The Clock Might Be Ticking...

The following was written by the president of the Registry and director of the Chromosome 18 Clinical Research Center, Dr. Jannine Cody:

The Clock Might Be Ticking, but There Is Still Time

I often hear parents of older affected individuals say that they are working hard for the Registry to help those children yet to be born with chromosome 18 abnormalities. They don’t think there will be any research insights or treatments that will help their own children who are young adults. I admit to being the eternal optimist; if I were not, I would not be doing this. That being said, I really would not paint such a fait accompli picture. In the last decade, we have learned that the brain is more similar to the rest of the body than we thought. It was once thought that the brain never added new cells and that brain cells died without being replaced. Now we know that the brain, like the other organs of the body, is undergoing constant remodeling. Since this is such a new finding, we know very little about the factors that influence this remodeling. Still, some interesting things are beginning to emerge that might just give us some hope, where there was none before.

For example, scientists have created a mouse with the same genetic mutation that causes neurofibromatosis (NF). These mice have been found to have problems with attention, problem solving, and visuospatial skills. These are the same sorts of behavioral problems that many people with NF have. Studies have shown which chemical processes are different in this mouse’s brain. This new knowledge and understanding of the altered chemistry provided scientists with ideas about possible treatments. Studies showed that these treatments worked to improve the behavioral problems in adult mice with the NF mutation. However, the treatment did not affect normal mice. This indicates that the treatment is indeed specific for the neurofibromatosis-like defect (Costa et al., 2002; Li et al., 2005).

Similarly, scientists have created a mouse model that has many of the same genetic changes as people with Down syndrome. These adult mice experience behavioral and cognitive improvement when treated with a drug that specifically normalizes the abnormal chemistry in the brain. Again, the same treatment did not improve or change the behavior of the normal mice. This suggests that this treatment is specific to the chemical processes affected by Down syndrome (Fernandez et al., 2007; Rueda et al., 2008)

These are just two examples of genetic conditions that have shown behavioral or cognitive improvement in adult mice following treatment. Other examples are Rubenstein-Taybi syndrome, tuberous sclerosis, Lhermitte-Duclos disease, Cowden syndrome, Fragile X syndrome, Angelman syndrome, and Rett syndrome (Ehninger et al., 2008). These findings have created a radical shift in thinking about the ability of the adult brain to remodel. In turn, this suggests that we can treat adults with developmental disabilities.

We are far from knowing exactly which genes on chromosome 18 cause the majority of developmental disability. We are even further from having targeted treatments. However, have no doubts about it; this is the path we are on. There is still time to make a difference.

References

Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno M, Kucherlapati R, Jacks T, Silva AJ. 2002 Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415:526-530.

Ehninger D, Weidong L, Fox K, Stryker MP, Silva AJ. 2008 Reversing Neurodevelopmental Disorders in Adults. Neuron 60:950-960.

Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC. 2007 Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci. 10:411-413.

Li W, Cui Y, Kushner SA, Brown RA, Jentsch JD, Frankland PW, Cannon TD, Silva AJ. 2005 The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 15:1961-1967.

Ruenda N, Florez J, Martinez-Cue C. 2008 Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome. Neurosci Lett. 433:22-27.