62 Stargardt Disease

S (STGD), first described in 1909 by Karl Stargardt,35 is by far the most common form of juvenile macular degeneration. Although the incidence of one in 10,000 is frequently cited, precise estimates of prevalence are not available. STGD is characterized by discrete yellowish deposits within the posterior pole. One variant of STGD, fundus flavimaculatus, was described by Franceschetti and Francois in 1963.19 The term was used to describe patients who had white pisciform flecks throughout the fundus but who typically retained good visual acuity until later in life. Molecular studies have more recently shown that autosomal recessive forms of fundus flavimaculatus, STGD, and some more widespread forms of cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are all associated with mutations in the ABCA4 (formerly ABCR) gene. A rare dominant form of macular disease with phenotypic similarity to STGD has been related to mutations in ELOVA4, a gene that is believed to be related to long-chain fatty acid metabolism.40

STGD typically begins in the first or second decade of life. Presenting symptoms include visual acuity that cannot be corrected to 20/20. Typically, there is a fairly rapid decline in acuity during the teenage years, with final acuity of 20/200 to 20/400 by adulthood.17 The full-field ERG is useful for ruling out more widespread forms of retinal degeneration.4 As shown in figure 62.1, responses are usually within the normal range in children with the disease. The cone electroretinogram (ERG) to 31-Hz flicker typically lies toward the lower limit of normal, and the cone b-wave implicit time is usually longer than mean normal but still within the normal range.22 Older patients with extensive macular generation may show subnormal cone and rod amplitudes (see figure 62.1), but the magnitude of loss is roughly predictable from the extent of macular degeneration. An important characteristic of STGD is that cone b-wave implicit time remains borderline normal despite advanced disease. This is an important prognostic indicator, since patients who retaining normal or near normal b-wave implicit times are likely to retain useful peripheral function throughout life.6 As we shall see, this discriminates patients with STGD from those with CRD, who, despite having similar gene mutations, nevertheless have a distinctly different visual prognosis.

While the full-field ERG is useful for discriminating the more localized pathology of STGD from widespread forms of retinal degeneration, it is of little value in the early detec-

tion of macular disease and for following patients in longitudinal studies and clinical trials. In evaluating the possible retinal basis for reduced acuity in a child, it is necessary to obtain a focal or multifocal ERG. The focal ERG should be conducted with direct visualization of the fundus to ensure that the response originates from the area of interest.34 Typically, in evaluating an acuity loss, the region of interest is the fovea. With the stimulus as small as 4 degrees, the stimulus is flickered at a frequency that is higher than the rod fusion frequency. The MaculoscopeTM, for example, based on the work of Sandberg et al.,34 employs a spot flickering at 42 Hz within a more intense, steady surround. The sensitivity and utility of this test for documenting the retinal basis of acuity loss have been reviewed previously.7 It is generally thought that the foveal response drops below the lower normal amplitude limit when visual acuity is 20/50 or less owing to macular degeneration.15 In STGD, the amplitude may be below the lower limit of normal before substantial loss of acuity, making this an important prognostic test.11,15,26

The multifocal ERG (mfERG) adds the capability for simultaneously measuring retinal function at dozens of locations throughout the macula.38 With the recent development of the fundus camera-based stimulus delivery system, it is now possible to monitor fundus position while testing. This is particularly important for patients with STGD, who may use a preferred eccentric locus of fixation whenever possible. In practice, it is useful to assess the fixation behavior of the patient through a fundus camera prior to mfERG testing. It is then possible to correct for eccentric fixation during testing. Maintaining the position of the optic disk helps to ensure that the stimulus pattern is centered on the fovea. Figure 62.2A shows the fundus of the left eye of a 20-year- old female with STGD. Characteristic flecks (lipofuscin) are scattered throughout the posterior pole but are not present in the macula, which has an atrophic appearance (more evident on fluorescein angiography). The mfERG from the same eye is characteristic of responses in a patient with recently diagnosed STGD (figure 62.2B). Despite only a modest reduction in acuity, responses from the central 10 degrees are severely reduced in amplitude, while responses from outside the macula are normal. The pattern of loss in the mfERG corresponds to that seen in the visual field (figure 62.2C).

