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Autosomal Dominant Crystalline Dystrophy
Autosomal Dominant Crystalline Dystrophy BRADLEY W. RICHARDS, MD,J DAVID E. BRODSTEIN, MD,l JULIAN J. NUSSBAUM, MD,l JOSEPH R. FERENCZ, MD,t KOICHI MAEDA, MD, 2 LESTER WEISS, MD3
Abstract: 'A black woman was identified with a tapetoretinal degeneration with sparkling intraretinal crystals, retinal pigment epithelial and choro idal atrophy, night blindness, color vision abnormalities , and paracentral scotomas. This constellation of findings is most consistent with the diagnosis of Bietti's crystalline dystrophy. Eight other family members were identified with intraretinal crystals similar to those seen in the proband but in varying degrees of progression . Transmission electron microscopy of circulating lymphocytes in several patients demonstrated crystals and granular osmophilic material of unknown composition contained within abnormallysosomes. These crystals are similar in appearance and locat ion to those seen in cholesterol ester storage disease . This family demonstrates an autosomal dom inant inheritance pattern , as well as other difference s from classic Bietti's crystalline dystrophy . The authors , therefore, suggest that this new entity be named autosomal dominant crystalline dystrophy. Ophthalmology 1991; 98:658-665
In 1937 and 1942, Bietti 1-3 reported several patients with an unusual ocular fundus appearance beginning in the third decade and characterized by a tapetoretinal degeneration with small, sparkling, yellow-white crystals in the posterior pole, atrophy of the retinal pigment epithelium, and choroidal sclerosis. Bietti's original patients also demonstrated sparkling yellow crystals in the superficial marginal cornea, although later reports have shown that this is not alwaysa constant feature of the disease. A recent histopathologic study of patients with Bietti's crystalline dystrophy" demonstrated crystals resembling cholesterol or cholesterol ester crystals in circulating lymphocytes under transmission electron microscopy (TEM), suggesting that Bietti's crystalline dystroph y may be due to a systemic abnormality of lipid metabolism . We examined a 54-year-old black woman with crystalline retinopathy identical in appearance to Bietti's crystalline dystrophy. Complete ophthalmic examinations were performed on all available family members. A num-
ber of other family members were found with various stagesof crystalline retinopath y in a pattern which suggests autosomal dominant rather than autosomal recessive inheritance as has previously been described for Bietti's crystalline dystrophy. In several patients, TEM of the buffy coat of peripheral blood demonstrated crystals that are identical in appearance to cholesterol ester crystals within abnormal storage lysosomes oflymphocytes. This finding has been previously described in cholesterol ester storage disease.' In addition, granular osmophilic material of unknown composition was found within the lysosomes of circulating lymphocytes under TEM. The findings in these family members are presented , and the differences between this disorder and classic Bietti's crystalline dystrophy are discussed. We propose that the name autosomal dom inant crystalline dystrophy be given to this new, separate disease entity.
MATERIALS AND METHODS Originally received: September 7, 1990. Revision accepted : Decemb er 27 , 1990 . Departm ent 01 Ophthalmology, Henry Ford Hospital, Detroit. 2 Departm ent 01 Hematology, Henry Ford Hosp ital, Detroit. 3 Department 01 Genetics , Henry Ford Hosp ital, Detroit. t
Reprint requ ests to Julian J. Nussbaum, MD, Department 01 Ophthalm ol· ogy, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202 .
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All available family members of the proband were contacted, and a pedigree chart was outlined for the family (Fig 1). Each family member was given an identifying number, corresponding to his/her position on the pedigree chart , and complete ophthalmologic examinations were performed on those patients willing to submit to exami-
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Fig 1. Pedigree chart of family with auto somal dominant crystalline dystrophy.
nation. Any patients identified with intraretinal crystals were photographed and , when possible, the following tests were performed. Full-field electroretinograms (ERGs) were recorded from both eyes after dilation and 30 minutes ofdark adaptation using Burian-Allen corneal contact lens electrodes. A Nicolet Ganzfeld (Madison, WI) stimulator generated a series of single flash and flicker stimuli in the following sequence: I) single flashes of dim blue light (blue filter, 0.25 strobe intensity), which generated a rod isolated scotopic response; 2) single flashes of red light (red filter, 1.25 strobe intensity), which generated a matched rod response plus early cone oscillations; 3) single flashes of white light (no filter 0.25 and 1.25 strobe intensity), which generated a mixed rod-cone response and a maximal response, respectively; 4) flashes of bright white light flickering at 30 Hz (no filter, 1.25 strobe intensity); and 5) light-adapted responses to single flashes of bright white light (1.25 strobe intensity with bright background illumination), which generated a cone-isolated (photopic) response. Electroretinographic responses were amplified (gain = 104 ) , filtered (bandwidth 1-250 Hz), and displayed on a Nicolet CA-1000 signal averaging computer. Both single responses and computer-averaged responses were examined and compared with those obtained from normal adults. Response parameters were considered abnormal if the y exceeded 2.5 times the standard deviation of the norm. Visual fields were plotted with the Humphrey visual field analyzer using the standard 30-2 program with the exception ofone patient in whom visual fields were plotted
on the Goldmann perimeter. Color vision of each eye was tested separately using the American Optical Company pseudo-isochromatic plates. Routine fluorescein retinal angiography also was done. Transmission electron microscopy of leukocytes collected from the buffy coat of peripheral venous blood was performed in the following manner. The buffy coat of peripheral blood was fixed in 30% cacodylate buffered glutaraldehyde, pH 7.4. These cells were postfixed in I % osmic acid, embedded in Araldite , stained with uranil acetate and lead citrate, and viewed with a TEM (Zeiss Model 109, Oberkochen, Germany).
CASE REPORTS Case 1 (proband, patient 111-3). A 54-year-old black woman was seen in February 1989, with complaints of gradually worsening visual acuit y. She had complained of poor night vision for man y years, and was noticing some difficulties with color perception . She had been seen at another institution 15 years previously, and was noted to have a visual acuity of 20/25 in both eyes and normal color vision as tested with pseudo-isochromatic plates. Results of ERG at that time were found to be subnormal, and the fundu s was described as having pigmentary clumping and multiple white "exudates." There was no family history of consanguinity or of family members with similar visual complaints. Her medical history was significant for diabetes controlled with oral hypoglycemic agents, hypertension, gout,
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Fig 2. (Case I, proband, patient III-3). Goldmann visual fields of both eyes (00 = right; OS = left) demonstrate enlarged blind spots and paracentral scotomas in both eyes.
