Bietti Crystalline Dystrophy

Clinical characteristics.

Bietti crystalline dystrophy (BCD) is a chorioretinal degeneration characterized by the presence of yellow-white crystals and/or complex lipid deposits in the retina and (to a variable degree) the cornea. Progressive atrophy and degeneration of the retinal pigment epithelium (RPE) / choroid lead to symptoms similar to those of other forms of retinal degeneration that fall under the category of retinitis pigmentosa and allied disorders, namely: reduced visual acuity, poor night vision, abnormal retinal electrophysiology, visual field loss, and often impaired color vision. Marked asymmetry between eyes is not uncommon. Onset is typically during the second to third decade of life, but ranges from the early teenage years to beyond the third decade. With time, loss of peripheral visual field, central acuity, or both result in legal blindness in most if not all affected individuals.

Diagnosis/testing.

The diagnosis of BCD is based on the finding of numerous small, glistening yellow-white retinal crystals associated with atrophy of the RPE, pigment clumps, and sclerosis of the choroidal vessels; variable crystalline deposits in the corneal limbus; varying degrees of rod and cone dysfunction on electroretinography; visual field defects; and reflective dots visualized by spectral domain optical coherence tomography. Identification of biallelic pathogenic variants in CYP4V2 by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Referral to low-vision specialists and organizations/professionals trained to work with the visually impaired.

Surveillance: Periodic ophthalmologic examination to monitor disease progression and periodic visual field testing particularly as it relates to determination of driving eligibility and eligibility for government programs and/or disability.

Genetic counseling.

BCD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Suggestive Findings

Bietti crystalline dystrophy should be suspected in individuals with the following clinical, electrophysiology, and optical coherence tomography (OCT) findings.

Establishing the Diagnosis

The diagnosis of Bietti crystalline dystrophy is established in a proband with the above Suggestive Findings. Identification of biallelic pathogenic variants in CYP4V2 by molecular genetic testing (see Table 1) can confirm the diagnosis if clinical features are inconclusive.

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing or multigene panel). Depending on the phenotype, more comprehensive genomic testing (exome sequencing, exome array, genome sequencing) could be considered if CYP4V2 pathogenic variants are not found by targeted testing.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Bietti crystalline dystrophy is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with chorioretinal degeneration are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Bietti crystalline dystrophy (BCD) is characerized by progressive chorioretinal degeneration with onset typically during the second to third decade of life (range: early teens to >3^rd decade). The symptoms, ranges of visual impairment, and disabilities are similar to those of individuals with autosomal recessive retinitis pigmentosa.

The presenting symptom, rate of disease progression, and disease severity are also highly variable in BCD, even among those of the same age, within the same family, and with the same CYP4V2 pathogenic variants [Lee et al 2005, Lin et al 2005, Xiao et al 2011]. Some individuals have a more diffuse retinal disease presentation, whereas others present with more localized disease in the paracentral and central regions.

Vision impairment. In most affected individuals, onset of disease is during the second or third decade of life; however, age of onset, presenting symptoms, and disease severity vary widely. Marked asymmetry between eyes with respect to fundus appearance, reduction in visual acuity, and visual field loss is not uncommon.

• Visual field loss (progressive). Visual field loss may manifest in different individuals as peripheral field loss (ring, paracentral, or central scotoma) or central or pericentral scotomas (usually associated with atrophic lesions that encroach on the foveal region of the macula).
• Nyctalopia (progressive). Night blindness (i.e., difficulty seeing in low light) is a nonspecific feature of BCD in that it is typical of many forms of inherited retinal degeneration.
• Reduction in visual acuity (progressive). Visual acuity can range from normal to hand motion. Although the reduction in visual acuity has been reported to typically result in legal blindness by the fifth or sixth decade, central vision can sometimes be spared even in persons with severe disease. More often, loss of central visual acuity reflects atrophy or degenerative change close to or including the fovea.
• Persons with BCD may also have impaired color vision, particularly if the atrophic lesion encroaches on the fovea or cystoid macular edema is present.

In early or milder stages of disease, affected individuals can drive a car; with time, however, loss of peripheral visual field and/or central acuity results in legal blindness in most if not all affected individuals. Whereas affected individuals typically have profound vision loss by the fifth or sixth decade of life, central acuity can be spared through late stages of the disease in some [Kaiser-Kupfer et al 1994, Lee et al 2005]. A study involving 21 families with BCD showed visual acuities ranging from normal to hand motion [Xiao et al 2011].