Mutations in the ABCA4 gene were identified as a cause of STGD in 1997.2,3 It is now thought that all cases of

F 62.1 Representative full-field ERGs from a normal subject (left column) and two patients with STGD at different stages of disease (middle and right column). Response amplitudes are bor-

derline reduced in the older patient, but b-wave implicit times are at the upper end of normal.

autosomal recessive STGD are due to ABCA4 mutations.20 The protein encoded by the ABCA4 gene is called rim protein (RmP) because it was initially described in frog rod outer segment rims.30 RmP is a member of the adenosine triphosphate–binding cassette (ABC) transporter superfamily.3 Because it produces increased ATPase activity from RmP in vivo, a likely substrate of RmP is all-trans-retinal.36 On the basis of findings in the abcr-/- mouse model, in which RmP is completely absent, Travis and colleagues have proposed a model for RmP (figure 62.3A).39 According to the model, RmP participates in the metabolism of vitamin A in the photoreceptors after exposure to light. After exposure of rhodopsin to light (hv), all-trans-retinal is released within the outer segment disk. All-trans-retinal combines with phosphatidylethanolamine (PE) normally present in the disk membranes. The all-trans retinal-PE complex is called N-retinylidine-PE (N-ret-PE). The RmP protein normally transports the N-ret-PE out of the disk, where all-trans- retinal is reduced to all-trans retinol (atROL) and eventually reconverted back to 11-cis-retinal within the RPE.

With missing or defective RmP, N-ret-PE accumulates within the intradiskal space (figure 62.3B). The consequences of this are far reaching. One consequence is that “naked” opsin may be activated by the excess levels of free all-trans-retinal within the intradiskal space (ops/atRAL). This activation is believed to produce a noisy receptor in the dark, leading to an equivalent background and consequently, to delays in dark adaptation. These delays have been reported in patients with STGD after exposure to adapting light that bleaches a substantial fraction of the visual pigment.16 This delay in dark adaptation parallels that found in both homozygote39 and heterozygote24 abcr knock-out mice.

A second consequence of the buildup of N-ret-PE is the combining of a second molecule of all-trans-retinal with N- ret-PE to produce N-retinylidene-N-retinyl-PE (A2PE-H2). A2PE-H2 is ultimately hydrolyzed to form N-retinylidene-N- retinyl-ethanolamine (A2E). Many of these reactions occur in the RPE after disks containing the excessive trapped A2PE-H2 are shed as part of the normal phagocytotic process. The A2E accumulates as lipofuscin in the RPE and may ultimately damage intracellular membranes and destroy the overburdened RPE cells within the macula.14

Also associated with ABCA4 mutations and therefore part of the spectrum of STGD is a subset of cone-rod dystrophy, a progressive retinal degeneration that is typically inherited as an autosomal-recessive disease. A common early symptom is decreased visual acuity due to macular degeneration. In fact, young patients with CRD form may be thought to have STGD because of the similarity in appearance, but with time, it develops into a more progressive disorder. The severe visual loss manifests as a posterior pole cellophane maculopathy and expanding central scotoma or widespread pos-

terior pole flecks, which then degenerate, leaving an atrophic macular scar. Both forms show the dark choroid effect outside the macular areas that may show hyperfluorescence due to the central degeneration. Patients with CRD have characteristic changes in the full-field ERG that include delayed cone b-wave implicit times.5 A subset of patients with CRD shows a prolonged time course of dark adaptation following a bleach.18 CRD is distinguished from RP on the basis of visual acuity, fundus appearance, ERG findings, and the absence of night blindness as a presenting symptom. In a large prospective study of 100 patients with either CRD or RP, it was shown that the rate of rod ERG loss was significantly lower in CRD than in RP.9 Moreover, the rate of rod loss in CRD was similar to the rate of cone loss. This is quite different from RP, in which rod ERG function is lost approximately three times faster than cone function.9 In addition, the patterns of visual field loss8 and ERG loss10 are different in CRD and RP. Thus, when ABCA4 mutations take the CRD pathway, it is a clinically distinct retinal disorder from STGD and RP that has widespread involvement of both cone and rod photoreceptors.