and a previous stroke with multiple lacunar infarcts noted on computed tomographic scan. The dietary history was unremarkable for ingestion of foods containing large amounts of oxalate, and the patient denied any prior surgical procedures under general anesthesia. On examination, the patient's visual acuity was 20/50 with a moderate myopic correction in both eyes. Muscle balance, extraocular movements, and intraocular tension measurements were all normal. Her pupils measured 3 mm in both eyes, were slightly sluggish, but without any relative afferent pupillary defect. Results of slit-lamp examination were normal; specifically, no marginal corneal crystals were noted. Goldmann visual fields showed enlarged blind spots and paracentral scotomas in both eyes (Fig 2). Color vision was decreased with the patient correctly identifying 6 of 18 color plates in each eye with difficulty. Results of dilated funduscopic examination showed numerous sparkling, refractile, yellow-white deposits scattered throughout the posterior pole in both eyes (Fig 3). These crystalline deposits were noted in all layers of the retina, and some had coalesced to form large clumps of yellow-white deposits. The refractile nature of these crystalline deposits is not easily reproduced with fundus photography. There were extensive areas of atrophic-appearing retinal pigment epithelium and several large pigment clumps in the posterior pole. The optic discs showed minimal pallor, and mild arteriolar narrowing was noted. Results of peripheral examination showed a few retinal crystals and occasional pigment aggregation. Fluorescein an-
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giography showed baring of fluorescence of medium and large choroidal vessels in the posterior pole during early stages, indicating retinal pigment epithelial depigmentation and choriocapillary loss (Fig 4). Later stages (Fig 5) showed large areas of choroidal and scleral staining. Electroretinography showed all wave forms to be diminished in amplitude to 50 to 60% of normal, especially in the cone responses. Implicit timing also was delayed in all wave forms. Results of VDRL and TPHA were both nonreactive. A complete blood count and serum ornithine levels were within normal limits. A serum lipid profile showed only moderate hypercholesterolemia. Case 2 (patient 11-4). A 74-year-old black woman (the maternal aunt of the proband) is the only living relative of the proband from a previous generation. This patient was not seen in our clinic. She was examined by her personal ophthalmologist who noted a visual acuity of 20/25 in both eyes and a fundus appearance consistent with Bietti's crystalline dystrophy (personal communication; M. Adams Hall, MD). This patient has refused further evaluation or testing, and no photographs are available. Case 3 (patient IV-9). A 30-year-old black woman (a daughter of the proband) was examined. She complained of poor night vision, but did not have color perception abnormalities. In both eyes, visual acuity was 20/20 and the pupils measured 4 mm, with no relative afferent pupillary defect. Results of slit-lamp examination were normal; specifically, no corneal crystals were noted. Color vision and Humphrey visual fields were normal. On funduscopic examination, the patient was noted to have multiple yellow-white sparkling crystalline deposits identical to those seen in the proband. These crystalline deposits were noted in both eyes clustered in a group temporal to the fovea. The remaining results of the fundus examination were normal. Fluorescein angiography demonstrated late hyperfluorescence of these deposits. Full-field ERG testing was normal. Case 4 (patient IV-12). A 25-year-old black woman (a daughter of the proband and a half sister to patient 3) was examined. She denied any night blindness or color vision abnormalities. On examination, her visual acuity was 20/20 in both eyes with a small myopic correction. Color vision and Humphrey visual field testing were normal. The pupils measured 3 mm in both eyes with no relative afferent pupillary defect, and results of slitlamp examination were normal with no corneal crystals present. Results of funduscopic examination showed multiple tiny yellowwhite crystals scattered throughout the posterior pole in both eyes, mainly temporal to the fovea (Fig 6). These crystals were much fewer in number than those found in the previous patients, and the remaining results of the fundus examination were normal. Although these crystalline deposits are clearly seen both clinically and in the photographs, the refractile nature of these deposits cannot be easily reproduced photographically. Fluorescein angiography showed no hyperfluorescence or hypofluorescence of these isolated crystalline deposits. Full-field ERG testing was within normal limits. Case 5 (patient IV-I0). A 28-year-old asymptomatic black man (the son of the proband and the brother of case 4) was examined. He denied any night blindness or color perception difficulties. On examination, visual acuity was 20/20 in both eyes. Color vision and Humphrey visual fields were normal. The pupils measured 4 mm in both eyes with no relative afferent pupillary defect. Results of slit-lamp examination were normal with no corneal crystals present. Results of fundus examination showed multiple yellow-white crystalline deposits in the posterior pole (Fig 7). These crystals were distributed mainly temporal to the fovea and were few in number, although more numerous in the right eye than the left. These crystalline deposits were identical to those seen in the previously described patients. Again, although they are easily seen clinically, fundus photographs do not dern-
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Fig 3. Top left , fundus photograph of the right eye of case I. Notice the multiple tiny crystalline.deposits, larger clumps of crystalline material, atrophy of the retinal pigment epithelium, and occasional pigment clumping. The fundus appearance of the left eye was identical. Fig 4. Top right, fluorescein retinal angiography of the right eye of case I. Baring of fluorescence of medium and large choroidal vessels is present, indicating RPE depigmentation and choriocapillaris loss. Fig S. Center left, fluorescein retinal angiography of the right eye of case I, later stage. Large areas of choroidal and scleral staining are present, again indicating RPE depigmentation and loss of choriocapillaris. Fig 6. Center right, fundus photograph of the left eye of case 4 (patient lV-12). Notice the tiny yellow-w hite crystals, few in number, scattered throu ghout the posterior pole. Fig 7. Bottom left , fundus photograph of the left eye of case 5 (patient IV-I 0). Occasional tiny yellow-white crystals are seen throughout the posterior pole in this patient also. Fig 8. Bottom right, fundus photograph of the left eye of case 6 (patient IV-2). Notice the tiny, yellow-white crystals seen throughout the posterior pole. o nstrate these intraretinal cry stals well. Fluorescein angiography was normaL Full-field ERG testing was abno rmal with reduced rod and cone components and dela yed im plicit timing. Case 6 (patient IV-2). A 32- year-old black woman (a niece of the proband) was examined with co m plaints of occasional trouble with night vision but no difficulties with color perception.
On examination,visual acu ity was 20/20 in both eyes. Co lor vision a nd Humphrey visual fields were normal. The pupils were equal a nd reactive with no relati ve afferent pupillary defect. Results of slit-la m p examination were normal with no marginal co rneal crystals present. On funduscop ic examination, multiple yellow-white crystalline deposits were noted in the fundus in
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both eyes (Fig 8). Although easily seen clinically, the crystalline deposits are difficult to document photographically. These crystalline deposits were identical to those seen in the other patients, although they were more numerous than those found in cases 4 and 5. The crystalline deposits were not arranged in groups as were those found in case 3 and were not nearly so numerous as those seen in the proband. The background color of the fundus and the retinal periphery were normal. Fluorescein angiography and full-field ERG testing were within normal limits. Case 7 (patient IV-l6). A 37-year-old asymptomatic black woman (a niece of the proband) was examined . She denied any night vision or color vision abnormalities. On examination, visual acuity was 20/20 in both eyes. Color vision and Humphrey visual field testing were normal. The pupils were equal in both eyes and no relative afferent pupillary defect was seen. Results of slit-lamp examination were normal with no corneal crystals present. Results of funduscopic examination demonstrated five or six yellow-white crystalline deposits located in the foveal area of the right eye only. These crystals were identical in appearance to those seen in the other patients. Fluorescein angiography was normal, and the patient refused to return for further testing or follow-up. Case 8 (patient 111-8). A 54-year-old black woman (a first cousin of the proband) who denied night blindness or color vision abnormalities was seen in the clinic. On examination, visual acuity was 20/20-2 in both eyes. Color vision and Humphrey visual field testing were normal. The pupils measured 3 mm in both eyes with no relative afferent pupillary defect. Results of slit-lamp examination were normal with no corneal crystals present. Results of funduscopic examination showed scattered intraretinal crystalsidentical in appearance and numbers to those seen in case 6. Fluorescein angiography and full-field ERG testing were within normal limits. Case 9 (patient IV-24). A 31-year-old black woman (first cousin once removed from the proband, the daughter of case 8) was examined . She denied any visual problems, color vision abnormalities , or night blindness. On examination , visual acuity was 20/15 in both eyes. Color vision and Humphrey visual fields were found to be normal. The pupils measured 3 mm in both eyes with no relative afferent pupillary defect. Results of slitlamp examination were normal with no corneal crystals present. Results of funduscopic examination showed fairly normal-appearing macular areas with only rare crystalline deposits. Temporal to the macula in the right eye, a large clump of crystalline deposits approximately 2 to 3 disc diameters in size was noted . The background color of the fundus was slightly different in this area. Fluorescein angiography and full-field ERG testing were within normal limits.
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Fig 9. Case I, proband, patient II1-3. Transmission electron micrograph of peripheral blood lymphocyte. A lysosome (arrow) containing a crystal and granu lar osmophilic materi al (original magn ification , X 17,069 ).