Retina. Numerous small, glistening yellow-white crystals are scattered throughout the posterior pole and sometimes extend to the midperiphery. The crystalline deposits are associated with atrophy of the retinal pigment epithelium (RPE) and choriocapillaris, pigment clumping, and sclerosis of the choroidal vessels.

The crystalline deposits have been observed to diminish or even disappear in areas of severe chorioretinal atrophy as the disease progresses to later stages [Chen et al 2008, Xiao et al 2011]. Areas in which crystals are still present may represent retina that is still only mildly degenerated or in the process of degenerating [Kojima et al 2012].

Fluorescein angiography reveals patchy hypofluorescent areas of RPE and choriocapillaris atrophy and a generalized disturbance of the RPE.

Additional potential retinal complications of BCD include choroidal neovascularization [Atmaca et al 2007, Gupta et al 2011, Li et al 2015] and macular hole [Zhu et al 2009].

Cornea. Crystalline deposits in the corneal limbus have been estimated to occur in one quarter to one third of persons with BCD [Kaiser-Kupfer et al 1994, Halford et al 2014]. It has also been reported that corneal deposits may be more common in persons of northern European background than in Asians [Traboulsi & Faris 1987].

If present, the deposits can usually be seen on slit lamp examination. However, some crystals may be so fine as to go undetected unless specifically and carefully sought; Takikawa et al [1992] suggest that in some individuals with BCD, corneal crystalline deposits may be too subtle to detect on slit lamp examination. Spectral microscopy may be more appropriate in such individuals.

Electrophysiology. The full-field electroretinogram (ffERG) can show varying degrees of rod and cone dysfunction, ranging from normal to reduced amplitudes of scotopic and photopic responses to undetectable responses [Usui et al 2001]. The ffERG is more likely to be abnormal in mid- to late-stage disease, when the peripheral visual field is markedly affected. The multifocal electroretinogram (mfERG) is more likely to be abnormal when central function (e.g., visual acuity, central visual fields) are abnormal. Subnormal responses occur more often for the mfERG earlier in the course of disease than amplitudes of the ffERG. Thus, electrophysiologic studies are not as critical to establishing the diagnosis of BCD as they are to establishing the magnitude and extent of retinal degeneration and in following progression over time.

Although studies have shown that the ffERG responses appear to correlate well with stages of disease severity [Usui et al 2001, Lee et al 2005, Mansour et al 2007], this is not always the case:

• The ffERG can remain normal or near normal even in later stages of the disease. Normal ffERG responses can occur in individuals with BCD with severe atrophy of the RPE and choroid, suggesting that the neural retina may remain viable despite disruption of retinal lamination [Rossi et al 2011].
• Regional forms of BCD that may have normal ffERGs have also been described [Wilson et al 1989, Weleber & Wilson 1991, Rossi et al 2011].

A multifocal electroretinogram (mfERG) may detect regional areas of abnormal retinal function when the ffERG is normal, particularly in those regional phenotypes that predominantly affect the posterior pole [Lockhart et al 2018].

This degree of variation of electrophysiology may be the result of testing at different stages of disease progression. This variability may also reflect variation in loss of function in the gene product, with alleles with residual function associated with greater retention of ffERG amplitudes.

Fundus autofluorescence (FAF) is useful in monitoring disease extent and progression over time with regions of RPE atrophy showing relative decrease in FAF (hypo-AF). Retinal crystals have not been reported to generate an autofluorescence signal [Halford et al 2014, Li et al 2015].

Optical coherence tomography (OCT). Spectral domain OCT is of value for both diagnosis and management of BCD.

Using OCT, the integrity of the outer retinal structure can be visualized in individuals with BCD, including the hyper-reflective dots thought to represent the crystalline deposits. The majority of OCT studies report that the crystalline deposits appear to reside in the RPE-choriocapillaris complex [Pennesi & Weleber 2010, Padhi et al 2011, Kojima et al 2012].

In addition to the crystalline deposits, other reflective spots of various shapes (called retinal tubulation by Zweifel et al [2009]) can be seen by OCT. Kojima et al [2012] reported the presence of spherical, hyper-refractive structures in the outer nuclear layer of the retina, particularly located in areas of RPE atrophy. Of note, Kojima et al [2012] also observed these same circular structures, but less frequently, in retinal dystrophies other than BCD. Drusenoid deposits can be observed at the RPE early in the disease course [Li et al 2015].

