Finding the genetic causes of spinal muscular atrophy

23 September 2013
​Kristien Peeters and Albena Jordanova, VIB Department of Molecular Genetics, Antwerp University, have identified BICD2 mutations as a cause of spinal muscular atrophy (SMA). Their findings expand the genetic heterogeneity and clinical spectrum of hereditary SMA and have important implications for the development of future diagnostic tests for this disease.

What is spinal muscular atrophy (SMA) and what makes it interesting to study?
Kristien: SMA affects the motor neurons in the spinal cord causing neuronal degeneration that leads to progressive weakness and atrophy of the muscles. Often, the disease shows up very early, with very young patients showing delays in reaching certain motor milestones or never learning to sit or walk. From a genetic point of view, SMA is an interesting condition to study, because it is very
heterogeneous. Although the gene responsible for the most common form of SMA is known (SMN1),
many patients suffer from forms of SMA for which the genetic cause has not yet been identifed.
This study highlights the importance of dyneinmediated motility in motor neuron functions in
humans.

Could you elaborate a little?
Dynein is responsible for the transport of vesicles, organelles and mRNA particles throughout the cell. To perform this crucial task, dynein interacts with adaptor proteins such as BICD2. Our study shows that mutations in BICD2 cause a pathology that is restricted to spinal motor neurons. This is a peculiar finding, since BICD2 and dynein function in all cell types. Neurons are the longest cells in the human body; consequently the dynein motor has to cover an enormous distance to reach the tip of the axon. This may explain why only neuronal cells are affected by BICD2 mutations, but further research is needed to resolve this question.

You identified BICD2 mutations as a cause of SMA. Does this have medical implications?
The BICD2 mutations we identified are dominant and patients have a 50% chance of transmitting the disease. Once the genetic defect is known, prenatal screening may prevent the disease in the next generation. 
One particular mutation was found in several unrelated patients and we proved that it had
originated independently. The occurrence of such de novo mutations has important implications for
genetic counseling. We recently encountered a healthy couple that had a little girl with SMA. They
intentionally had no other children, fearing they might also be afflicted. Because we demonstrated
that neither parent carried the mutation causing the SMA in their daughter, they are now hoping for a second child.

Albena, you perform tests on individual patients and families. How involved are you, as a
researcher, with these people? And how do you deal with this?
Albena: It is a matter of balance. I sampled many of the Bulgarian patients myself, visiting their
homes and relatives. This personal contact is very motivating. You feel compassion for them
because of their health problems. On the other hand, you need to keep a cool head to make the
right decisions. My past experience with genetic diagnostics and counseling patients with inherited
disorders helps me find the right balance.

You work as a researcher at both VIB/University of Antwerp and the Medical University of Sofia. Why do you choose this double affiliation?
It gives me access to specific patient populations, which is very beneficial for my research. I live and work mostly in Antwerp, though, with frequent trips to Sofia.

Peeters et al.
The American Journal of Human Genetics, 2013

Albena Jordanova & Kristien Peeters