Fig 10. Transmission electron micrograph, higher power view of Figure IO(case I). The lysosome shows a long narrow crystal (arrow) and granular osmophilic material with clear spaces (original magnification, X67,645).
PATHOLOGIC FINDINGS
Three of our affected patients were willing to submit samples of peripheral blood for TEM analysis. The results of this analysis follow. Case 1 (proband, patient 111-3). Occasional circulating lymphocytes demonstrated abnormallysosomes containing crystals and inclusions (Figs 9-12). The appearance of these crystals resembled that of the cholesterol ester crystals which are seen in cholesterol ester storage disease.' The crystals measured up to 0.54 JLm in length and 0.18 JLm in width, and, like the crystals seen in cholesterol ester storage disease, were clearly present in the lysosomes of the circulating lymphocytes. The crystals were combined with granular osmophilic material of unknown composition within the lysosomes. Other lysosomes were noted that contained only this granular osmophilic material with no crystals. Case 5 (patient IV-lO). Occasional lymphocytes showed abnormallysosomes containing granular osmophilic material. No clear spaces or crystals were observed.
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Fig 11. Transmission electron micrograph of lymphocyte with two abnorrnallysosomes in case I. The larger lysosome clearly shows crystals (arrow) (original magnificati on , X 18,716).
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Fig 12. Transmission electron micrograph, higher power of Figure 12 (case I). The larger lysosome contains 3 crystals (original magnification, Xn,077).
Fig 13. Case 8, patient III-8. Transmission electron micrograph oflymphocyte. Lysosomes containing osmophilic granular material are present. One of the Iysosomes contains a clear space resembling a crystal (arrow) (original magnification, X91,671).
Case 8 (patient 111-8). Occasional circulating lymphocytes demonstrated abnormal lysosomes containing granular osmophilic material. The osmophilic material contained minute clear spaces somewhat resembling crystals. However, no definite crystal formation was observed (Fig 13).
DISCUSSION Since Bietti's original articles, cases of Bietti's crystalline dystrophy have been described in patients from Europe 6-12 Brazil.P Algeria 13 Qatar 13 Lebanon 14 China/5-18 Japan,lIl-24 and the' United States.4. 17,25 T~o brothers who were identified in the United States with Bietti's crystalline dystrophy are the only two black patients described with this disorder in the literature." In our study, a large family of black patients was examined for the presence of crystalline retinopathy. All available relatives of the proband who were willing to be examined
were accepted into this family study, and a total of 26 patients were seen. The proband had a clinical,angiographic, and ERG appearance which was identical to Bietti's crystalline dystrophy; case 2 (patient 11-4) was identified as having a similar funduscopic appearance. Seven other family members were identified with intraretinal crystals identical to those seen in the proband but without most of the other signs of Bietti's crystalline dystrophy. Intraretinal crystals have been described in a number of other situations, including the Sjogren-Larsson syndrome," calcific aortic stenosis." calcified macular drusen," and primary oxalosis, an autosomal recessive disorder." Intraretinal oxalate crystals have been described less commonly in patients with secondary oxalosis caused by thiamine or pyridoxine deficiency. Oxalosis also can be caused by ingestion of ethylene glycol as well as spinach or rhubarb gluttony, but no cases of retinal crystals from these sources have been reported." In addition, oxalate crystals have been found in the retina after longstanding retinal detachments'" as well as after administration of methoxyflurane general anesthesia." Crystalline deposits in the fundus have been described in systemic cystinosis. However, these were believed to lie primarily within the choroid.F Tamoxifen, an anti-estrogen medication, has been noted to cause retinal crystals after 12 to 18 months in some patients.P:" Macular crystalline deposits also have been noted after the use of canthaxanthine, a skintanning agent." Retinal crystals also are seen in talc retinopathy, a condition seen in intravenous drug abusers who inject crushed oral medications containing talc compounds intravenously." None of the previously mentioned conditions have the same clinical appearance as our patients, in that our proband showed marked retinal pigment epithelium and choroidal atrophy as well as diminished ERG amplitudes in addition to retinal crystals. Gyrate atrophy is an autosomal recessive disorder with retinal pigment epithelium and choroidal atrophy, subnormal or extinguished ERGs, and hyperornithinemia." Takki 38 noted numerous glistening crystals scattered at the equator in the most advanced stages of gyrate atrophy, but the retinal appearance of gyrate atrophy is quite different from our patients, and ornithine levels were found to be normal in the proband. The clinical picture seen in our patients also might be confused with any of a number of flecked retina syndromes. However, these flecked retina syndromes do not have the distinctive crystalline appearance that our patients demonstrated. The constellation of crystalline retinal deposits, retinal pigment epithelium and choroidal atrophy, central or paracentral scotomas on visual fields, and diminished ERGs has only been described previously in Bietti's crystalline dystrophy. The occurrence of Bietti's crystalline dystrophy in siblings and in the offspring of consanguineous parents has been seen in a number of cases and, therefore, an autosomal recessive inheritance pattern has been postulated for this disease. In several of the published reports, available family members were examined, but most studies have simply noted that no family members were known to have ocular disease. In an extensive family survey reported by HUl6 from China, 35 patients with
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Bietti's crystalline dystrophy were identified from 25 separate families. No parents or children of the affected patients were found with the disease, although 19.2% of siblings were found to be affected. In addition, parental consanguinity was found in approximately 20% of the cases. Therefore, an autosomal recessive inheritance pattern was believed to be likely. Of the 26 patients examined in our study, seven were younger than 14 years of age, all from generation V. In classic Bietti's crystalline dystrophy, the onset of disease is usually in the third decade, and the youngest reported case was 15 years of age." All of the young patients in our study were, indeed, negative for any crystalline retinopathy. Of the remaining 19 patients (age range, 18-78 years), 9 (47%) were found to have sparkling intraretinal crystals similar to those described in Bietti's crystalline dystrophy. Two of these patients (cases 1 and 2) had fundus findings which were consistent with the diagnosis of Bietti's crystalline dystrophy, whereas the other patients had intraretinal crystals alone. The absence of affected individuals in generation V suggests a late onset of the disorder. Five of the individuals examined in generation V were the offspring of mothers with crystalline deposits, and none was affected . In this pedigree, only one individual, patient IV-2, was affected and had a parent, patient III-I , who was apparently unaffected. The parents of all other affected individuals who were examined, were affected . With multiple generations affected in a nonconsanguineous family, and males as well as females affected, autosomal dominant inheritance is likely. The possibility of recessive inheritance ofthe crystalline retinopathy with heterozygotes manifesting onl y crystals (pseudodominance) is unlikely because the proband and her maternal aunt are both affected with retinopathy, and we could not elicit a history of consanguinity between the proband's father and either maternal grandparent. This genetic transmission is different from that