Mutations in 3 Genes Linked to Vision Loss and MS Severity in Hopkins Study

Mutations in genes related to the immune system’s first line of defense are associated with a greater likelihood of more severe forms of multiple sclerosis (MS) linked to faster vision loss, a team led by Johns Hopkins Medicine researchers report.

Combining high-resolution eye scans and genetic tests, researchers identified three genes involved in the complement immune pathway that are tied to a more rapid degeneration of nervous tissue in the eye and loss of sight. These genetic variants (mutations) could serve as markers for monitoring MS and predicting its severity, the researchers said.

Their study, “Early complement genes are associated with visual system degeneration in multiple sclerosis,” was published in the journal Brain.

In MS, the body’s immune system mistakenly attacks the myelin sheaths of nerve fibers — the fat-rich coat around nerve fibers — resulting in inflammation, degeneration, nerve cell death, and ultimately disrupting communication between the brain and spinal cord, and the rest of the body.

Vision problems are among disease symptoms.

Although several genetic risk factors are known to predispose people to MS, no mutations have been linked with MS severity. This gap results in part due to the inability of current clinical scales to detect early degenerative changes that underlie disease progression.

Optical coherence tomography (OCT) is a noninvasive imaging test that enables doctors to see eye structures with exquisite detail. For instance, it is used to look at nervous tissue of the retina in the back of the eye, and check for signs of disease. Taking advantage of OCT’s potential, scientists are exploring it as an imaging tool to measure nerve cell degeneration at early stages in MS, as well as disease progression.

To discover possible genetic predictors of MS severity, Peter Calabresi, MD, the study’s senior leader and a professor at Johns Hopkins University, and his team assessed 374 patients (average age of 43 ) with all MS types using OCT, and crossed this information with genetic tests performed on patients’ blood samples.

“Although we have treatments for the type of MS where symptoms come on in bursts — called relapsing-remitting MS — we don’t have any way to stop the kind of MS in which the nerve cells start to die, known as progressive MS,” Calabresi, who is a director of the Johns Hopkins Precision Medicine Center of Excellence for MS, said in a university news release.

OCT was used to measure thinning (degeneration) in the layer of nerve cells — known as ganglion cells — in the retina over time. On average, 4.6 OCT scans were performed on each patient between 2010 and 2017.

Scans showed that MS patients lost an average of 0.32 micrometers (one-millionth of a meter) of retinal nervous tissue per year.

Researchers then searched for mutations in patients with the fastest retinal deterioration rates, and identified 23 DNA variations. They all mapped to gene C3, which codes for a protein involved in the complement pathway of the immune system.

The team employed a similar approach to a separate group of 835 MS patients, but instead of searching for OCT degeneration, they now looked for genetic factors in patients with a rapidly declining ability to see faint letters, mimicking low light conditions using the low-contrast letter acuity (LCLA) test.

Researchers based their analysis on this vision test because it correlates with clinical disability and nerve cell loss in MS, and is emerging as a valid clinical measure of the disease.

Specific mutations in the genes C1QA and CR1 were more frequent in patients whose visual ability deteriorated faster. Those with certain variants in C1QA were 71% more likely to develop difficulty detecting visual contrast, while those with CR1 variants were at a 40% greater risk of such problems.

Like C3, both C1QA and CR1 are genes involved in the complement pathway.

These results showed that “early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration,” the researchers wrote.

“We believe that our study opens up a new line of investigation targeting complement genes as a potential way to treat disease progression and nerve cell death,” Calabresi said in the release.

“[O]ther researchers discovered that complement proteins bind to the connections between neurons and helps them grow in specific directions. But, too much complement was found to causes damage to the nerve cells, eventually killing them. Our findings fit well into this system,” he added.

The team believes that these three genes could also be used as markers to monitor and predict disease progression and severity.

“Our next step will be to repeat these studies in larger populations,” said Kathryn Fitzgerald, ScD, a Johns Hopkins professor and the study’s lead author of the study.

Animal studies are likely to follow, to detail how the complement system is involved in neurodegeneration during MS. “From there we can possibly think about how to design new therapies,” Fitzgerald said.