Week in Review: Number 25

A Rare Case of Singleton-Merten Syndrome Type II
The Gibson family, California transplants to Michigan, had for generations lived with an unusual constellation of symptoms for a condition for which they had no name. Those symptoms included childhood glaucoma and psoriasis-looking skin rashes, along with calcium build-up throughout the body, and arthritis or spontaneous tendon rupture. Some members of the family had additional symptoms such as light sensitivity (both ocular and dermatological) and teeth abnormalities (e.g., retained baby teeth). The Gibsons thought only male members of the family were affected. When their then 3-year-old daughter Rachel developed sudden eye pain, however, the family turned to C.S. Mott Children’s Hospital and the Kellogg Eye Center for more answers. Successful surgeries followed for Rachel, and also her father, Stan, for various ocular problems due to their condition. After their then 13-year-old son Adam experienced sudden vision loss from elevated eye pressure (which was mostly recovered thanks to emergency glaucoma surgery), an ophthalmic genetic specialist and a glaucoma geneticist became involved with the family's mysterious condition to dig deeper for an underlying cause. The answer ultimately came from genetic analysis (whole exome sequencing) in collaboration with the NEI/NIH of both immediate and distant family members, which determined that the condition has an autosomal dominant inheritance pattern. In particular, the data revealed a novel mutation in the DDX58 gene that had never been reported; this gene encodes for an RNA binding protein involved in the immune system. Genetic testing, and comparing notes about another family in Brazil with the same peculiar set of clinical findings and the same genetic variant of DDX58, helped the researchers to diagnose the case as Singleton-Merten syndrome type II, a rare autosomal dominant condition with only three families documented in the literature.

The team at Kellogg Eye Center then led an international study to provide the first complete molecular and histological assessment of the eye and skin findings in Singleton-Merten syndrome type II, demonstrating that the mutation in the DDX58 gene sets off an inflammatory cascade in the body in the absence of a definitive RNA trigger. Working with the Brazilian clinicians and researchers, who were studying a family with a more severe presentation of the condition, also improved understanding of how environmental factors could affect the presentation of Singleton-Merten syndrome type II, which could guide preventative measures for children who have the mutation but have yet to develop symptoms. Some individuals only present with common features, such as childhood glaucoma, so awareness of this rare condition's other features would be useful to clinicians, since these pediatric patients can go on to develop other, more severe symptoms later in life. While eventually finding a treatment for the disease would be a "miracle," the Gibsons are happy to simply put a name to their symptoms. Stan's wife, Eryn, applauds the research team, saying, "Their curiosity led to answers, but also helped us feel like we were finally being heard and cared about. Finally, after generations of unanswered questions and enormous health challenges someone took this seriously and had access to the resources to find answers about this condition." The U-M researchers next plan to generate an animal model to study targeted drug therapy, as well as study the connection between the RNA binding protein and glaucoma pathogenesis to hopefully find a way to block the receptor or the downstream signaling to prevent glaucoma from developing.

Study Aims to Determine Which Diabetic Individuals Should Donate Corneas for DMEK
A new study funded by the National Eye Institute aims to determine which diabetic individuals can successfully donate corneas for transplant, and which should not. The new Diabetes Endothelial Keratoplasty Study (DEKS) will involve 16 eye banks and 30 clinical sites around the country, with an anticipated 1,420 donors and over 1,000 patients. Although recent eye bank data suggest that roughly one-third of the corneal transplant surgeries in the United States involve people with diabetes who donate their corneas after death, the medical community has learned that not all corneal tissue from diabetics is suitable for keratoplasty. The number of diabetic donors has also seen a 50-72% increase in recent years simply because the number of diabetics has increased. The study will focus on Descemet membrane endothelial keratoplasty (DMEK), the most common procedure performed by high-volume corneal transplant surgeons. Previous research showed that there were more problems encountered when preparing corneas from diabetic donors for the DMEK procedure, leading many surgeons to increasingly avoid corneas from diabetic donors for DMEK. One of the researchers adds, “This study could also help identify some of the reasons why 2 to 3% of donated corneas fail for no apparent reason, which is a reason for frustration among patients and surgeons.” Goals of the study include comparing the one-year keratoplasty success rate following DMEK with corneas from donors with and without diabetes, comparing the one-year endothelial cell loss in the central cornea after DMEK with corneas from donors with and without diabetes, and exploring how the severity of a donor’s diabetes affects outcomes one year after DMEK surgery. This study is especially relevant given the steady rise in corneal transplant surgeries in recent years (accounting for the lull during the COVID-19 pandemic). Knowing how diabetes affects the success of corneal surgeries can help to screen for effective tissue donors for corneal cases. Equally important, the study results will provide information to screen out sub-optimal donors.