described in Bietti's crystalline retinopathy, and we suggest that the name autosomal dominant crystalline dystrophy be given to this new disorder. Since many of the reported cases of Bietti's crystalline dystrophy have not had family members examined, some of these families may have the same gene as is present in the subjects in our report. The fact that only one of the nine affected individuals in our family presented with symptoms shows quite clearly that many affected individuals could be missed unless closely examined. Those patients in whom intraretinal crystals were found with no other signs of crystalline dystrophy probably represent incomplete penetrance of the dominant gene or a forme-fruste of the disease. This theory is borne out by several of our patients. Case 5 (patient IV-IO), although completely asymptomatic, demonstratedabnormal ERG potentials in addition to the intraretinal crystals. He also was found to have abnormal Iysosomes containing granular osmophilic material on TEM. Case 8 (patient III-8) also showed these granular materials within lysosomes of the circulating lymphocytes despite being completely asymptomatic. Neither of these patients demonstrated complete crystal formation within the lysosomes, whereas 664
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the proband, who was symptomatic and showed more extensive retinopathy, did have crystal formation. It is uncertain at this point whether those patients identified in our study with crystalline deposits alone would progress in time. Although numbers and distribution of crystalline deposits varied in our study patients, this could be explained by incomplete expression of a dominant gene rather than progressive stages of the complete disease . Bietti's crystalline dystrophy is usually diagnosed around the third decade with a history of visual impairment dating years earlier. This pattern of progression was followed by our proband; however, all the patients in our study with crystals alone have been asymptomatic, despite the age range of 25 to 54 years. This again suggests limited expression of the disease rather than early stages of progression in these patients. There are other findings in our group of patients which distinguish this crystalline retinopathy from that described by Bietti. Corneal crystals were not found in any family members, although many cases of Bietti's crystalline dystrophy described in the literature have not shown these marginal corneal crystals either. Several reports of Bietti's crystalline dystrophy have stressed a male preponderance, although a review of cases shows that there is only a slightly higher rate of occurrence in males. Of the 37 cases of Bietti's crystalline dystrophy in the literature in whom sex was identified, 21 were male and 16 were female. In contrast, the family in our study shows a marked female preponderance of affected patients. In those patients older than 18 years of age who were examined, 8 (73%) of 11 females were affected, whereas only one (14%) of seven males was affected. This was found to be significant by the chi-square test (P = 0.016). The excess of females to males in this pedigree is unexplained. We find no evidence of lethality in males with the gene since the sex ratio of the offspring of affected individuals is 25 males to 19 females. The numbers in our pedigree are so small that this could be due to chance alone, or it may be another manifestation of a disorder distinct from Bietti's crystalline dystrophy. In 1989, Wilson et al" conducted a histopathologic study on three patients with Bietti's crystalline dystrophy. Corneal biopsy specimens from two of these patients demonstrated crystals resembling cholesterol or cholesterol ester and complex lipid inclusions in corneal and conjunctival fibroblasts under TEM. These crystals were variably combined with granular osmophilic material. Similar crystals and inclusions were noted in circulating lymphocytes under TEM. These findings were believed to indicate that Bietti 's crystalline dystrophy may be due to a systemic abnormality of lipid metabolism. In the patients in our study, we have identified crystals and granular osmophilic material similar to those described in Bietti's crystalline d ystrophy in the study by Wilson et al." We have clearl y localized the inclusions to abnormal lysosomes of the circulating lymphocytes. In case 8 (patient III-8) , minute clear spaces were observed within the granular osmophilic material. The nature of the granular osmophilic material is not known. It may represent a precursor to crystal formation, but further biochemical study of the lymphocytes would be required
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to confirm this. The pathologic findings of crystals and granular osmophili c material within abnormallysosomes of circulating lympho cytes are very similar to those reported in cholesterol ester storage disease. Similar findings were described in the cases of Bietti's crystalline dystrophy described by Wilson et al," although no mention is made in that report of abnormal lysosomes. This suggests that both Bietti's crystalline dystrophy and autosomal dominant crystalline dystrophy may be metabolically very similar to each other and to cholesterol ester storage disease, although each disease seems to have distinct clinical presentat ions. Since complete examinations of all family members were not performed in Wilson et al's study, it is possible that his patients may have represented autosomal dominant crystalline dystrophy rather than Bietti's crystalline dystrophy, although Wilson et al's findings of corneal crystals are in contrast to the lack of crystals seen in our pedigree. In either case, the findings of corneal crystals, retinal crystals and pathologic findings seem to link these three disease conditions together as similar but distinct disease entities. The findings of hypercholesterolemia and hyperbetalipoproteinem ia noted by investigators in some cases of documented autosomal recessive Bietti's crystalline dystrophy seem to support this theory.6,9.12 Testing for acid lipase deficiency was not performed on the patients in our study but might provide a link to cholesterol ester storage disease in future cases of crystalline dystrophy.
REFERENCES 1. Bietti G. Su alcu ne forme atipic he 0 rare di degenerazione retinica (degenerazioni tapp eto-retiniche e qua dri mo rbosi similari). Boll Ocul 193 7: 16 :1159-244. 2. Bietti G. Ueb er familiares Vorko mmen vo n " Retinitis pun ctata albesce ns " (verbunden mit " Dystrophia margina lis cristallinea corneae") , Glitzern de s Glask6rpers und anderen degenerativen Augenveranderun gen . Klin Monatsbl Augenh eilkd 1937 ; 99 :737-56. 3 . Bietti G . Fondo punctato a/besc ente co n emera /opia congenita e sindattili a familiare. Boll Ocu list 1942 ; 21 :636-50. 4. Wilson DJ , Weleber RG, Klein ML , et al. Bietti 's crys talline dystroph y: clinicopathologic correlative study. Arch Ophtha lmol 1989; 107:2132 1. 5. Sch mitz G , Assmann G . Acid lipase deficiency: Wolman disease and c holesteryl ester storage disease. In: Scriver CR, Beaudet AL , Sly WS, Valle D, ed s. The Metabolic Basis of Inherited Disease, 6th ed . Vol. II. New York: McGr aw-Hili, 1989 ; 1623-44. 6. Bagotini B, lolr-Soada G. Bietti's tapetoretinal degeneration with marginal corneal dys trophy. Am J Op hthalrnol 1968; 65 :53-60. 7. Grizzard WS, Deutrnan AF, Nijhuis F, de Kerk AA . Crys talline retino pathy. Arn J Ophthalmo l 1978; 86:81-8. 8. Harrison RJ, Ac heso n RR, Dean-Hart JC. Bietti 's tapetoretinal degeneration with margina l co rneal dystrophy (cry stalline retino pathy) : case repo rt. Br J Ophthalmo/ 1987 ; 71 :220- 23. 9. Craa ndijk A, Houtsrnuller AJ . Hypo and abe talipoproteinemia. In: Winkelman JE, Crone RA, eds. Persp ect ives in Ophthalmology . Vol. 2. Am sterdam : Except a Medica 1970: 96- 102. 10. Noble KG, Carr RE, Siegel 1M. Fluorescein angiog raphy of the hereditary cho roida l dystrophie s. Br J Op hthalmol 1977 ; 61:43- 53 . 11. Webe r U, Owczarek J, Kluxen G, Bernsrneier H. Klinischer Veriauf bei Bietti sch er kristalliner tap etoretin aler Degeneration . Klin Monatsbl Aug enheilkd 1983; 183:259-61 .
