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Potential Implications for Pathophysiology in a Type 1 Diabetic Patient Affected by Stargardt Disease

Potential Implications for Pathophysiology in a Type 1 Diabetic Patient Affected by Stargardt Disease

European Review for Medical and Pharmacological Sciences 2002; 6: 75-79 Potential implications for pathophysiology in a type 1 diabetic patient affected by

C. GIUSTI

Department of , “Campus Bio-Medico” University - Rome (Italy)

Abstract. – Purpose/Method: To present a ly) affected, presenting a history of gradual 35-year-old woman affected by type 1 bilateral deterioration of central vision. The mellitus, Stargardt and probability of maintaining 20/40 or better vi- flavimaculatus. To our knowledge, this associa- tion is unusual and not yet described in the oph- sion in at least one eye is estimated to be thalmic literature. 52% by age 19 and 22% by age 39. Once vi- Results/Conclusions: was re- sual acuity drops below 20/40, it tends to de- duced to < 20/200 in both eyes, color vision was crease rapidly to 20/200, which usually occurs absent and computerized perimetry showed an by the end of the third decade. No treatment absolute central . Pattern visual evoked is effective, although the use of antioxidants potentials and electroretinogram (ERG) (sco- 2,3 topic, photopic and flicker) were considerably has been suggested . reduced in amplitudes. Full-field ERG was within In this paper, we present a 35-year-old normal limits whereas oscillatory potentials woman affected by mellitus, were reduced in number and amplitude. STGD1 and FFM, an association that is un- angiography confirmed the diagno- usual to our knowledge and not yet described sis of Stargardt maculopathy and fundus flavi- in the ophthalmic literature. An updated re- maculatus but no diabetic was clini- view of this early onset cally evident. Potential interactions between the diabetic and the retinal degen- has also been done. erative disorder are hypothesized and dis- cussed. Key Words: Case Report Diabetic retinopathy; Fundus flavimaculatus; Maculopathy; Stargardt disease; Type 1 diabetes melli- I.Z., a 35-year-old female affected by tus. STGD1 and FFM, presented with central vi- sion loss in both eyes (OU) lasting more than five years. The diagnosis of STGD1 and FFM had been already confirmed in the past not only clinically but also genetically by linkage Introduction to the ABCA4 gene region. Family history was negative both for diabetes and for any The term Stargardt disease (STGD1 – type of inherited degenerative retinal disor- McK 24820)1 refers to a maculopathy with der. various degrees of retinal pigment epithelial The patient, also affected by type 1 - changes (atrophy, dispersion, granulation) dependent diabetes mellitus (IDDM), was throughout the macula. Peripheral, yellowish, regularly attending the Center for the Study ill-defined pisciform (fishtail-shaped) flecks of Diabetes (Institute of Internal Medicine II, may be associated, thus representing the so University of Rome “La Sapienza”) and clas- called fundus flavimaculatus (FFM)2,3. sified according to the National Diabetes Children between the ages of 6 and 20 Data Group criteria4. Duration of the disease years are more commonly (but not exclusive- was about 25 years and glycemic control was

75 C. Giusti somewhat irregular, as demonstrated by a toma in OU. Pattern visual evoked potentials glycosylated hemoglobin (HbA1c) always be- and electroretinogram (ERG) (scotopic, pho- tween 9.5 and 10%. The subject was not tak- topic and flicker) were considerably reduced ing other medication than subcutaneous hu- in amplitudes. Full-field ERG was within man insulin (regular and long acting) and, de- normal limits whereas oscillatory potentials spite the presence of microalbuminuria, were reduced in number and amplitude. pressure and serum creatinine concen- trations were within normal limits. No other systemic diseases were present. Best corrected visual acuity was < 20/200 in Discussion OU. Slit lamp examination of the anterior segment demonstrated no relevant abnormal- The terms STGD1 and FFM are often used ities. The was transparent in OU and the interchangeably to describe a degenerative intraocular pressure was normal (13 mmHg). retinopathy occurring within the posterior Fundus examination and fluorescein angiog- pole and in the pre-equatorial and raphy confirmed the clinical diagnosis of both disease, which may be variations of a STGD1 and FFM, showing the typical retinal single disorder, are inherited in an autosomal pigment epithelial atrophy in a “bull’s-eye” recessive pattern1. Mutations in the photore- pattern. In contrast, no clinical signs of dia- ceptor ATP-binding cassette transporter betic retinopathy (DR) were present (Figure (ABCR) gene (ABCA4), are responsible for 1). Color vision was absent and computerized this disease5-8. ABCR resides in the internal perimetry showed an absolute central sco- disc membranes of photoreceptor outer seg-

Figure 1. Stargardt disease and fundus flavimaculatus ().