Despite the distinctive characteristics of each phenotype, mutations in the human ABCA4 gene that cause STGD have been implicated in a subset of patients with recessive RP and recessive CRD.13,23,27,37 As in STGD, one consequence of the defect in RmP is the accumulation of all-trans- retinaldehyde within the rod outer segment disks and the production of a persistent “equivalent background” due to transient accumulation of the “noisy” photoproduct. This equivalent background is believed to be a major factor causing the slowed time course of adaptation in patients with ABCA4 mutations. The time course of dark adaptation following a photobleach is shown in figure 62.4 for a patient with CRD. Also shown is the average time course (±1 standard deviation) based on the 15 control subjects. Compared to normal, the time course of recovery in the patient with CRD is remarkably slow. Whereas the average control subject returns to within 0.2 log unit of the prebleach (fully dark-adapted) threshold by 25.4 minutes, it took 59 minutes for this patient with CRD to return to within 0.2 log unit of the preexposure value. The median recovery time for 11 patients with CRD associated with ABCA4 mutations of 41.6 minutes was significantly longer (t = -4.38, p < .001) than the 25.4 minutes required for the average control subject.12 Similar delays in the time course of dark adaptation have been reported previously in a subset of patients with CRD.18 Also similar to this phenotype in CRD patients is the delayed recovery of rod sensitivity following light exposure in mice homozygous39 and heterozygous24 for a null mutation in the abcr gene.

After 30 minutes of dark adaptation following a photobleach, thresholds for normal subjects were at their prebleach values, while thresholds for the majority of patients

A

F 62.2 A, Fundus photo from left eye showing lipofuscin accumulation within the posterior pole. B, mfERG from same

with CRD remained elevated. To determine whether the persistent elevation was associated with an equivalent or noisy background, pupil size was measured after 30 minutes in the dark.30 Patients with CRD and associated ABCA4 mutations had significantly smaller pupil diameters than did normal subjects 30 minutes following a bleach, and the test eye pupil diameter (OS) was consistently smaller than the chemically dilated pupil diameter (OD). This phenotype is apparently due to the accumulation of all-trans- retinaldehyde, which interacts with opsin apoprotein to form a “noisy” photoproduct.21,23,37 Loss of this transport activity also results in the accumulation of toxic bis-retinoids in the retinal pigment epithelium,24,25 which may predispose to photoreceptor degeneration.

Research with patients and with animal models of STGD and CRD may also shed light on the mechanisms involved in age-related macular degeneration (AMD). In analyzing data from over 1700 patients with AMD at several centers, Allikmets found that particular ABCA4 alleles raise the risk of AMD.1 The two most commonly associated variants were

B

patient showing selective loss of responses from the central 10 degrees. (See also color plate 30.)

G1961E and D2177N. The increase in risk is between threefold and fivefold. Consistent with a role for ABCA4 mutations in heterozygote carriers of ABCA4 are the findings from of transgenic mice. Abcr+/- (abca4+/-) heterozygous mice accumulate A2E in the RPE at a rate approximately intermediate between wild-type and homozygeous mice.24 Delays in recovery from a bleach are also present but are less severe than those in the abcr -/- mice. Interestly, delayed dark adaptation has also been reported in AMD.28,29

It is interesting that a single gene, ABCA4, can be associated with STG, CRD, RP, and, to some extent, AMD. It has been proposed that the severity of disease is related to the amount of residual RmP activity in a given patient.13 Thus, a heterozygote carrying one mutant ABCA4 allele may be at risk for AMD, the degree of risk being related to the severity of the allele. A patient with two mild to moderate mutant alleles would have SRGD. CRD or RP would be the result of inheriting two severe mutant alleles. Although of heuristic value, this model is clearly an oversimplification, and exceptions to this scheme have been documented.12 Patients with CRD may

:

C

F 62.2 (continued) C, Humphrey static perimetric fields from central 24 degrees (left) and 10 degrees (right) showing loss of sensitivity corresponding to mfERG regional loss.