12. Web er U, Adler K, Henn ekes R. Kristalline Choriore tinopathie rnit mar ginaler kornealer Beteiligung . Klin Monatsbl Augenhel ikd 1984; 185 : 268- 71. 13. Francois J, DeLaey JJ . Bietti 's cry stalline fundus dystroph y. Ann Op hthalmol1978 : 10:709-16. 14. Trabo ulsi EI, Faris BM. Crystal line retinop athy. Ann Ophthalmo l 1987; 19:156 -8. 15. Matsuo H, Togashi M, Suzuki R. A case of peculiar fundus with twinkled small white flec ks. Jpn J Clin Op hthalmol 1972; 26:1395-401 . 16. Hu D-N. Opht halmic gene tics in China. Ophthalmic Paediatr Genet 1983 ; 2:39-45. 17. Gass JDM. Discussion, 176-7. Of: Welch RB. Bietti's tapetoretinal degeneration with marginal corneal dystrophy: crys talline retinopathy. Trans Am Ophthalmol Soc 1977 ; 75 :164-79 . 18. Welch RB. Bietti's tapetor etin al degene ration with marg inal co rneal dyst rophy: crystalline retinopa thy . Trans Am Ophthalmol Soc 1977 ; 75 :164-79. 19. Ueno H, Matsuo N, Hasegawa E, et al. Studies on a new patt ern of the flecked retina. Jpn J Clin Ophthal mol1976 ; 30:33-46. 20. Okub o A, Mori R, Takaha shi S. A rare case of the flecked retina . Folia Ophthalmol Jpn 1980 ; 31 :1536-43 . 21. Fujiwara H, Nishikiori T, Kono M. Two cases of c rystalline retinop athy. Jpn J Clin Op hthalmo l 1982; 36:30 1-6. 22 . Hayasak a S, Okuyama S. Crystalline retinopathy. Retina 1984 ; 4:17781 . 23 . Yoshida A, Nara Y, Takahashi M. Crystalline retinop athy: Evaluation of blood-retinal barrier by vitreous f1uorophotometry . Jpn J Ophthalmol 1985; 29:290-300 . 24 . Yuzawa M, Mae Y, Matsui M. Bietti's crystalline retinopathy . Oph thalmic Paediatr Genet 1986 ; 7:9-20 . 25. Mauldin WM, O 'Con nor PS. Crystalline retinopathy (Bietti's tapetore tinal degeneration without marginal corneal dystrophy). Am J Op hthalmol 1981 : 92 :640- 6. 26. Gilbert WR Jr, Smith JL, Nyhan WL. The Sjogren-Larsso n syndrome. Arch Ophthalrnol 1968 ; 80:308-16. 27 . Anderson B Jr . Disc ussion, 175-6. Of: Welch RB. Bietti's tapetoretinal degeneration with marg inal co rneal dystro phy: crys talline retinopathy . Trans Am Op hthalmol Soc 1977 : 75:164-79. 28 . Sarks SH, Sarks JP. Ag e-related mac ular degeneration : atroph ic form . In: Ryan SJ, ed. Retina. Vol. 2: Medica/ Retina, St. Louis: CV Mosby Co , 1989 ; 149-73. 29 . Toussaint D, Vereerstra eten P, Goffin P, et al. Hyperoxalurie prirnaire. Etude clinique, histologique et cristallographique des lesions oculaires. Arc h Ophthalm ol (Paris) 1976; 36 :97-112. 30. Cog an DG , Kuwabara T, Silbert J, et al. Calcium oxalate and calcium phosphate crystals in de tache d retinas. Arc h Ophthalmol 1958 ; 60 : 366-71. 31 . Bullock JD, Albert DM, Skinner CW, et at Calcium oxalate retinopathy associated with generalized oxalosis: x-ray diffrac tion and elec tron mic rosco pic studies of crystal deposits. Invest Op hthalmol 1974; 13: 256-65. 32 . Donaldso n DD . Cys tinosis with extensive choroidal involvement. Arc h Op hthalmol 1965: 74:868-9. 33 . Kaiser -Kupfer MI, Kupfer C, Rodrigues MM . Tarnoxifen retinopathy: a clinicopathologic rep ort. Ophthalmology 198 1; 88 :89- 93 . 34. Fraunfelder FT. Interim report: National Registry of Possible DrugInduced Ocular Side Effects. Oph thalmo logy 1980; 87 :87-90. 35. Boudr eault G, Co rtin P, Co rriveau L-A, et al. La retlnop athie la can Iha xanthine : 1. Elude clinique de 5 1 consommateurs. Can J Ophthalmol 1983; 18:325-8. 36. Fribe rg TR, Gragoudas ES, Regan CDJ. Talc em boli and rnacu lar ischemia in intravenous drug abuse . Arch Ophthalmol1 979 ; 97:1089-
a
91 . 37. Deutman AF. Atrophia gy rata und Hyperornithinamie. Klin Monat sbl Augen helikd 1976 ; 168:278. 38. Takki K. Gyrate atrophy of the choroid and retina associated with hyperornithinaemia. Br J Ophthalmol1974; 58 :3-23.
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Abstract: 'A black woman was identified with a tapetoretinal degeneration with sparkling intraretinal crystals, retinal pigment epithelial and choro idal atrophy, night blindness, color vision abnormalities , and paracentral scotomas. This constellation of findings is most consistent with the diagnosis of Bietti's crystalline dystrophy. Eight other family members were identified with intraretinal crystals similar to those seen in the proband but in varying degrees of progression . Transmission electron microscopy of circulating lymphocytes in several patients demonstrated crystals and granular osmophilic material of unknown composition contained within abnormallysosomes. These crystals are similar in appearance and locat ion to those seen in cholesterol ester storage disease . This family demonstrates an autosomal dom inant inheritance pattern , as well as other difference s from classic Bietti's crystalline dystrophy . The authors , therefore, suggest that this new entity be named autosomal dominant crystalline dystrophy. Ophthalmology 1991; 98:658-665
In 1937 and 1942, Bietti 1-3 reported several patients with an unusual ocular fundus appearance beginning in the third decade and characterized by a tapetoretinal degeneration with small, sparkling, yellow-white crystals in the posterior pole, atrophy of the retinal pigment epithelium, and choroidal sclerosis. Bietti's original patients also demonstrated sparkling yellow crystals in the superficial marginal cornea, although later reports have shown that this is not alwaysa constant feature of the disease. A recent histopathologic study of patients with Bietti's crystalline dystrophy" demonstrated crystals resembling cholesterol or cholesterol ester crystals in circulating lymphocytes under transmission electron microscopy (TEM), suggesting that Bietti's crystalline dystroph y may be due to a systemic abnormality of lipid metabolism . We examined a 54-year-old black woman with crystalline retinopathy identical in appearance to Bietti's crystalline dystrophy. Complete ophthalmic examinations were performed on all available family members. A num-
ber of other family members were found with various stagesof crystalline retinopath y in a pattern which suggests autosomal dominant rather than autosomal recessive inheritance as has previously been described for Bietti's crystalline dystrophy. In several patients, TEM of the buffy coat of peripheral blood demonstrated crystals that are identical in appearance to cholesterol ester crystals within abnormal storage lysosomes oflymphocytes. This finding has been previously described in cholesterol ester storage disease.' In addition, granular osmophilic material of unknown composition was found within the lysosomes of circulating lymphocytes under TEM. The findings in these family members are presented , and the differences between this disorder and classic Bietti's crystalline dystrophy are discussed. We propose that the name autosomal dom inant crystalline dystrophy be given to this new, separate disease entity.
MATERIALS AND METHODS Originally received: September 7, 1990. Revision accepted : Decemb er 27 , 1990 . Departm ent 01 Ophthalmology, Henry Ford Hospital, Detroit. 2 Departm ent 01 Hematology, Henry Ford Hosp ital, Detroit. 3 Department 01 Genetics , Henry Ford Hosp ital, Detroit. t
Reprint requ ests to Julian J. Nussbaum, MD, Department 01 Ophthalm ol· ogy, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202 .