76 Potential implications for pathophysiology in a type 1 diabetic patient affected by Stargardt disease ments and appears to function as a specific symptoms and signs of cone-rod type transporter that delivers all-trans-retinal to pigmentosa, including , narrowing the enzyme retinol dehydrogenase in order to of retinal vessels and ERG abnormalities2,3. have it converted to all-trans-retinol and, It has been recently proposed that patients thereafter, delivered to the retinal pigment with STGD1 and FFM may be classified into epithelium (RPE) to begin the visual cycle three different groups based on the absence again9. Approximately 250 missense, or presence of generalized loss of either pho- frameshift, point and nonsense mutations topic or photopic and scotopic function13. In have been identified together with several particular: group 1 – severe pattern ERG ab- polymorphisms and a high allelic heterogene- normalities with normal scotopic and full- ity5,6. For example, a unique sequence varia- field ERGs; group 2 – additional loss of pho- tion in exon 19 of the ABCA4 gene, causing topic function; group 3 – loss of both scotopic an amino acid substitution T972N in the and photopic function. It has been hypothe- ABCR protein, has been recently found to sized that these three groups may represent determine a different clinical expression of distinct phenotypic subtypes of Stargardt dis- the disease in two pairs of siblings with ease13. STGD17. Moreover, missense mutations, Post-mortem histopathologic examination mapping outside known functional regions of of patients with FFM demonstrated that the the ABCA4 gene, have been reported to al- RPE cells are much larger and more densely low a longer residual ABCR activity, thus de- packed with an intense PAS-positive sub- termining a later onset of the disease8. stance, which is believed to be lipofuscin. The A clinically similar disease, the Stargardt- greatest concentration of lipofuscin pigment like macular distrophy (STGD3 – McK is within the posterior pole and the focal ar- 600110)1, is genetically differentiated by the eas of cellular hypertrophy are probably re- autosomal dominant inheritance and its cor- sponsible for the nonfluorescent yellow related mutations (ELOVL4 gene, located on flecks2,3. One major component of human chromosome 6q16)10-12. RPE lipofuscin is a diretinoid adduct, A2E, Initial clinical macular changes in STGD1 that appears to form within the photorecep- include ill-defined yellowish perifoveal flecks; tor outer segments from the spontaneous with progression, diffuse pigment epithelial condensation of phoshatidylethanolamine abnormalities are recognized as a glistening and the all-trans-retinal released from the area described as “beaten bronze”. Foveal photoactivated rhodopsin. Phagocytosis of changes in early stages may not be clinically outer segments by the RPE results in accu- apparent at all and fluorescein angiography mulation of A2E within the RPE where it ap- may reveal subtle central pigment epithelial pears to be trapped within phagolysosomes. defects that were not clinically obvious2,3. A2E efficiently absorbs blue light and is pho- As observed in our patient (Figure 1), totoxic to RPE cells in culture; its progressive “choroidal silence” or dark is present accumulation within the RPE suggests that in some cases of STGD1-FFM and may be the RPE may become increasingly suscepti- due to the increased filtering action of lipo- ble with age to the phototoxic damage. Thus, fuscin-laden RPE. In contrast to drusen, with both photoreceptor and RPE photodamage which the fishtail flecks may be confused, the may be mediated, at least in part, by retinoids yellow flecks of FFM typically appear nonflu- or retinoid derivates and ABCR, involved in orescent; if hyperfluorescence is present, it all-trans-retinal recycling, is found to be un- appears in an irregular pattern that does not usually sensitive to all-trans-retinal-mediated correspond to the flecks2,3. photooxidative damage in vitro9. The full-field ERG is usually normal in Population studies have indicated that STGD1 limited to the macula, while a de- some ABCR variant alleles may enhance sus- layed but otherwise normal b-wave pattern ceptibility to age-related macular degenera- may be seen with peripheral FFM. tion (AMD), the most common cause of visu- Electrooculogram (EOG) tends to be sub- al impairment in the elderly14, and carrier rel- normal in some patients, indicating a wide- atives of STGD1 patients may be predisposed spread functional disturbance of the RPE. A to develop this severe disease15. However, subgroup of patients with STGD1 develops conflicting results have been found in another

