New research from the Dysautonomia Center at NYU shows the first possible link between the FD genotype and the severity of the disease.
The vestibular system in our inner ear send signals to the brain that provide us with our sense of spacial orientation and motion, our 6th sense. These tiny semicircular canals in the ears make up part of the sensory nervous system and play an important role in our ability to coordinate movements and balance.
The IKBKAP gene contains the DNA blueprint for building the elongator-1 protein (also known as IKAP). IKAP plays an important role in the development of the nervous system, particularly when it comes to the sensory branches. Children born with familial dysautonomia inherit two mutations in the IKBKAP gene handed down from each of their patients. This causes them to produce low levels of the IKAP protein, which affects the development of their sensory nerves, essentially robbing them of their ability to control many of the automatic functions in the body that we take for granted – like for example balance and coordination.
Patients with familial dysautonomia are remarkably unsteady on their feet. Without the sense of balance, they cannot walk straight. Using an electrophysiological test, investigators at the Center have been able to map how fast the information is transmitted from the vestibular nerve in the ear towards the brain and muscles.
Not surprisingly, they found that the patients with familial dysautonomia had very delayed and small vestibular reflex responses. In other words, these patients have less information coming in from their vestibular systems, making it harder for them to coordinate their movements. Sure enough, when you compare FD patients with age matched controls, you see that they have vestibular reflex responses that are not only slower, but also smaller in amplitude.
But not all patients were the same. FD is a recessively inherited genetic disease. Over 99% of patients diagnosed are homozygous for the common founder mutation. Meaning, they inherited 2 identical copies of the same IKBKAP mutation from each of their patients. However, there are a small number of patients that are heterozygotes, with a copy of the common founder mutation paired with another very rare mutation. This handful of ultra-rare patients appear to have something rather unique. Their vestibular reflex responses were not as badly affected and were essentially the same as in normal healthy controls. This means that something in these patients must have rescued their vestibular signaling pathways.
It is the first time we have been able to show evidence of a link between the genotype and the phenotype. While all the homozygous patients cluster together showing very abnormal vestibular reflexes, those that are heterozygotes have a different pattern, with only very mild involvement. This may explain why the heterzygous patients can reach well into their 20s without requiring a walker or a wheelchair for mobility.
So what do these results tell us? When you combine this finding with the wealth of work that we have in animal models, it becomes increasingly likely that changing the genetic code can affect the severity of FD. We found a way to objectively measure the function of the sensory pathways in FD. Along the way, we discovered a group of patients that are measurably less affected who had a different mutation that we assume is less severe. This opens the door to the possibility of genetic therapies.
A little more IKAP appears to go a long way. If we can fix the underlying genetic cause, we can hopefully fix some of the sensory deficits that these patients suffer from.
If we can fix the severity of the underlying genetic cause, we can hopefully fix some of the sensory deficits that these patients suffer from. Better days may be on the horizon, and the quest to find genetic therapies in full speed ahead, with a number of laboratories collaborating to speed up drug discovery.
Read the paper here:
Gutiérrez JV, Kaufmann H, Palma JA, Mendoza-Santiesteban C, Macefield VG, Norcliffe-Kaufmann L. Founder mutation in the IKBKAP gene cases vestibular impairment in familial Dysautonomia. Clin Neurophysiol. 2017 Nov 26;129(2):390-396. doi: 10.1016/j.clinph.2017.11.010.
Dr. Gutiérrez JV was a visiting professor at the NYU Dysautonomia Center who was supported by the Dysautonomia Foundation, Inc. a non-profit organization dedicated to serving the FD population around the world.