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All available family members of the proband were contacted, and a pedigree chart was outlined for the family (Fig 1). Each family member was given an identifying number, corresponding to his/her position on the pedigree chart , and complete ophthalmologic examinations were performed on those patients willing to submit to exami-
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IV
. ...
a Male
11
o Female
eAOCO
l'
IZ1 Deceased
f) Crystals
Only
[:] Examiled-Normal
Fig 1. Pedigree chart of family with auto somal dominant crystalline dystrophy.
nation. Any patients identified with intraretinal crystals were photographed and , when possible, the following tests were performed. Full-field electroretinograms (ERGs) were recorded from both eyes after dilation and 30 minutes ofdark adaptation using Burian-Allen corneal contact lens electrodes. A Nicolet Ganzfeld (Madison, WI) stimulator generated a series of single flash and flicker stimuli in the following sequence: I) single flashes of dim blue light (blue filter, 0.25 strobe intensity), which generated a rod isolated scotopic response; 2) single flashes of red light (red filter, 1.25 strobe intensity), which generated a matched rod response plus early cone oscillations; 3) single flashes of white light (no filter 0.25 and 1.25 strobe intensity), which generated a mixed rod-cone response and a maximal response, respectively; 4) flashes of bright white light flickering at 30 Hz (no filter, 1.25 strobe intensity); and 5) light-adapted responses to single flashes of bright white light (1.25 strobe intensity with bright background illumination), which generated a cone-isolated (photopic) response. Electroretinographic responses were amplified (gain = 104 ) , filtered (bandwidth 1-250 Hz), and displayed on a Nicolet CA-1000 signal averaging computer. Both single responses and computer-averaged responses were examined and compared with those obtained from normal adults. Response parameters were considered abnormal if the y exceeded 2.5 times the standard deviation of the norm. Visual fields were plotted with the Humphrey visual field analyzer using the standard 30-2 program with the exception ofone patient in whom visual fields were plotted
on the Goldmann perimeter. Color vision of each eye was tested separately using the American Optical Company pseudo-isochromatic plates. Routine fluorescein retinal angiography also was done. Transmission electron microscopy of leukocytes collected from the buffy coat of peripheral venous blood was performed in the following manner. The buffy coat of peripheral blood was fixed in 30% cacodylate buffered glutaraldehyde, pH 7.4. These cells were postfixed in I % osmic acid, embedded in Araldite , stained with uranil acetate and lead citrate, and viewed with a TEM (Zeiss Model 109, Oberkochen, Germany).
CASE REPORTS Case 1 (proband, patient 111-3). A 54-year-old black woman was seen in February 1989, with complaints of gradually worsening visual acuit y. She had complained of poor night vision for man y years, and was noticing some difficulties with color perception . She had been seen at another institution 15 years previously, and was noted to have a visual acuity of 20/25 in both eyes and normal color vision as tested with pseudo-isochromatic plates. Results of ERG at that time were found to be subnormal, and the fundu s was described as having pigmentary clumping and multiple white "exudates." There was no family history of consanguinity or of family members with similar visual complaints. Her medical history was significant for diabetes controlled with oral hypoglycemic agents, hypertension, gout,
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,· · aD. - "I ...
....
1
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·- .. -=. ..·,-. . ,
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Fig 2. (Case I, proband, patient III-3). Goldmann visual fields of both eyes (00 = right; OS = left) demonstrate enlarged blind spots and paracentral scotomas in both eyes.
and a previous stroke with multiple lacunar infarcts noted on computed tomographic scan. The dietary history was unremarkable for ingestion of foods containing large amounts of oxalate, and the patient denied any prior surgical procedures under general anesthesia. On examination, the patient's visual acuity was 20/50 with a moderate myopic correction in both eyes. Muscle balance, extraocular movements, and intraocular tension measurements were all normal. Her pupils measured 3 mm in both eyes, were slightly sluggish, but without any relative afferent pupillary defect. Results of slit-lamp examination were normal; specifically, no marginal corneal crystals were noted. Goldmann visual fields showed enlarged blind spots and paracentral scotomas in both eyes (Fig 2). Color vision was decreased with the patient correctly identifying 6 of 18 color plates in each eye with difficulty. Results of dilated funduscopic examination showed numerous sparkling, refractile, yellow-white deposits scattered throughout the posterior pole in both eyes (Fig 3). These crystalline deposits were noted in all layers of the retina, and some had coalesced to form large clumps of yellow-white deposits. The refractile nature of these crystalline deposits is not easily reproduced with fundus photography. There were extensive areas of atrophic-appearing retinal pigment epithelium and several large pigment clumps in the posterior pole. The optic discs showed minimal pallor, and mild arteriolar narrowing was noted. Results of peripheral examination showed a few retinal crystals and occasional pigment aggregation. Fluorescein an-
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giography showed baring of fluorescence of medium and large choroidal vessels in the posterior pole during early stages, indicating retinal pigment epithelial depigmentation and choriocapillary loss (Fig 4). Later stages (Fig 5) showed large areas of choroidal and scleral staining. Electroretinography showed all wave forms to be diminished in amplitude to 50 to 60% of normal, especially in the cone responses. Implicit timing also was delayed in all wave forms. Results of VDRL and TPHA were both nonreactive. A complete blood count and serum ornithine levels were within normal limits. A serum lipid profile showed only moderate hypercholesterolemia. Case 2 (patient 11-4). A 74-year-old black woman (the maternal aunt of the proband) is the only living relative of the proband from a previous generation. This patient was not seen in our clinic. She was examined by her personal ophthalmologist who noted a visual acuity of 20/25 in both eyes and a fundus appearance consistent with Bietti's crystalline dystrophy (personal communication; M. Adams Hall, MD). This patient has refused further evaluation or testing, and no photographs are available. Case 3 (patient IV-9). A 30-year-old black woman (a daughter of the proband) was examined. She complained of poor night vision, but did not have color perception abnormalities. In both eyes, visual acuity was 20/20 and the pupils measured 4 mm, with no relative afferent pupillary defect. Results of slit-lamp examination were normal; specifically, no corneal crystals were noted. Color vision and Humphrey visual fields were normal. On funduscopic examination, the patient was noted to have multiple yellow-white sparkling crystalline deposits identical to those seen in the proband. These crystalline deposits were noted in both eyes clustered in a group temporal to the fovea. The remaining results of the fundus examination were normal. Fluorescein angiography demonstrated late hyperfluorescence of these deposits. Full-field ERG testing was normal. Case 4 (patient IV-12). A 25-year-old black woman (a daughter of the proband and a half sister to patient 3) was examined. She denied any night blindness or color vision abnormalities. On examination, her visual acuity was 20/20 in both eyes with a small myopic correction. Color vision and Humphrey visual field testing were normal. The pupils measured 3 mm in both eyes with no relative afferent pupillary defect, and results of slitlamp examination were normal with no corneal crystals present. Results of funduscopic examination showed multiple tiny yellowwhite crystals scattered throughout the posterior pole in both eyes, mainly temporal to the fovea (Fig 6). These crystals were much fewer in number than those found in the previous patients, and the remaining results of the fundus examination were normal. Although these crystalline deposits are clearly seen both clinically and in the photographs, the refractile nature of these deposits cannot be easily reproduced photographically. Fluorescein angiography showed no hyperfluorescence or hypofluorescence of these isolated crystalline deposits. Full-field ERG testing was within normal limits. Case 5 (patient IV-I0). A 28-year-old asymptomatic black man (the son of the proband and the brother of case 4) was examined. He denied any night blindness or color perception difficulties. On examination, visual acuity was 20/20 in both eyes. Color vision and Humphrey visual fields were normal. The pupils measured 4 mm in both eyes with no relative afferent pupillary defect. Results of slit-lamp examination were normal with no corneal crystals present. Results of fundus examination showed multiple yellow-white crystalline deposits in the posterior pole (Fig 7). These crystals were distributed mainly temporal to the fovea and were few in number, although more numerous in the right eye than the left. These crystalline deposits were identical to those seen in the previously described patients. Again, although they are easily seen clinically, fundus photographs do not dern-
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Fig 3. Top left , fundus photograph of the right eye of case I. Notice the multiple tiny crystalline.deposits, larger clumps of crystalline material, atrophy of the retinal pigment epithelium, and occasional pigment clumping. The fundus appearance of the left eye was identical. Fig 4. Top right, fluorescein retinal angiography of the right eye of case I. Baring of fluorescence of medium and large choroidal vessels is present, indicating RPE depigmentation and choriocapillaris loss. Fig S. Center left, fluorescein retinal angiography of the right eye of case I, later stage. Large areas of choroidal and scleral staining are present, again indicating RPE depigmentation and loss of choriocapillaris. Fig 6. Center right, fundus photograph of the left eye of case 4 (patient lV-12). Notice the tiny yellow-w hite crystals, few in number, scattered throu ghout the posterior pole. Fig 7. Bottom left , fundus photograph of the left eye of case 5 (patient IV-I 0). Occasional tiny yellow-white crystals are seen throughout the posterior pole in this patient also. Fig 8. Bottom right, fundus photograph of the left eye of case 6 (patient IV-2). Notice the tiny, yellow-white crystals seen throughout the posterior pole. o nstrate these intraretinal cry stals well. Fluorescein angiography was normaL Full-field ERG testing was abno rmal with reduced rod and cone components and dela yed im plicit timing. Case 6 (patient IV-2). A 32- year-old black woman (a niece of the proband) was examined with co m plaints of occasional trouble with night vision but no difficulties with color perception.