A

B

F 62.3 Model for the function of RmP (ABCR) protein in disk membranes. A, Wild-type, in which ABCT is a transporter (flippase) for N-ret-PE. B, abcr-/- mouse (and patients with reduced flippase activity). N-ret-PE trapped in the disk combines with a second molecule of all-trans-retinal to produce A2PE-H2. A2PE-H2 is ultimately hydrolyzed to form A2E. Many of these reactions occur in the RPE after disks containing the excessive trapped A2PE-H2 are shed as part of the normal phagocytotic process. The A2E accumulates as lipofuscin in the RPE and may ultimately damage intracellular membranes and destroy the overburdened RPE cells within the macula. A2E: N-retinylidene-N- retinyl-ethanolamine; A2PE-H2: N-retinylidene-N-retinyl-PE; atRAL: all-trans-retinal; atRDH: all-trans-retinal dehydrogenase; atROL: all-trans-retinol; ops: opsin; PE: phosphatidylethanolamine; PM: plasma membrane. (From Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH: Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell 1999; 98:13–23.) (See also color plate 31.)

have the same allele as patients with STGD, even within the same family, and there is no obvious difference in predicted RmP activity that would explain whether a patient has CRD or RP. At the present time, molecular biology appears to have a limited diagnostic role in ABCA4 mutations. Electrophysiology continues to be the technique of choice for determining whether a patient with an ABCA4 mutation has STGD, CRD, or RP. Clearly, the implications of these phenotypic distinctions are enormous for visual prognosis.

Our rapidly evolving understanding of the etiology of STGD is already leading to suggestions for clinical trials to arrest visual loss. On the basis of work in abcr -/- mice, which show less A2E buildup when kept in the dark,39 it

F 62.4 Time course of dark-adaptation in patient with CRD. Open circles are measured thresholds, solid line is best fit of linear component dark adaptation model. Also shown is the bestfit function for values from 15 normal subjects. The gray area shows

±1 standard deviation. Thresholds were followed until they returned to within 0.2 log unit of the patient’s prebleach threshold (dashed lines).

seems prudent to recommend that patients with STGD minimize light exposure to the greatest extent practical. Drugs may be available or under development that could inhibit the accumulation of A2E in RPE cells. In this regard, isotretinoin was recently reported to be effective in limiting A2E accumulation in abcr -/- mice.31 Finally, drugs and gene therapy have the potential to stimulate under active RmP activity.

Supported by EY05235, EY09076, and the Foundation Fighting Blindness.

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. .

History of the disease

In 1937, Bietti4,5 described three patients with retinal degeneration beginning in the third decade of life. All were characterized by glittering crystals in the posterior pole and in the superficial paralimbal cornea. Welch, in 1977, first used the term crystalline retinopathy, which so aptly describes the most characteristic feature of this disease.37 Over 90 cases have been reported worldwide. The disease appears to be more frequent among Asians.16,21 Although most accepted cases have crystals in both the cornea and the retina, some patients, who are otherwise typical, lack crystals in the cornea.10,14,28,33 Other patients will show only retinal crystals for years before corneal crystals become evident.19 As the disease progresses to later stages, the crystals in the retina become less apparent and eventually disappear.3,35 Heterogeneity probably exists for Bietti’s crystalline dystrophy (BCD). Wilson et al.38 have suggested that the electrophysiological findings can differentiate two subtypes of BCD: a diffuse type (figures 63.1 to 63.3), with a profoundly abnormal electroretinogram (ERG),2,4,38,39 and a regional or localized type (figures 63.4 to 63.6), with a more intact ERG that may be either normal or only mildly abnormal (figure 63.7).14,34,38,39 Reports have detailed the progressive nature of BCD and have provided long-term follow-up information for 11,38 16,21 20,2 26,21 and 30 years.19,20 Some reports suggest that patients can progress from the regional to the diffuse phenotype.3,19,20 Whether these two types represent allelic or genetic homogeneity remains unclear. Interestingly, the patient reported by Jurlies et al.19 demonstrated at 34 years of age an electronegative scotopic ERG, a feature that was not reported by others with regional expression of the disease, even at age 58 years.38

