Association of Adipose and Red Blood Cell Lipids With Severity of Dominant Stargardt Macular Dystrophy (STGD3) Secondary to an ELOVL4 Mutation

Abstract

To determine whether adipose and red blood cell membrane lipids, particularly long-chain polyunsaturated fatty acids such as docosahexaenoic acid and eicosapentaenoic acid, are significantly correlated with phenotype in a family with autosomal dominant Stargardt macular dystrophy (gene locus STGD3). A mutation in the ELOVL4 gene is responsible for the macular dystrophy in this family, and its disease-causing mechanism may be its possible involvement in fatty acid elongation in the retina. Methods: The subjects in this study included 18 adult family members known to have a 2-base pair deletion in the ELOVL4 gene. Control subjects included 26 family members without the mutation. Each subject received a complete eye examination including fundus photographs, the results of which were used to grade the severity of macular dystrophy on a 3-tier scale. Red blood cell membrane and adipose tissue lipids were analyzed as an indication of short-term and long-term dietary fatty acid intake. Results: When adipose lipids were analyzed, there was a significant inverse relationship between phenotypic severity and the level of eicosapentaenoic acid (r=−0.54; P=.04). When red blood cell lipids were analyzed, there were significant inverse relationships between phenotypic severity and levels of eicosapentaenoic acid (r=−0.55; P=.02) and docosahexaenoic acid (r=−0.48; P=.04). Conclusions: These results indicate that the phenotypic diversity in this family may be related to differences in dietary fat intake as reflected by adipose and red blood cell lipids. Clinical Relevance: This study demonstrates that dietary factors can influence the severity of an inherited human macular dystrophy.

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…The goal of the present work is to examine the time course of cone loss in the ELOVL4/TG1-2 mouse model of STGD3 to define an accurate time window for the application of putative therapies. 14,[22][23][24] Present results complement former descriptions of the degenerative process in ELOVL4/TG1-2 mice 13,20 and show that alteration of the cone mosaic is delayed by almost 1 year from initial rod loss.…”

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…The goal of the present work is to examine the time course of cone loss in the ELOVL4/TG1-2 mouse model of STGD3 to define an accurate time window for the application of putative therapies. 14,[22][23][24] Present results complement former descriptions of the degenerative process in ELOVL4/TG1-2 mice 13,20 and show that alteration of the cone mosaic is delayed by almost 1 year from initial rod loss.…”

Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice

“…The robust increases in RPE VLC-PUFA levels are interesting because they could serve as precursors for the neuroprotective elovanoids described by Bazan's group (27), but our analytical methods were not designed to detect the presence of these metabolites in eye tissues, so further study is warranted. RBC membranes are long-term biomarkers of dietary PUFA status (14,28), and we confirmed a positive dose response to varying levels of long-term supplementation. In the liver, chronic feeding of our synthetic VLC-PUFA led to detectable 32:6 n-3 only in the 2 mg/d group, indicating either that liver is not a preferred site of accumulation or that it ordinarily degrades VLC-PUFAs.…”

Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration

“…VLC-PUFAs are generally rare FAs that comprise a large proportion (∼12%) of newly formed retinal lipids (33). Consistent with their importance for human vision, clinical studies showed reduced VLC-PUFA levels in AMD donor eyes (9) and an inverse association between the severity of STGD3 and dietary intake of VLC-PUFA precursors (8). A key role for VLC-PUFAs in the regulation of phototransduction and/or photoreceptor survival was also suggested by the observations of anatomical and functional deficits in TG mouse models deficient in C 28 -C 36 acyl phosphatidylcholines (4,12,14,21).…”

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…The goal of the present work is to examine the time course of cone loss in the ELOVL4/TG1-2 mouse model of STGD3 to define an accurate time window for the application of putative therapies. 14,[22][23][24] Present results complement former descriptions of the degenerative process in ELOVL4/TG1-2 mice 13,20 and show that alteration of the cone mosaic is delayed by almost 1 year from initial rod loss.…”

Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice

“…The robust increases in RPE VLC-PUFA levels are interesting because they could serve as precursors for the neuroprotective elovanoids described by Bazan's group (27), but our analytical methods were not designed to detect the presence of these metabolites in eye tissues, so further study is warranted. RBC membranes are long-term biomarkers of dietary PUFA status (14,28), and we confirmed a positive dose response to varying levels of long-term supplementation. In the liver, chronic feeding of our synthetic VLC-PUFA led to detectable 32:6 n-3 only in the 2 mg/d group, indicating either that liver is not a preferred site of accumulation or that it ordinarily degrades VLC-PUFAs.…”

Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration

“…VLC-PUFAs are generally rare FAs that comprise a large proportion (∼12%) of newly formed retinal lipids (33). Consistent with their importance for human vision, clinical studies showed reduced VLC-PUFA levels in AMD donor eyes (9) and an inverse association between the severity of STGD3 and dietary intake of VLC-PUFA precursors (8). A key role for VLC-PUFAs in the regulation of phototransduction and/or photoreceptor survival was also suggested by the observations of anatomical and functional deficits in TG mouse models deficient in C 28 -C 36 acyl phosphatidylcholines (4,12,14,21).…”

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…The goal of the present work is to examine the time course of cone loss in the ELOVL4/TG1-2 mouse model of STGD3 to define an accurate time window for the application of putative therapies. 14,[22][23][24] Present results complement former descriptions of the degenerative process in ELOVL4/TG1-2 mice 13,20 and show that alteration of the cone mosaic is delayed by almost 1 year from initial rod loss.…”

Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice

“…The robust increases in RPE VLC-PUFA levels are interesting because they could serve as precursors for the neuroprotective elovanoids described by Bazan's group (27), but our analytical methods were not designed to detect the presence of these metabolites in eye tissues, so further study is warranted. RBC membranes are long-term biomarkers of dietary PUFA status (14,28), and we confirmed a positive dose response to varying levels of long-term supplementation. In the liver, chronic feeding of our synthetic VLC-PUFA led to detectable 32:6 n-3 only in the 2 mg/d group, indicating either that liver is not a preferred site of accumulation or that it ordinarily degrades VLC-PUFAs.…”

Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration

“…VLC-PUFAs are generally rare FAs that comprise a large proportion (∼12%) of newly formed retinal lipids (33). Consistent with their importance for human vision, clinical studies showed reduced VLC-PUFA levels in AMD donor eyes (9) and an inverse association between the severity of STGD3 and dietary intake of VLC-PUFA precursors (8). A key role for VLC-PUFAs in the regulation of phototransduction and/or photoreceptor survival was also suggested by the observations of anatomical and functional deficits in TG mouse models deficient in C 28 -C 36 acyl phosphatidylcholines (4,12,14,21).…”