluorescence, fluorescein angiography, and indocyanine-green angiography are all useful in BCCD in the identification of areas of chorioretinal atrophy. These areas often correspond to any defects found on visual field testing. Ocular coherence tomography

typically shows hyperreflective dots well distributed through all retinal layers, corresponding to the aforementioned crystalline deposits. Electroretinographic findings are known to be very variable in BCCD. Genetic testing for mutations in CYP4V2 may be useful in the event of diagnostic-uncertainty (3,6).

Management and Prognosis:

With the genetic and phenotypic diversity seen in BCCD, there is currently no effective treatment for the disease. Most patients invariably become legally-blind by 30 to 40 years following the onset of symptoms. After diagnosis, patients may undergo routine follow-up in order to monitor the progression of their symptoms and disease, and to look for the development of complications as described further below. With progression of the disease, patients may benefit from the input of low-vision specialists in order to maximise their functional status and quality of life (3,6). Genetic testing may be useful in family-planning for those affected by BCCD, and for those with close relatives that have been diagnosed with BCCD.

Complications:

As with other chorioretinal dystrophies, neovascularisation at the macula is a recognised complication of BCCD, which may be managed with intravitreal injections of anti-vascular- endothelial-growth-factor drugs. Macular holes and cystoid macular oedema are also known complications of BCCD (3,6,7).

References:

1. Bietti GB. Ueber familiares Vorkommen von” Retinitis punkutata albescens”(verbunden mit” Dystrophia marginalis cristallinea corneae”), Glitzern des Glaskorpers und anderen degenerativen Augenveranderungen. Klin Monbl Augenheilkd. 1937;99:737–56.
2. Yin X, Yang L, Chen N, Cui H, Zhao L, Feng L, et al. Identification of CYP4V2 mutation in 36 Chinese families with Bietti crystalline corneoretinal dystrophy. Exp Eye Res. 2016 May;146:154–62.
3. Saatci AO, Ataş F, Çetin GO, Kayabaşı M. Diagnostic and Management Strategies of Bietti Crystalline Dystrophy: Current Perspectives. Clinical Ophthalmology. 2023 Mar; Volume 17:953–67.
4. Lee J, Jiao X, Hejtmancik JF, Kaiser-Kupfer M, Gahl WA, Markello TC, et al. The Metabolism of Fatty Acids in Human Bietti Crystalline Dystrophy. Invest Ophthalmol Vis Sci. 2001 Jul 1;42(8):1707–14.
5. Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, et al. Bietti Crystalline Corneoretinal Dystrophy Is Caused by Mutations in the Novel Gene CYP4V2. The American Journal of Human Genetics. 2004 May 1;74(5):817–26.
6. Sadda SR, Schachat AP, Sarraf D, Freund KB, Hinton DR, Wilkinson CP, et al. Ryan’s Retina: Seventh Edition. Seventh Ed. London: Elsevier [London]; 2023.
7. Iacono P, Da Pozzo S, Papayannis A, Romano F, Arrigo A, Parodi MB. Dystrophy-Related Choroidal Neovascularization. In: Chhablani J, editor. Choroidal Neovascularization. Singapore: Springer Singapore; 2020. p. 139–49.