On examination,visual acu ity was 20/20 in both eyes. Co lor vision a nd Humphrey visual fields were normal. The pupils were equal a nd reactive with no relati ve afferent pupillary defect. Results of slit-la m p examination were normal with no marginal co rneal crystals present. On funduscop ic examination, multiple yellow-white crystalline deposits were noted in the fundus in
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both eyes (Fig 8). Although easily seen clinically, the crystalline deposits are difficult to document photographically. These crystalline deposits were identical to those seen in the other patients, although they were more numerous than those found in cases 4 and 5. The crystalline deposits were not arranged in groups as were those found in case 3 and were not nearly so numerous as those seen in the proband. The background color of the fundus and the retinal periphery were normal. Fluorescein angiography and full-field ERG testing were within normal limits. Case 7 (patient IV-l6). A 37-year-old asymptomatic black woman (a niece of the proband) was examined . She denied any night vision or color vision abnormalities. On examination, visual acuity was 20/20 in both eyes. Color vision and Humphrey visual field testing were normal. The pupils were equal in both eyes and no relative afferent pupillary defect was seen. Results of slit-lamp examination were normal with no corneal crystals present. Results of funduscopic examination demonstrated five or six yellow-white crystalline deposits located in the foveal area of the right eye only. These crystals were identical in appearance to those seen in the other patients. Fluorescein angiography was normal, and the patient refused to return for further testing or follow-up. Case 8 (patient 111-8). A 54-year-old black woman (a first cousin of the proband) who denied night blindness or color vision abnormalities was seen in the clinic. On examination, visual acuity was 20/20-2 in both eyes. Color vision and Humphrey visual field testing were normal. The pupils measured 3 mm in both eyes with no relative afferent pupillary defect. Results of slit-lamp examination were normal with no corneal crystals present. Results of funduscopic examination showed scattered intraretinal crystalsidentical in appearance and numbers to those seen in case 6. Fluorescein angiography and full-field ERG testing were within normal limits. Case 9 (patient IV-24). A 31-year-old black woman (first cousin once removed from the proband, the daughter of case 8) was examined . She denied any visual problems, color vision abnormalities , or night blindness. On examination , visual acuity was 20/15 in both eyes. Color vision and Humphrey visual fields were found to be normal. The pupils measured 3 mm in both eyes with no relative afferent pupillary defect. Results of slitlamp examination were normal with no corneal crystals present. Results of funduscopic examination showed fairly normal-appearing macular areas with only rare crystalline deposits. Temporal to the macula in the right eye, a large clump of crystalline deposits approximately 2 to 3 disc diameters in size was noted . The background color of the fundus was slightly different in this area. Fluorescein angiography and full-field ERG testing were within normal limits.
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Fig 9. Case I, proband, patient II1-3. Transmission electron micrograph of peripheral blood lymphocyte. A lysosome (arrow) containing a crystal and granu lar osmophilic materi al (original magn ification , X 17,069 ).
Fig 10. Transmission electron micrograph, higher power view of Figure IO(case I). The lysosome shows a long narrow crystal (arrow) and granular osmophilic material with clear spaces (original magnification, X67,645).
PATHOLOGIC FINDINGS
Three of our affected patients were willing to submit samples of peripheral blood for TEM analysis. The results of this analysis follow. Case 1 (proband, patient 111-3). Occasional circulating lymphocytes demonstrated abnormallysosomes containing crystals and inclusions (Figs 9-12). The appearance of these crystals resembled that of the cholesterol ester crystals which are seen in cholesterol ester storage disease.' The crystals measured up to 0.54 JLm in length and 0.18 JLm in width, and, like the crystals seen in cholesterol ester storage disease, were clearly present in the lysosomes of the circulating lymphocytes. The crystals were combined with granular osmophilic material of unknown composition within the lysosomes. Other lysosomes were noted that contained only this granular osmophilic material with no crystals. Case 5 (patient IV-lO). Occasional lymphocytes showed abnormallysosomes containing granular osmophilic material. No clear spaces or crystals were observed.
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Fig 11. Transmission electron micrograph of lymphocyte with two abnorrnallysosomes in case I. The larger lysosome clearly shows crystals (arrow) (original magnificati on , X 18,716).
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Fig 12. Transmission electron micrograph, higher power of Figure 12 (case I). The larger lysosome contains 3 crystals (original magnification, Xn,077).
Fig 13. Case 8, patient III-8. Transmission electron micrograph oflymphocyte. Lysosomes containing osmophilic granular material are present. One of the Iysosomes contains a clear space resembling a crystal (arrow) (original magnification, X91,671).
Case 8 (patient 111-8). Occasional circulating lymphocytes demonstrated abnormal lysosomes containing granular osmophilic material. The osmophilic material contained minute clear spaces somewhat resembling crystals. However, no definite crystal formation was observed (Fig 13).
