A Ray of Hope in Retinal Degeneration

A recent study sheds light on the root cause of late-onset retinal degeneration and its potential treatment

Late-onset retinal degeneration (L-ORD), or late-onset retinal dystrophy, is an inherited rare autosomal dominant disorder characterized by the presence of thick, lipid-rich deposits between the retinal pigment epithelium (RPE) and Bruch’s membrane.

Individuals with L-ORD typically do not experience problems with their eyesight until midlife, around 50- to 60-years-old, when they begin to have early symptoms. These include difficulty with light and dark adaptation, with the inability to see in dim light or at night. As the disease progresses, loss of central and peripheral vision occurs, and there may be comorbidities involved such as choroidal neovascularization, glaucoma and retina-wide pigmentary retinopathy, as well. Ultimately, deterioration in visual acuity can lead to complete vision loss.

The gene in play

A recent study led by the National Eye Institute (NEI) and researchers from the Bazan Lab at the LSU Health New Orleans Neuroscience Center of Excellence demonstrated how the dominant behavior of CTRP5 mutation leads to L-ORD and suggested a potential treatment — in the form of the drug metformin.1 

Using induced pluripotent stem cells-derived RPE from L-ORD patients (L-ORD-iRPE), the authors demonstrated that the dominant pathogenic CTRP5 variant leads to reduced CTRP5 secretion.1 Lower CTRP5 levels are linked to a sustained activation of 5’ AMP-activated protein kinase (AMPK), which leads to insensitivity to changes in cellular energy status.

According to Dr. Nicolas Bazan, Boyd Professor and director of LSU Health New Orleans Neuroscience Center of Excellence, AMPK in the retinal pigment epithelium (RPE) is a key regulator of the conversion of DHA into protective mediators.2

The study found that, in cells of L-ORD patients, dysregulation of fatty-acid and lipid metabolism contributed to the atrophy of RPE cells (this mechanism has been suggested in age-related macular degeneration, as well). There were also reduced secretions of CTRP5. 

“Reduced secretion of CTRP5 and predicted lower binding affinity of mutant CTRP5 to the receptor for the gene that makes lipoproteins that carry fats in the bloodstream is the likely reason for the genetically dominant behavior of this disease,” Dr. Bazan noted.2 

Potential treatment

Importantly, the study also demonstrated that lower levels of CTRP5 secretion in the cells of patients with L-ORD can be overcome by overexpressing CTRP5. In addition, they tested the anti-diabetic drug metformin to determine if it influenced AMPK activity and reversed RPE deterioration. Researchers obtained positive results that metformin re-sensitizes AMPK to changes in cellular stress, restores energy stability, and alleviates the disease’s cellular phenotypes. 

A 2018 study in mice showed that metformin made photoreceptors and the RPE highly resistant to oxidative stress, thus preventing DNA damage and oxidative injury.3 

These discoveries provide new insight into the role of CTRP5 in the RPE and how the pathogenic variant in late-onset retinal degeneration causes dominant disease — while opening new doors to the use of metformin as a promising intervention for L-ORD.

Risk of misdiagnosis

Meanwhile, a review article by U.S. researchers cautioned that L-ORD can be mistakenly diagnosed during the early stages as age-related macular degeneration (AMD), or confused with other retinal dystrophies.4 

They reported a case study of a 60-year-old female from Singapore who presented with vision abnormalities due to issues in light adaptation, depth perception, night blindness and loss of central vision over the course of a decade. She had received previous therapy, including intravitreal ranibizumab injections in the left eye for treatment of choroidal neovascular membrane (CNVM), and has a family history of L-ORD. 

A retinal examination was performed and it revealed well-circumscribed scalloped areas of atrophy in both eyes, especially in the outer retinal and choroidal areas. The presence of a central fibrotic CNVM was also seen in the left eye. Spectral domain optical coherence tomography (SD-OCT) showed outer retinal atrophy and subretinal fibrosis to a greater degree in the left than the right eye. Due to the presence of sub-RPE deposits in the retina, as well as discerned areas of RPE loss and choroidal atrophy in the macula and periphery, a diagnosis of L-ORD was made for both eyes.

The authors suggested that in diagnosing L-ORD, a thorough review of the patient’s detailed medical and family history, review of systems, and ophthalmic and physical examination should be done to ensure an accurate diagnosis. This is because during the early stages of the disease, L-ORD can often be confused with Sorsby fundus dystrophy (SFD) or AMD. Symptoms of night blindness and a strong family history of L-ORD provide further support to the diagnosis. The loss of peripheral vision observed in patients with L-ORD is not usually seen in patients with AMD, they noted. 


  1. Miyagishima KJ, Sharma R, Nimmagadda M, et al. AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration. Commun Biol. 2021;4(1):1360
  2. Louisiana State University Health Sciences Center. “Late-onset retinal degeneration mechanism and potential Rx.” ScienceDaily, 9 December 2021. Available at Accessed on February 20, 2022.
  3. Xu L, Kong L, Wang J, Ash J D. Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2018; 115(41): 10475–10480.
  4. Crawford CM, Hwang Y, Wesley T. Characteristics of late onset retinal degeneration (L-ORD). Adv Ophthalmol Vis Syst. 2017;6(4):107-108.

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