Sisley-Jerome Lejeune Prize Recipient, Randi Hagerman, MD, FAAP

On March 10, 2015 Randi Hagerman, MD, FAAP received the Sisley-Jerome Lejeune Prize at a ceremony in Strasbourg, France. Dr. Hagerman is an internationally recognized clinician and researcher. She is the director of the Fragile X Research and Treatment Center at the MIND Institute and holds an Endowed Chair in Fragile X Research at UC Davis. Dr. Hagerman has written over 300 peer-reviewed articles and numerous book chapters on neurodevelopmental disorders and several books on fragile X, including a 3rd Edition of Fragile X Syndrome: Diagnosis, Treatment, and Research (2002). She has also edited Treatment of Neurodevelopmental Disorders: Targeting Neurobiological Mechanisms (2014).

Lejeune USA president, Mark Bradford, interviewed Dr. Hagerman on developments in fragile X research:

MB: Congratulations on being selected to receive the Sisley-Jerome Lejeune Prize this year. I think you are the first researcher to receive this prize that is not working in the area of Down syndrome. Would you briefly explain what fragile X syndrome is?

RH: Fragile X is the most common inherited cause of intellectual disability and is caused by an expansion of CGG repeats on the front end of the FMR-1 gene. In an individual with fragile X, the CGG repeat is over 200 and is frequent enough to cause the gene to be silenced. This causes a lack of a crucial protein that is critical for normal development of the brain and synaptic plasticity throughout life. Common features of fragile X, in addition to intellectual disability, are hyperactivity, poor eye contact, and unusual hand flapping. About 60% are also on the autism spectrum. In fact, this is the most common single genetic cause of autism.

MB: When we last spoke in 2011, trials on targeted treatments were already underway and you expected results within two years. Can you give us a brief update on the progress being made in fragile X research?

RH: Unexpectedly the MGLUR5 antagonist being developed by Roche and Novartis, did not demonstrate efficacy with adolescents or adults. Also, the GABA-B agonist arbaclofen did not demonstrate efficacy in adults or adolescents, but did in children 5 to 11. There were improvements in the phenotype, including improved social interactions, improvement in parent stress and some aspects of behavior, so this should be further studied in young children. We have shown that low dose sertaline in children 2 to 6 with fragile X can have improvements in receptive and expressive language trajectories in a retrospective study, and preliminary data from a control of 30 patients with low dose sertraline shows significant improvement. Full results will be available by the end of the year. In a control trial of menocycline in children ages 6 – 17 efficacy was demonstrated, but there was also a placebo effect. Menocycline lowers MMP-9 and does looks like it is quite helpful in children. We are currently looking at further treatments including ganaxolone, a GABA-B agonist, metadoxine, a medication used to treat attentional problems made by Alcobra, and also an IGF-1 analog made by Neuren Pharmaceuticals are currently being studied as targeted treatments for FX. All targeted treatments demonstrated efficacy in mice, however, efficacy may be far more difficult to demonstrate in the treatment of patients with fragile X syndrome.

MB: I was fascinated to hear you say in your presentation in Strasbourg that there are some individuals who have both Down syndrome and fragile X. Do you have any statistics of that dual diagnosis, and what challenges does that dual diagnosis present to researchers?

RH: There is some evidence that nondisjunction can occur at an increased rate in individuals who are permutation carriers of fragile X, . We see fragile X in Kleinfelter’s syndrome or other sex chromosome disorders at a higher rate, as well as Down syndrome, and other genetic anomalies. The frequency of Down syndrome and fragile X occurring together would be the prevalence of one multiplied by the prevalence of the other. Of course, if there is a predisposition in carriers, then the prevalence would be higher.

When Down syndrome and fragile X appear together, then autism usually is present also. It is recommended that individuals with Down syndrome and autism be screened for fragile X, and that fragile X can exacerbate the Down syndrome phenotype. There are really no good epidemiological studies yet on this topic, but the incidence is probably higher than simply multiplying the two prevalences together. It is estimated that 10% – 15% of those with Down syndrome also have autism and there may be additional genetic hits that include fragile X syndrome as well.

MB: I know researchers don’t like to predict the future, but from the position of fragile X research today, what do you see emerging with regard to novel research targets or strategies, and also for the lives of those living with fragile X syndrome?

RH: With the advent of targeted treatments, we have the opportunity to make a significant impact on cognitive deficits in both fragile X and Down syndrome, particularly with the GABA-A inverse agonists for Down syndrome, but we can’t just depend on targeted treatments to buoy up cognitive functioning. Medications need to be reinforced with intensive educational interventions that improve synaptic plasticity. This becomes even more important when trying to reverse intellectual disability in adults and adolescents. Intensive reading programs are important throughout the age range and should be boosted primarily because they expand one’s ability to understand language, carry out abstract reasoning, and understand more about their environment so they can read on their own and learn about the world in addition to what is being learned with a tutor. Digital learning technology can reduce the amount of time special education teachers work with individuals, but it does not replace the importance of individual intervention. People are now starting with more digital learning aids earlier and earlier in childhood. IPad apps are fabulous to boost language and reading abilities. We’re in an age where new medical treatments are emerging, but also an age of more innovative educational programming.

I want to emphasize that antioxidants are also very important. EGCG is one example of an antioxidant that is being studied for intellectual disability. Most neurodevelopmental problems are the result of the effect of oxidative stress on vulnerable neurons, and antioxidants can be quite helpful in strengthening them from very early on. The aging phenotype is a common issue for many intellectual disabilities and we know that oxidative stress and mitochondrial function are important for aging. They are important at both ends of the age spectrum - for early development and also for aging. The aging phenotype in Down syndrome and Parkinson’s disease in fragile X and others are the result of aging problems. Research being done in these populations will certainly help the general population as well.

Bill Mobley talks a lot about Down syndrome and Alzheimer’s disease and how research in Down syndrome will benefit research in Alzheimer’s disease. The same is true for research in other disabilities with regard to benefits that will accrue for the general population.

Read the press release about Dr. Hagerman receiving the Sisley-Jerome Lejeune Prize

Watch a 2011 interview with Dr. Hagerman about breakthroughs in Down syndrome research