77 C. Giusti study in which the ABCA4 gene did not betic retinopathy and of retinal degenerative seem to be involved in statistically significant disorders and this is also confirmed by the fraction of AMD cases16. Finally, ABCR mu- observation that hyperbaric oxygen delivery tations have been suspected to predispose to has been proposed not only for RP patients, retinal toxicity in patients under chloroquine in order to bring about the rescue of retinal or hydroxychloroquine therapy17. photoreceptors21, but also for high risk DR22. A family manifesting both STGD1 and re- Moreover, a severe endothelial dysfunction, tinitis pigmentosa (RP) has been recently ob- probably mediated by the endothelin and the served18 and the notion that the severity of immune systems, characterize the early retinal disease is inversely related to the pathophysiology of diabetic microangiopathy, residual ABCR activity has been confirmed even in angiographically normal retinas23, in this study. On the contrary, while RP-af- thus representing a main cause of fected diabetics have already been described and hypoxia that would presumably have a in the ophthalmic literature, the association greater adverse impact in patients affected by between STGD1 and type 1 diabetes melli- STGD1 than it would in the context of a nor- tus, as observed in our patient, is, to our mal ABCR function. In fact, partial loss of knowledge, unusual. ABCR function produces progressive retinal RP and diabetes, if associated, occur inde- disease and the hypothesis that any environ- pendently. However, although each condition mental process, leading to a decrease in is relatively common, the number of subjects ABCR function, may increase the risk or ac- with both conditions is quite small, usually celerate the development of retinal disease configuring some of the classical clinical find- has already been postulated9. ings of Alstrom and Kearns-Sayre In conclusion, much remains to be investi- syndromes3. In these patients, DR is usually gated. However, we would like to emphasize absent and the protective factor is thought to the hypothesis that any factor, potentially be represented by a reduction in retinal me- able to reduce the retinal oxygen availability, tabolism, due to photoreceptor loss, impor- should be seriously taken into account in the tantly rods, that require a great deal of energy management of patients with tapetoretinal and a large oxygen supply for their metabolic degenerations and, therefore, a systemic dis- requirements19. In fact, it is certain that the di- ease such as diabetes should be considered abetic retina rather than being hyperoxic, as is with caution. At the same time, our clinical commonly supposed, borders on the patho- case seems to confirm that degenerative reti- logical anoxia and this seems to be especially nal diseases represent a protective factor true in dark , since in such circum- against the development of diabetic microan- stances the already low retinal PO2 markedly giopathy, even though the exact mechanism, decreases. Moreover, there is evidence not by which a cone dystrophy such as STGD1 only that a very small decrease in normal oxy- (unlike to a cone-rod typical RP) may act, re- gen supply may affect the retinal function, but mains to be clarified. also that the diabetic retina suffers from oxy- gen lack before the onset of a clinically evi- dent DR19. Finally, the hypoxic upregulation of vascular endothelial growth factor (VEGF), a main risk factor for DR, has been References found to be largely absent in diabetics who do 1) MCKUSICK VA. Mendelian Inheritance in Man. not develop a clinically evident retinopathy, Catalogs of Human Genes and Genetic despite the long-standing diabetes20. Disorders. Baltimore: John’s Hopkins University Considering all these previously published Press, 1998 (12th edition). reports, the clinical case that we present 2) GASS JDM. Stereoscopic atlas of macular dis- should not be simply regarded as fortuitous eases. Diagnosis and treatment. St. Louis: Mosby and of limited interest, as potential interac- 1987. tions between the diabetic microangiopathy 3) RYAN SJ. Retina. St. Louis: Mosby 1989. and the STGD1 might be hypothesized. In 4) NATIONAL DIABETES DATA GROUP. Classification of dia- fact, retinal oxygen availability represents a betes mellitus and other categories of in- critical point in the development both of dia- tolerance. Diabetes 1979; 28: 1039-1057.