Clinical description and natural history

Little information has been assembled on the natural history of BCD, especially with regard to consideration of the two possible subtypes. Patients report onset of symptoms anywhere from the second to the sixth decade of life, with the great majority in the third decade of life.35 When patients are first examined, their Snellen visual acuity may be rela-

tively good, but as paracentral scotomas develop, deepen, and enlarge, near visual tasks such as reading become progressively more difficult. Symptoms related to paracentral scotomas may exist early but often are difficult for patients to verbalize other than noting that their central vision is blurred or that reading is difficult. With the diffuse type of BCD, early symptoms of night blindness and peripheral field loss are prominent and indicate diffuse photoreceptor abnormalities. With the localized or regional type, patients become symptomatic from scotomas close to fixation, which are generally perceived as central or pericentral vision loss. With both types, the scotomas correspond to the areas of retinal pigment epithelium (RPE) and choriocapillaris abnormalities. With the diffuse type, progression is more rapid, and the final visual impairment and subsequent disability are much greater (see figure 63.3). Color vision can be abnormal in both diffuse and regional disease and is usually of the tritan type.38–40

The two types differ in fundus appearance. In the diffuse type, tiny yellow crystals are present at various levels in the retina. RPE defects with pigment mottling and deposition can be seen diffusely throughout the fundus. In the localized or regional type, the disease begins in the posterior pole in the form of RPE defects. Subsequent atrophy of the choriocapillaris leads to prominence of medium-sized and larger choroidal vessels. With fluorescein angiography, a zone of hyperfluorescence will often separate the involved retina from the more normal-appearing peripheral retina (see figures 63.4 and 63.6). This type of BCD progresses by slow extension of the areas of RPE hyperfluorescence with further atrophy of the RPE and choroid in these regions.

The concept of subtypes of Bietti’s dystrophy is not universally accepted, and many researchers have previously explained the wide range of clinical manifestations by different stages of the same disease. For example, Yuzawa et al. describe three stages of evolution to explain the disparity of clinical involvement seen with Bietti’s crystalline dystrophy.39 Stage 1 involved primarily RPE disease, stage 2 involved subsequent localized atrophy of the choriocapillaris, and stage 3 involved diffuse atrophy of the choriocapillaris. Presumably, all patients progress from stage 1 to stage 2, but to our

F 63.1 Fundus appearance (A) and fluorescein angiogram (B and C) of the right eye of a Japanese woman (patient of Wilson et al.38) with the diffuse form of Bietti’s crystalline dystro-

phy of cornea and retina at 36 years of age. (From Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38 Used by permission.)

F 63.2 Same patient as in figure 63.1 at 45 years of age (A and B). Note the further loss of pigment epithelium and choriocapillaris

over the nine-year interval. (From Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38 Used by permission.) (See also color plate 32.)

A

B

F 63.3 Goldmann perimetric visual fields for patient shown in figure 63.1 with the diffuse form of Bietti’s dystrophy at 36 (A) and 45 (B) years of age. Her visual acuity decreased from 20/30 J1 OU at 36 years of age to 20/50 J1 OU at 47 years of age. From

47 to 48 years of age, her visual acuity dropped to finger counting at 4 feet OD and at 7 feet OS; she was unable to read any Jaeger type at near distance. (From Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38 Used by permission.)

F 63.5 Goldmann perimetric visual fields of a 49-year-old man with the regional form of Bietti’s crystalline dystrophy (patient 2 in Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38).

in Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38). Note that crystals are prominent in the transition zone of disturbed RPE between atrophic retina and normal peripheral retina.

Same patient as shown in figure 63.4. Although his visual acuity was 20/25 in each eye, the patient was greatly bothered by pericentral scotomas.

