New Macular Dystrophy Discovered

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Researchers from the NEI have identified a novel macular dystrophy that has yet to be named.¹ The finding came in an evaluation of individuals who had maculopathy without some of the hallmarks of classic Sorsby fundus dystrophy (SFD).

“We were able to identify a new mechanism for a maculopathy that has distinct characteristics,” said Robert Hufnagel, MD, PhD, at the NEI. “Our findings suggest that the diagnostic odyssey of patients with macular dys­trophy does not necessarily end with the first genetic test. A reconsideration of genetic variants in light of other findings and functional data is required to improve SFD diagnosis and manage­ment.”

NOVEL DYSTROPHY. Retinal images of a patient with a TIMP3 mutation causing atypical symptoms. Despite extensive damage in the retina (dark circles), CNV is absent.

Background. SFD is an autosomal dominant form of macular dystrophy that typically presents in adults. Muta­tions in TIMP3, the gene that encodes tissue inhibition of metalloproteinases-3, have been implicated in SFD. Muta­tions in the C-terminal of TIMP3 cause accumulation of protein aggregates in the extracellular matrix between the retinal pigment epithelium (RPE) and vascular choriocapillaris. However, little is known about the role of mutations in the C-terminal of TIMP3 in SFD.

Study specifics. The NEI research­ers set out to evaluate the pathogenic effects of mutations in the N-terminal of TIMP3 in two families who had diffuse maculopathy without choroidal neovascularization (CNV). They conducted clinical imaging, molecular genetic testing, and coseg­regation analysis. They also performed biochemical anal­ysis of TIMP3 variants to understand the pathogenic mechanisms of TIMP3-related macular dystrophy.

Findings. The researchers sequenced the DNA of 17 in­dividuals and found that all 11 individuals with macu­lopathy harbored mutations in the N-terminal signal peptide variations (L10H or G12R) of TIMP3. These mu­tations were absent in the six individuals without macular dystrophy.

Distinct clinical charac­teristics. The 11 affected par­ticipants had clinical features atypical of SFD, including early onset, preserved useful central vision, paracentral scotomas due to paracentral atrophy, mottled hypoautofluorescence on fun­dus imaging, and outer retinal degener­ation and RPE atrophy on OCT. None of the affected individuals had CNV or hemorrhage.

A new mechanism for retinopathy. “Considering that TIMP3 is a secreted protein and that signal peptides regu­late protein trafficking and secretion, we hypothesized that the L10H and G12R variants would show altered protein secretion,” Dr. Hufnagel said. Indeed, analysis of protein localization showed that although wild-type TIMP3 was abundant in the extracellular ma­trix, TIMP3-L10H and TIMP3-G12R peptide variants showed little to no extracellular deposition. In addition, while the SFD-associated S38C variant of TIMP3 showed impaired secretion and normal cleavage, the L10H and G12R variants exhibited defects in both cleavage and protein trafficking.

What’s next? In commenting on the clinical relevance of these findings, Dr. Hufnagel said, “As we are developing gene therapies or mutation-agnostic therapies for retinal dystrophies, we must keep in mind that even when mutations are within the same protein, differences in pathogenic mechanisms could have different clinical outcomes and may require different treatment approaches.”

He added, “We need to better un­derstand the fundamental mechanisms of this new type of macular dystrophy and compare them to the mechanisms of other TIMP3-related retinopathies. We still need to understand the natural history of this condition so that we can identify the treatments and outcome measures that we should be considering.”

—Christos Evangelou, PhD

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1 Guan B et al. JAMA Ophthalmol. 2022;140(7):730-733.

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Relevant financial disclosures: Dr. Hufnagel— None.

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