78 Potential implications for pathophysiology in a type 1 diabetic patient affected by Stargardt disease

5) FUMAGALLI A, FERRARI M, SORIANI N, et al. Mutational 14) BERNSTEIN PS, LEPPERT M, SINGH N, et al. Genotype- scanning of the ABCR gene with double-gradient phenotype analysis of ABCR variants in macular denaturing-gradient gel electrophoresis (DG- degeneration probands and siblings. Invest DGGE) in Italian Stargardt disease patients. Hum Ophthalmol Vis Sci 2002; 43: 466-473. Genet 2001; 109: 326-338. 15) SHROYER NF, LEWIS RA, YATSENKO AN, et al. 6) BRIGGS CE, RUCINSKI D, ROSENFELD PJ, et al. Cosegregation and functional analysis of mutant Mutations in ABCR (ABCA4) in patients with ABCR (ABCA4) alleles in families that manifest both Stargardt macular degeneration or cone-rod de- Stargardt disease and age-related macular degen- generation. Invest Ophthalmol Vis Sci 2001; 42: eration. Hum Mol Genet 2001; 10: 2671-2678. 2229-2236. 16) GUYMER RH, HEON E, LOTERY AJ, et al. Variation of 7) EKSANDH L, EKSTROM U, ABRAHAMSON M, BAUER B, codons 1961 and 2177 of the Stargardt disease ANDREASSON S. Different clinical expressions in two gene is not associated with age-related macular de- families with Stargardt’s macular distrophy generation. Arch Ophthalmol 2001; 119: 745-751. (STGD1). Acta Ophthalmol Scand 2001; 79: 524- 530. 17) SHROYER NF, LEWIS RA, LUPSKI JR. Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline 8) YATSENKO AN, SHROYER NF, LEWIS RA, LUPSKI JR. Late- retinopathy: is retinal toxicity by chloroquine and onset Stargardt disease is associated with mis- hydroxychloroquine related to Stargardt disease? sense mutations that map outside known func- Am J Ophthalmol 2001; 131: 761-766. tional regions of ABCR (ABCA4). Hum Genet 2001; 108: 346-355. 18) SHROYER NF, LEWIS RA, YATSENKO AN, LUPSKI JR. Null missense ABCR (ABCA4) mutations in a family 9) SUN H, NATHANS J. ABCR, the ATP-binding cas- with Stargardt disease and . sette transporter responsible for Stargardt macu- Invest Ophthalmol Vis Sci 2001; 42: 2757-2761. lar dystrophy, is an efficient target of all-trans-reti- nal-mediated photooxidative damage in vitro. 19) ARDEN GB. The absence of diabetic retinopathy in Implications in retinal disease. J Biol Chem 2001; patients with retinitis pigmentosa: implications for 276: 11766-11774. pathophysiology and possible treatment. Br J Ophthalmol 2001; 85: 366-370. 10) DONOSO LA, EDWARDS AO, FROST A, et al. Autosomal dominant Stargardt-like macular dis- 20) MARSH S, NAKHOUL FM, SKORECKI K, et al. Hypoxic trophy. Surv Ophthalmol 2001; 46: 149-163. induction of vascular endothelial growth factor is markedly decreased in diabetic individuals who 11) BERNSTEIN PS, TAMMUR J, SINGH N, et al. Diverse do not develop retinopathy. Diabetes Care 2000; macular dystrophy phenotype caused by a novel 23: 1375-1380. complex mutation in the ELOVL4 gene. Invest Ophthalmol Vis Sci 2001; 42: 3331-3336. 21) VINGOLO EM, PELAIA P, F ORTE R, et al. Does hyper- baric oxygen (HBO) delivery rescue retinal pho- 12) EDWARDS AO, DONOSO LA, RITTER R 3RD. A novel toreceptors in Retinitis Pigmentosa? Doc gene for autosomal dominant Stargardt-like mac- Ophthalmol 1999; 97: 33-39. ular distrophy with homology to the SUR4 protein family. Invest Ophthalmol Vis Sci 2001; 42: 2652- 22) DUMITRU R. The hyperbaric method in the treat- 2663. ment of diabetic retinopathy: an alternative to laser therapy? Ophthal 1993; 37: 12-16. 13) LOIS N, HOLDER GE, BUNCE C, FITZKE FW, BIRD AC. Phenotypic subtypes of Stargardt macular dystro- 23) GIUSTI C. Retinopathy in juvenile diabetes: a 10- phy-fundus flavimaculatus. Arch Ophthalmol year (1990-2000) review. Pediatric Diabetes 2001; 119: 359-369. 2001; 2: 83-93.

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