Researchers discover the pathology for a cause of childhood blindness

Researchers at the Virginia Tech Carilion Research Institute (VTCRI) revealed an important link between the CASK gene and optic nerve hypoplasia, a medical condition that is the leading causes of childhood blindness in developed nations.

“What is striking about this is that it is the number of people with optic nerve hypoplasia has been increasing for decades. Something is changing that is causing the increase of optic nerve hypoplasia disorders,” said Konark Mukherjee, who is an assistant professor at the Virginia Tech Carilion Research Institute (VTCRI) and the Virginia Tech College of Science.

The research is being funded by a $2 million National Institutes of Health grant to Mukherjee to study the optic nerve, and why and how optic nerve hypoplasia occurs.

Optic nerve hypoplasia is a condition that occurs when the optic nerves aren’t fully developed. Because of the underdevelopment, the optic disk tends to be smaller than usual. Before Mukherjee’s research, little was known about the CASK gene and the cause of several medical conditions, including optic nerve hypoplasia.

The rodent model experiment was done by manipulating the genome of male and female mice. The mice were then not able to make the protein formed by the CASK gene.

“When he (Mukherjee) did this, he was able to show that this mouse model matched many aspects of human patients that lacked or had a nonfunctional CASK, including microcephaly, cerebral hypoplasia and optic nerve hypoplasia,” said Michael Fox, the director of the Center for Developmental and Translational Neurobiology.

CASK supports the connection of optic nerves between the brain and the retina. If an optic nerve is smaller than normal, the connection between the eye and the brain is broken. Therefore, on top of causing brain malfunctions and some forms of autism, the abnormalities in CASK can also cause visual impairment.

“In manipulating the CASK gene, you start analyzing mouse structures and behaviors,” said Alicia Kerr, a graduate student at Virginia Tech’s translational biology, medicine, and health program.

When they were dissecting the brains, they found that while the retina itself remained the same, there was thinness in the optic nerve.

One issue is determining early on why the child is visually impaired — is it optic nerve hypoplasia or optic nerve atrophy? These are two very close conditions that can’t be determined until after birth. While hypoplasia is when the optic nerve is already impaired, optic nerve atrophy is when the nerve is first generated normally, and then later degenerates.

“Often times when people are born, they have little visual acuity, and can’t see very far, and can’t communicate this. Visual impairment is often hard to diagnose and it takes a year or two before a parent realizes there is an impairment. Once they take them to the eye doctor, they realize the connection is much smaller in the optic disk, which is the end of the nerve, and you basically have a blind spot (where the nerve originates),” Fox said.

The CASK gene is also X-linked, which means it is found on the X chromosome. Since females have two X chromosomes, they have two CASK genes. Males only have one X chromosome, so they only have one. The CASK gene is critical to growth in the organism. If male organisms are missing the CASK gene, they are most likely not going to survive.

However, females will survive, but they will have the medical conditions related to CASK abnormalities.

“We wanted to see if removing the CASK gene causes optic nerve atrophy or optic nerve hypoplasia. We took away the CASK gene from a female (mouse), and we saw what happened. It would be hypoplasia if the condition starts early on the life, and atrophy if it occurs after. During the developmental time period, there was a broken link between retina and brain, so it was hypoplasia,” Mukherjee said.

While previous experiments have been done, none of them have come to a definite conclusion like this one. Now, the next step is to see what causes the molecular changes in the nerves that cause the optic nerve hypoplasia. Since the condition is totally random, it’s going to be hard to figure out. But, with the research they have after this rodent model experiment, they can try and find ways to restore abnormal optic nerves.

“As researchers, we create animal models to replicate human diseases. Kids don't get diagnosed unless they are 1 or 2 years old. We don’t know whether the kids have a problem pre- or post-birth. This is important for therapeutic intervention, to help restore or prevent things associated with optic nerve hypoplasia. We hope to try therapeutic interventions, to see whether or not we can remake a healthy optic nerve,” Kerr said.