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 >3rd 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].
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].