The degeneration in BCD seen by OCT is most prominent in the outer retina, including the photoreceptor layer, but typically the degeneration is not uniformly distributed.

Genotype-Phenotype Correlations

A study of 125 individuals of Chinese ancestry with BCD showed that individuals who were compound heterozygous for the most common pathogenic variant c.802-8_810delinsGC had an earlier age of onset than those who did not have this pathogenic variant [Zhang et al 2018]. Individuals homozygous for c.802-8_810delinsGC also tended to have a younger age of onset than individuals with other pathogenic variants, although not to a statistically significant degree.

Another study of 18 individuals of Chinese descent with BCD showed that those who were homozygous for c.802-8_810delinsGC or compound heterozygous for variants c.802-8_810delinsGC and c.1091-2A>G had more severe disease based on electrophysiologic testing; namely, lower EOG Arden indices and higher likelihood of a nonrecordable scotopic ffERG and 30-Hz flicker ERG when compared with individuals with pathogenic variants in the coding region. The level of visual loss in BCD is related to the severity of retinal thinning [Lai et al 2007].

The variant c.332T>C (p.Ile111Thr) has only been reported in European individuals. One individual with this homozygous pathogenic variant was reported to have an unusual central and paracentral corneal distribution of crystalline deposits, without limbic involvement. Two unaffected elderly heterozygous carriers from the same family were also found to have multiple subepithelial and anterior stromal crystalline deposits in the central and paracentral cornea. This was absent in the young heterozygous carriers. This could suggest a dose-dependent phenotype of this variant [García-García et al 2013].

Of note, individuals without two identified pathogenic CYP4V2 variants were phenotypically indistinguishable from those found to have pathogenic variants [Astuti et al 2015].

The high degree of clinical variability in BCD suggests the influence of factors other than the primary CYP4V2 defect. The uncommon reports of regional retinal involvement may represent disease caused by pathogenic variants that are associated with retention of either a small amount of functional gene product or other modifying factors. Inflammatory or infectious disease (e.g., sinusitis) may be associated with worsening of disease, and treatment with antibiotics, steroids, and surgery may lead to short-term improvement in visual symptoms as well as visual acuity and visual fields, suggesting the possibility of an inflammatory component to the disease [Lockhart et al 2018].

Prevalence

While BCD is generally considered to be a rare disease, it may be underdiagnosed. For example, in a study done by Mataftsi et al [2004], approximately 10% of persons with autosomal recessive retinitis pigmentosa (RP) were also diagnosed with BCD. Furthermore, it has been estimated that up to 3% of individuals initially diagnosed with RP can be accounted for by BCD [Mataftsi et al 2004]. According to Hartong et al [2006], worldwide prevalence of RP was one in 4,000, with autosomal recessive RP accounting for 50%-60% of the affected individuals. This implies a prevalence of BCD of up to 1:67,000, representing almost 5,000 individuals in the US alone.

BCD appears to be more common in people of East Asian descent, particularly the Chinese and Japanese [Hu 1983, Tian et al 2015]; however, individuals of European, Middle Eastern, African, and North and South American origin have also been reported [Mataftsi et al 2004, Lin et al 2005, Lai et al 2007, Zenteno et al 2008, García-García et al 2013, Astuti et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Bietti crystalline dystrophy (BCD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Fundoscopic examination
• Full-field electroretinogram (ffERG) to establish a baseline
• Visual field testing (perimetry) to evaluate the degree of visual field constriction or presence of scotomas and to establish a baseline
• Optical coherence tomography to evaluate for complications such as choroidal neovascularization (CNV) or macular hole formation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific treatment for BCD currently exists; however, affected individuals should be referred to services specific to those with vision impairment:

• Low-vision specialists can prescribe low-vision aids/devices to optimize remaining vision.
• State services for the blind or organizations/professionals trained to work with the visually impaired provide access to services related to employment, education, and counseling regarding the psychosocial adaptation to visual loss.

Note: CNV is uncommon in BCD. Laser photocoagulation is not usually considered for CNV in inherited forms of retinal degeneration and has recently been superseded by the use of antivascular endothelial growth factor (anti-VEGF) therapy in a fashion similar to its use in age-related macular dystrophy.

Surveillance

Ophthalmologic examination is recommended every one to two years to monitor disease progression. Examination should include visual field testing particularly as it relates to determination of driving eligibility and eligibility for government programs and/or disability.

Affected individuals should be aware of the possibility of CNV and the option of self-monitoring using an Amsler grid under direction of their primary care ophthalmologist.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.