A

C

F 63.6 Fundus appearance (A) and fluorescein angiogram

(B) of the left eye and Goldmann perimetric visual fields (C) of a 61- year-old man with the regional form of Bietti’s crystalline dystrophy

B

(patient 3 in Wilson et al.38). The visual fields had not changed over those determined nine years previously, but the visual acuity had decreased from 20/30 J1 to 20/40 J2. (See also color plate 33.)

F 63.7 Ganzfeld ERGs of two patients with the regional form of Bietti’s crystalline dystrophy (patients 2 and 3 in Wilson et al.38) as compared with a normal ERG on the left. ERGs from the right and left eyes were averaged to produce the tracings shown for the normal individual and patient 2. The stimulus spikes for the 30-Hz flicker and the photopic and scotopic responses for the normal ERG and patient 2 were set at 50, 50, and 75 mV and 75, 75, and 100 mV, respectively, to provide a vertical calibration scale.

knowledge, no case has ever been reported to progress from purely regional disease with preservation of normal peripheral retina to diffuse disease of the entire fundus. This observation has led us to propose that two subtypes of the disease exist.

The corneal lesions, which have been reported in approximately one fourth of cases,21 are very fine, whitish-yellow crystals that appear just inside the limbus in superficial stroma and often require high magnification for detection (figure 63.8). With time, the crystals become less apparent. Unlike those seen with nephropathic infantile cystinosis, the crystals are not visible within the more central cornea or the conjunctiva on biomicroscopy.

Reports of affected siblings, both males and females being affected, and the high frequency of consanguinity among otherwise normal parents,2,9,10,14–16,33,39 strongly argue for autosomal-recessive inheritance. Two reports, however, suggest autosomal-dominant inheritance.30,31

For these tracings, the 100-ms horizontal scale applies. For patient 3, the calibration scale is noted for 40 ms and 200 mV. The numbers to the left of the normal waveforms preceded by a plus or minus sign indicate the intensity of the white light stimulus in log foot- lambert-seconds. For the red and blue light responses, the numbers indicate the photostimulator intensity settings. (From Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38 Used by permission.)

F 63.8 Corneal crystals in peripheral corneal stroma of the right eye of a 54-year-old man with regional retinal involvement (patient 2 in Wilson et al.38). (From Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38 Used by permission.)

Known histopathology/pathophysiology of the disease

H On biopsy, crystals that have the appearance of cholesterol or cholesterol ester are present within corneal and conjunctival fibroblasts (figure 63.9).38 Complex lipid inclusions are also present. Wilson et al.38 have demonstrated inclusions in circulating lymphocytes similar to those seen in the cornea (figure 63.10), which suggests that this disorder may represent a systemic abnormality of lipid metabolism.

Kaiser-Kupfer et al.21 reported studies on crystalline lysosomal material in lymphocytes and fibroblasts from three members of a Chinese family with BCD and the ocular pathology of eyes from the 88-year-old grandmother of the proband. Biochemistry failed to show that the deposits were cholesterol or cholesterol ester, and the true nature of the stored compounds remains uncertain.21 The ocular pathology showed panretinal degeneration with complex lipid deposition within choroidal fibroblasts.21

P Although the finding of inclusions in circulating lymphocytes suggests a systemic defect of lipid metabolism, no consistent abnormalities have been found with routine laboratory evaluations, including plasma and urine levels of amino acids, plasma lipoproteins and steroid determination, serum protein electrophoresis and immunoelectrophoresis, and leukocyte cellular cystine assay. Mild elevations of serum cholesterol have been reported in some but not all patients, and the significance of such a finding in older patients is unclear.2,14,34,38

At present, nothing definitive is known about the pathophysiology of this disease. Lee et al.25 have found a 32-kDa fatty acid–binding protein missing from lymphocytes in Bietti crystalline dystrophy. Biochemistry studies found that BCD is characterized by a lower than normal conversion of FA precursors into n-3 polyunsaturated fatty acids and suggest that BCD is the result of deficient lipid binding, elongation, or desaturation.26 Linkage studies have found a localization to chromosome 4q35.18 There is no consensus as to whether the diffuse and regional phenotypes are truly different genetic diseases or different stages of one disease. Although some suggest that the variable phenotypes of BCD reflect different stages of progression, we believe that locus or allelic heterogeneity or the effects of modifying genes could easily account for the variable phenotypes and natural history.*

