Our ability to see depends on dozens of tiny ganglion cells in our retina that encode our visual world. These cells send electrical signals through the optic nerve to the brain where they are interpreted.
For patients with familial dysautonomia (FD) – a rare Jewish genetic disease, their world progressively darkens overtime as they lose visual acuity. They become unable to distinguish colors or their intensity as well as differences between light and shade. Instead of being sharp and well defined, objects become murky and impossible to perceive at a distance, especially at night.
Peering into the eyes of patients with FD, Dr. Carlos Mendoza – a specialist in nerve cells in the eye – noticed something quite odd. Their optic nerves were pale and appeared to be dying. Using a technique known as optical coherence tomography (OCT) he was able to measure the thickness of the specific layers in the retina, and showed how they thin overtime. “We knew there was a problem,” explained Dr. Mendoza, “but which cells were dying and why they were dying was not clear”.
Before Adam* lost his fight against FD he made clear to his parents that he wanted to donate his body to help others with the disease. His decision provided scientists with the possibility of understanding why patients with FD lose their site.
FD is caused by a single mutation in just one base pair along the strand of DNA that encodes for a protein known as IKAP. This “typo” in the genetic code has catastrophic consequences. Dr. Mendoza suspected that the loss of vision was due to mitochrondrial dysfunction. Previous findings had also suggested that there was a problem with the mitochrondria.
Mitochondria are tiny bodies that live within a cell and are responsible for generating energy. These energy-generating machines are essential to the health of each cell. The average cell has several hundred mitochondria, which are shuttled around the cell to balance its energy needs. Dr. Mendoza had seen many patients with optic neuropathies due to mitochondrial dysfunction. To him the eye in FD looked strikingly similar.
Progress in the battle to save sight
In collaboration with Tufts University, the team at the Center was able to study the eyes from patients with FD with microscopic detail. Not only did they confirm that the ganglion cells in the retina were dying overtime, they also showed a distinct problem with the mitochrondria. These tiny energy-making machines were degenerating, leaving the cells of the retina starved of energy. The cells that the patients were losing were the ones with the highest energy demands – the ones that needed their mitochondria the most.
The findings are very important. By rescuing the mitochrondria and boosting their health we have a new target to help save vision. “This is an incredible discovery,” explained Dr. Kaufmann – Director of the Center “it gives us new opportunities of drugs we can try. Each day we come to work thinking of ways we can help stop patients going blind. This is a real step forward in that mission.”
* Not his real name.
Read more: Mendoza-Santiesteban CE, Palma JA, Hedges TR 3rd, Laver NV, Farhat N, Norcliffe-Kaufmann L, Kaufmann H. Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia.J Neuropathol Exp Neurol. 2017 Mar 1;76(3):238-244. doi: 10.1093/jnen/nlw118. PMID: 28395083
This work was supported by the Dysautonomia Foundation, a Charity dedicated to supporting clinical care, research and advocacy for families living with familial dysautonomia.