Small Uveal Melanomas Not Always Harmless
Researchers from the Liverpool Ocular Oncology Centre conducted a retrospective case-control study demonstrating the benefit of early treatment in small high-risk uveal melanomas. According to the researchers, the current paradigm suggests that small uveal melanomas pose little threat to metastatic spread and, furthermore, that local treatment does not influence survival due to metastasis. They explain that prior studies were based on large tumors, and moreover, that very few genetic studies were understaken on small uveal melanomas in general, leading them to be labeled as safe. Based on data from 940 patients over a 7-year study period, the Liverpool researchers found that over a quarter of small uveal melanomas (≤2.5 mm thickness) have genetic abnormalities (such as monosomy 3 and several gene mutations in both monosomy and disomy 3) that categorize them as highly metastatic tumors. They therefore propose that these small uveal melanomas with a high genetic risk be treated early, as compared to observation, to improve patients' chances of survival. The first author of the study comments, "Liverpool is one of the only ocular oncology centres in the world that offers prognostic biopsies to all of its melanoma patients, and we have therefore collected a large molecular genetic cohort of small tumours. This is the first study to show that over a quarter of these smaller uveal melanomas have lethal genetic mutations, and suggests that we may be able to influence patient survival and mortality outcomes with earlier treatment of these small melanomas." Although the study is small and comparatively niche, the Liverpool Ocular Oncology Centre demonstrated how their "unique collection of tiny intraocular biopsies of small uveal melanomas with follow-up clinical data" improved understanding of ocular disease and patient outcomes.

Progress in Therapeutic Lasers to Treat Eye Diseases
As a spinoff of PhD work in electrical biomedical engineering, a start-up company is developing new imaging technology that more precisely guides laser treatment of retinal diseases. The founder of the start-up PulseMedica was interested in ophthalmic imaging applications to treat age-related macular degeneration (AMD), a leading cause of visual decline in people over 60 years of age. In particular, he was most interested in dry AMD; though less sight-threatening than wet AMD, dry AMD accounts for the vast majority of AMD cases. Furthermore, most patients with wet AMD progress to that stage from dry AMD, thus a treatment strategy that slows or halts progression from earlier stages could be helpful. Current treatments for dry AMD include (and are limited to) eye vitamins following the AREDS2 formula. Where laser treatments are used for wet AMD, the researcher argues that current technology is imprecise, resulting in collateral damage to the retina. He instead wanted to bring the technology being developed in engineering labs to create faster, more precise lasers to treat earlier stages of AMD. He comments, “We were doing really cool things in the lab, but I started to think, ‘How do we take this into the real world, how do we use it so we can actually help people?’” PulseMedica's innovations include a 3-D retinal scanning head that uses machine-learning algorithms to map the regions of the eye associated with retinal disease; that imaging would then be used to guide therapeutic lasers. The next stage of their project is to add new-generation femtosecond lasers to the scanning head, after which they would proceed to studies in animals. Although the company founder's main interest is in dry AMD, advancements in photodisruptive lasers could subsequently be used to treat other eye diseases, such as glaucoma and diabetic retinopathy, that affect additional hundreds of millions of people. The entrepreneur concludes with a motivation for his project in connection with his university. He states, “I know so many people who graduated from the U of A who were absolutely amazing individuals, really talented people, and where did they end up going? They ended up leaving Alberta, and that is sad...I decided that I need to be part of the ecosystem that starts businesses and keeps those talented people in Alberta.”

Study Measures Parental Concern Related to Children's Eyesight and Television-Watching
Two researchers published a large nationwide population-based longitudinal study in Japan assessing parental concern about their children's visual acuity as related to the amount of time the children spent watching television. The study used a national Japanese database (Longitudinal Survey of Newborns in the Twenty-First Century) of more than 47,000 children born between two time periods (January 10 to 17, 2001 or July 10 to 17, 2001). These children were surveyed annually between 1.5 to 5.5 years of age regarding daily duration of television- and video-watching, and followed in the second half of the study with annual surveys from ages 7 to 12 regarding parental concerns about their children's visual acuity. The investigators report, "Longer daily duration of television-watching at 2.5 years was significantly associated with concerns for the child’s decreased visual acuity between the ages of 7 and 12 years, but not at the ages of 3.5, 4.5, and 5.5 years." This association remained significant among the more than 28,000 children whose parents completed the survey in all six years. It is relevant to note that objective measures of visual acuity were not reported in this study. Nevertheless, the article states, "Parents have a close eye on their child’s visual development from an early age and any concern over a child’s eyesight is an accurate indicator of its visual health," and further explains that children in Japan undergo annual eye exams at school after age 6, which are graded from A through D, and that parental concern is closely related to this assessment. Interestingly, but not surprisingly, as a child’s age increased, the parent’s concern during later years decreased. Although there are clearly subjective and indirect connections between the research methods and the suggested conclusions that limit the study's design from fully extending beyond anecdotal evidence (as intended), this study nonetheless involved a large sample size and thus strongly reflects the cultural values and respect for parents in the study population. Because there does seem to be differences between ages 2.5 and 3.5 and between 1 and 2 hours of daily television exposure, future studies that include objective measures could elaborate on these findings.

In Other News
(1) Myopia and children, preventative measures (Related)
(2) All that extra screen time may be causing eye issues in kids
(3) Orthokeratology clinical trial in school-aged children in Japan