Relevant testing and findings

Since the diagnosis is easily made by clinical examination, reports on affected individuals are often incomplete with regard to other studies. Few investigators have reported the results of extensive retinal function tests on patients with Bietti’s dystrophy. Patients tend to fall into two groups: those with regional disease, in whom the retinal function tests appear as one would predict considering a localized process, and those with diffuse disease, in whom the retinal function tests indicate widespread abnormalities. The ERG reflects the degree of involvement of the fundus. The ERG is normal to moderately abnormal in the regional type14,21,33,34,38,39 and severely subnormal to nonrecordable in the diffuse type.2,38,39 Negative ERGs have been reported.2,10 The a-wave analyses of three cases of BCD have shown

F 63.9 Ultrastructural appearance of crystalline spaces (arrows) seen on a corneal biopsy specimen from a patient previously reported by Welch37 (Top, 13,000¥; bottom, 64,000¥). (From Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38 Used by permission.)

* The gene for Bietti’s crystalline dystrophy has been found to be a novel gene, CYP4V2, the product of which has homology to other proteins of the CYP540 family, suggesting a role of the gene product in fatty acid and steroid metabolism. (Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, Hayakawa M, Kanai A, Chen MS, Lewis RA, Heckenlively J, Weleber RG, Traboulsi EI, Zhang Q, Xiao X, Kaiser-Kupfer M, Sergeev Y, Hejtmancik JF: Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am J Hum Genet 2004; 78:817–826.)

F 63.10 Ultrastructural appearance of crystals seen in circulating lymphocytes (top left, 13,000¥; top right, 110,000¥; bottom left, 44,000¥; bottom center, 20,000¥; bottom right,

variable findings with normal to decreased Rmp3 for rod and cone responses and reduced rod S (sensitivity). However, for all three subjects, the cone S was normal, suggesting that cones may be less involved than rods in this disease.33 No eyes were found to have normal Rmp3 and decreased S in rods and cones, suggesting that in the early stage of the disease, photoreceptor loss and/or outer segment shortening may be present with normal phototransduction. Although two-color static perimetry has not yet been reported on these patients, the finding of diffuse and regional forms of Bietti’s dystrophy is similar to the reported classification of autosomaldominant retinitis pigmentosa (RP) into type I (diffuse) and type II (regional) disease.24,27

The electro-oculogram (EOG) appears abnormal in diffuse disease or advanced disease38 but can be normal or only mildly abnormal in early disease of the regional type.21,38 In one patient with late regional disease, the EOG was abnormal, and the fast oscillations of the EOG were found to be absent.38 Dark adaptometry showed an elevation of both the cone and rod portions of the curve, with minimal if any discernible cone-rod break. Further dark adaptation occurred in one patient with moderately

22,000¥). (From Wilson DJ, Weleber RG, Klein ML, Welch RB, Green WR.38 Used by permission.).

advanced diffuse disease after patching for 14 hours, but the retinal threshold was still elevated 1.3 log units above that normally seen after 30 minutes.38

Differential diagnosis

The differential diagnosis of Bietti’s crystalline dystrophy includes retinal oxalosis secondary to prolonged anesthesia with methoxyflurane,7 cystinosis,11,32 canthaxanthine retinopathy,6,8 talc emboli,1,12 tamoxifen retinopathy,22,23,29 and Sjögren-Larsson syndrome.13,17 X-linked retinoschisis has also been reported with retinal crystals.36 The diagnosis of Bietti’s dystrophy is almost always made or suspected on clinical grounds. Perimetry is performed to assess the extent of visual field loss and to allow correlation of fundus appearance with visual field defects. The ERG appears to play a major role in defining diffuse from regional disease. EOG, dark adaptometry, and color vision tests are ancillary tests that help to establish the level and extent of retinal dysfunction and are useful in providing vocational and prognostic counseling and in following patients for rate of progression.

Supported by The Foundation Fighting Blindness and by Research to Prevent Blindness.

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