DISCUSSION Since Bietti's original articles, cases of Bietti's crystalline dystrophy have been described in patients from Europe 6-12 Brazil.P Algeria 13 Qatar 13 Lebanon 14 China/5-18 Japan,lIl-24 and the' United States.4. 17,25 T~o brothers who were identified in the United States with Bietti's crystalline dystrophy are the only two black patients described with this disorder in the literature." In our study, a large family of black patients was examined for the presence of crystalline retinopathy. All available relatives of the proband who were willing to be examined
were accepted into this family study, and a total of 26 patients were seen. The proband had a clinical,angiographic, and ERG appearance which was identical to Bietti's crystalline dystrophy; case 2 (patient 11-4) was identified as having a similar funduscopic appearance. Seven other family members were identified with intraretinal crystals identical to those seen in the proband but without most of the other signs of Bietti's crystalline dystrophy. Intraretinal crystals have been described in a number of other situations, including the Sjogren-Larsson syndrome," calcific aortic stenosis." calcified macular drusen," and primary oxalosis, an autosomal recessive disorder." Intraretinal oxalate crystals have been described less commonly in patients with secondary oxalosis caused by thiamine or pyridoxine deficiency. Oxalosis also can be caused by ingestion of ethylene glycol as well as spinach or rhubarb gluttony, but no cases of retinal crystals from these sources have been reported." In addition, oxalate crystals have been found in the retina after longstanding retinal detachments'" as well as after administration of methoxyflurane general anesthesia." Crystalline deposits in the fundus have been described in systemic cystinosis. However, these were believed to lie primarily within the choroid.F Tamoxifen, an anti-estrogen medication, has been noted to cause retinal crystals after 12 to 18 months in some patients.P:" Macular crystalline deposits also have been noted after the use of canthaxanthine, a skintanning agent." Retinal crystals also are seen in talc retinopathy, a condition seen in intravenous drug abusers who inject crushed oral medications containing talc compounds intravenously." None of the previously mentioned conditions have the same clinical appearance as our patients, in that our proband showed marked retinal pigment epithelium and choroidal atrophy as well as diminished ERG amplitudes in addition to retinal crystals. Gyrate atrophy is an autosomal recessive disorder with retinal pigment epithelium and choroidal atrophy, subnormal or extinguished ERGs, and hyperornithinemia." Takki 38 noted numerous glistening crystals scattered at the equator in the most advanced stages of gyrate atrophy, but the retinal appearance of gyrate atrophy is quite different from our patients, and ornithine levels were found to be normal in the proband. The clinical picture seen in our patients also might be confused with any of a number of flecked retina syndromes. However, these flecked retina syndromes do not have the distinctive crystalline appearance that our patients demonstrated. The constellation of crystalline retinal deposits, retinal pigment epithelium and choroidal atrophy, central or paracentral scotomas on visual fields, and diminished ERGs has only been described previously in Bietti's crystalline dystrophy. The occurrence of Bietti's crystalline dystrophy in siblings and in the offspring of consanguineous parents has been seen in a number of cases and, therefore, an autosomal recessive inheritance pattern has been postulated for this disease. In several of the published reports, available family members were examined, but most studies have simply noted that no family members were known to have ocular disease. In an extensive family survey reported by HUl6 from China, 35 patients with
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Bietti's crystalline dystrophy were identified from 25 separate families. No parents or children of the affected patients were found with the disease, although 19.2% of siblings were found to be affected. In addition, parental consanguinity was found in approximately 20% of the cases. Therefore, an autosomal recessive inheritance pattern was believed to be likely. Of the 26 patients examined in our study, seven were younger than 14 years of age, all from generation V. In classic Bietti's crystalline dystrophy, the onset of disease is usually in the third decade, and the youngest reported case was 15 years of age." All of the young patients in our study were, indeed, negative for any crystalline retinopathy. Of the remaining 19 patients (age range, 18-78 years), 9 (47%) were found to have sparkling intraretinal crystals similar to those described in Bietti's crystalline dystrophy. Two of these patients (cases 1 and 2) had fundus findings which were consistent with the diagnosis of Bietti's crystalline dystrophy, whereas the other patients had intraretinal crystals alone. The absence of affected individuals in generation V suggests a late onset of the disorder. Five of the individuals examined in generation V were the offspring of mothers with crystalline deposits, and none was affected . In this pedigree, only one individual, patient IV-2, was affected and had a parent, patient III-I , who was apparently unaffected. The parents of all other affected individuals who were examined, were affected . With multiple generations affected in a nonconsanguineous family, and males as well as females affected, autosomal dominant inheritance is likely. The possibility of recessive inheritance ofthe crystalline retinopathy with heterozygotes manifesting onl y crystals (pseudodominance) is unlikely because the proband and her maternal aunt are both affected with retinopathy, and we could not elicit a history of consanguinity between the proband's father and either maternal grandparent. This genetic transmission is different from that described in Bietti's crystalline retinopathy, and we suggest that the name autosomal dominant crystalline dystrophy be given to this new disorder. Since many of the reported cases of Bietti's crystalline dystrophy have not had family members examined, some of these families may have the same gene as is present in the subjects in our report. The fact that only one of the nine affected individuals in our family presented with symptoms shows quite clearly that many affected individuals could be missed unless closely examined. Those patients in whom intraretinal crystals were found with no other signs of crystalline dystrophy probably represent incomplete penetrance of the dominant gene or a forme-fruste of the disease. This theory is borne out by several of our patients. Case 5 (patient IV-IO), although completely asymptomatic, demonstratedabnormal ERG potentials in addition to the intraretinal crystals. He also was found to have abnormal Iysosomes containing granular osmophilic material on TEM. Case 8 (patient III-8) also showed these granular materials within lysosomes of the circulating lymphocytes despite being completely asymptomatic. Neither of these patients demonstrated complete crystal formation within the lysosomes, whereas 664
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the proband, who was symptomatic and showed more extensive retinopathy, did have crystal formation. It is uncertain at this point whether those patients identified in our study with crystalline deposits alone would progress in time. Although numbers and distribution of crystalline deposits varied in our study patients, this could be explained by incomplete expression of a dominant gene rather than progressive stages of the complete disease . Bietti's crystalline dystrophy is usually diagnosed around the third decade with a history of visual impairment dating years earlier. This pattern of progression was followed by our proband; however, all the patients in our study with crystals alone have been asymptomatic, despite the age range of 25 to 54 years. This again suggests limited expression of the disease rather than early stages of progression in these patients. There are other findings in our group of patients which distinguish this crystalline retinopathy from that described by Bietti. Corneal crystals were not found in any family members, although many cases of Bietti's crystalline dystrophy described in the literature have not shown these marginal corneal crystals either. Several reports of Bietti's crystalline dystrophy have stressed a male preponderance, although a review of cases shows that there is only a slightly higher rate of occurrence in males. Of the 37 cases of Bietti's crystalline dystrophy in the literature in whom sex was identified, 21 were male and 16 were female. In contrast, the family in our study shows a marked female preponderance of affected patients. In those patients older than 18 years of age who were examined, 8 (73%) of 11 females were affected, whereas only one (14%) of seven males was affected. This was found to be significant by the chi-square test (P = 0.016). The excess of females to males in this pedigree is unexplained. We find no evidence of lethality in males with the gene since the sex ratio of the offspring of affected individuals is 25 males to 19 females. The numbers in our pedigree are so small that this could be due to chance alone, or it may be another manifestation of a disorder distinct from Bietti's crystalline dystrophy. In 1989, Wilson et al" conducted a histopathologic study on three patients with Bietti's crystalline dystrophy. Corneal biopsy specimens from two of these patients demonstrated crystals resembling cholesterol or cholesterol ester and complex lipid inclusions in corneal and conjunctival fibroblasts under TEM. These crystals were variably combined with granular osmophilic material. Similar crystals and inclusions were noted in circulating lymphocytes under TEM. These findings were believed to indicate that Bietti 's crystalline dystrophy may be due to a systemic abnormality of lipid metabolism. In the patients in our study, we have identified crystals and granular osmophilic material similar to those described in Bietti's crystalline d ystrophy in the study by Wilson et al." We have clearl y localized the inclusions to abnormal lysosomes of the circulating lymphocytes. In case 8 (patient III-8) , minute clear spaces were observed within the granular osmophilic material. The nature of the granular osmophilic material is not known. It may represent a precursor to crystal formation, but further biochemical study of the lymphocytes would be required
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AUTOSOMAL DOMINANT CRYSTALLINE DYSTROPHY
to confirm this. The pathologic findings of crystals and granular osmophili c material within abnormallysosomes of circulating lympho cytes are very similar to those reported in cholesterol ester storage disease. Similar findings were described in the cases of Bietti's crystalline dystrophy described by Wilson et al," although no mention is made in that report of abnormal lysosomes. This suggests that both Bietti's crystalline dystrophy and autosomal dominant crystalline dystrophy may be metabolically very similar to each other and to cholesterol ester storage disease, although each disease seems to have distinct clinical presentat ions. Since complete examinations of all family members were not performed in Wilson et al's study, it is possible that his patients may have represented autosomal dominant crystalline dystrophy rather than Bietti's crystalline dystrophy, although Wilson et al's findings of corneal crystals are in contrast to the lack of crystals seen in our pedigree. In either case, the findings of corneal crystals, retinal crystals and pathologic findings seem to link these three disease conditions together as similar but distinct disease entities. The findings of hypercholesterolemia and hyperbetalipoproteinem ia noted by investigators in some cases of documented autosomal recessive Bietti's crystalline dystrophy seem to support this theory.6,9.12 Testing for acid lipase deficiency was not performed on the patients in our study but might provide a link to cholesterol ester storage disease in future cases of crystalline dystrophy.
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