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ix-year-old Cody Hardin, his mom, and his granddad have more than blood in common. They share a love of sports, a passion for riding four-wheelers across the woods near their family home in Kingston, Georgia, and the abnormal gene for fragile X. Cody was only 2 when April Hardin, a nurse, started looking for answers for her son’s slowness to speak, his distress at unexpected happenings, his hand flapping, and rocking. At the suggestion of a speech therapist, Hardin had her son tested for fragile X syndrome, the most frequently inherited form of mental retardation, which affects one in 4,000 males and one in 8,000 females. At age 3, he was confirmed to have the mutated gene and the syndrome.
     Around the time of Cody’s birth, April’s father, Joe Pratt, was experiencing health problems of his own. The 52-year-old businessman and high school basketball official developed a tremor that prevented him from lifting fork to mouth. At first, physicians in Chattanooga, where Pratt lives, diagnosed Parkinson’s disease. However, after Cody’s condition surfaced, Pratt underwent genetic testing along with his daughter. It turned out that April Hardin is among the one out of every 259 women who carry the abnormal gene, which she inherited from Pratt.
     The news was devastating to the family and particularly to the doting grandfather. Until a few years ago, grandfathers were not tested for fragile X. Since carriers evidence none of the symptoms of their affected offspring, testing had been offered only to family members at risk for having a fragile X child. But observations of seemingly related health problems by the family members themselves pointed fragile X researchers down a different path. They have found that one in five female carriers of the fragile X gene—but not those with the syndrome—have early menopause. Working on that research front, Emory geneticist Stephanie Sherman is studying premature ovarian failure in carriers. Researchers also found that some male fragile X carriers develop neurologic or neuropsychologic problems in their 50s or 60s, a new disease they called fragile X tremor ataxia syndrome (FXTAS).
     Genetic and neurologic testing clearly indicated that Pratt has FXTAS rather than Parkinson’s. While the grandfather is not cured, he is back on the basketball court, thanks to recommendations by an Emory neurologist. He also has joined his daughter and grandson in Emory’s research programs.
     “I’m doing this for Cody,” Pratt says. “Anything to help them hurry and find a treatment to give him as normal a life as possible.”

tephen Warren, chair of Emory’s Department of Human Genetics, and his colleagues have indeed been in a hurry. In 1991, Warren led the international research team that discovered the fragile X gene responsible for the syndrome. He was among the first to develop genetic tests to diagnose the disease in children and predict the possibility of having a child affected by the disease. He now heads the world’s single largest NIH-funded fragile X research program, one that has mapped in detail the molecular as well as the clinical consequences of the fragile X gene mutation.
     “Finding the fragile X gene gave us the toehold we needed to understand the biology of the disorder, what really causes the problems,” says Warren. The team determined that the normal gene, the gene without the fragile X mutation, produced a specific protein necessary to regulate synthesis of other proteins involved in maintaining synapses between neurons, connections that are the basis of learning and memory. The damaged fragile X gene produces none of this regulatory protein, resulting in lost synaptic connections. In an effort to compensate for these lost connections, the brain signals the neurons to make more and more of the various synaptic proteins. This acceleration creates a protein overload, causing the dendrites of the neuron to become more rigid and less able to respond, thereby disrupting the cognitive process and possibly contributing to the behavioral problems seen in fragile X syndrome.
     In carriers, the fragile X gene still produces this important protein, thus preventing the problems seen in offspring who have fragile X syndrome. As Joe Pratt knows firsthand, however, all carriers are not home free. Emory fragile X researchers have discovered why. They identified a minuscule difference—a series of triple repeats—in the fragile X gene in carriers who develop FXTAS. All genes are made of combinations of four chemicals, abbreviated A, C, G, and T. Within the fragile X gene, the CGG, CGG, CGG grouping is repeated only 30 times in unaffected people but between 230 and 1,000 times in those with fragile X syndrome.
     Since many FXTAS patients respond to drugs developed for Parkinson’s disease, some clinicians had expressed skepticism that FXTAS was really a different disorder. That is, until Emory fragile X researcher Peng Jin placed the repeat portion of the gene in normal fruit flies, resulting in a sudden neurologic decline that definitively proved the impact of the altered gene. Warren and Sherman now lead a large clinical research group on the ataxia syndrome, seeking to more closely define what changes occur and how best to combat them.

he good news for Cody Hardin and thousands of other families like his is that Emory researchers now understand the function of fragile X’s protein well enough to develop a drug that will help compensate for the damaged gene’s effects. Warren hopes to have such a drug in clinical trials within the next decade.
Once the investigators understood the sequence of events resulting from the defective gene, they immediately saw where they could intervene. In the push and pull of protein production and utilization, the fragile X gene removes the neuronal brakes. The researchers could compensate by finding a drug that takes the pressure off the gas, the brain’s signal to the neuron to accelerate production of more and more synaptic proteins.
     The team already has identified compounds that do that in fruit flies and mice. Although the human body takes up these compounds imperfectly, chemists may be able to manipulate them into useful drugs. That will take years however, which neither the Emory team nor Cody Hardin’s grandfather wants. Cody starts softball this year, and his family eagerly hopes he can master the patience to wait on base until another runner hits the ball.
     To speed the process, Warren has taken another road: his team is screening every drug ever approved by the FDA, almost 2,000 of them, looking for one or more with the same abilities as the compounds that have worked in the lab. He is confident they will find a match, and when they do, he says, with the safety and efficacy studies already complete, “we can move rapidly into clinical trials with fragile X patients.”
     While the new drug may fail to completely reverse the cognitive deficit seen in children and adults with fragile X syndrome, Warren thinks it may have a big impact on behavioral problems that do so much to impede learning. “Fragile X kids differ from children with other types of retardation,” he notes. “While the basic cognitive deficits are often less deep, their own behaviors distract them. You can look in their eyes and see how sharp they are. They are aware that something is wrong, and it pains them not to know how to make it right.”
     While the researchers look for the drug, they are using their clinical knowledge to focus on early interventions shown to have a powerful impact on behavior and learning, as they have done with young Cody. Because of the efficacy of early intervention, not to mention the promise of an effective drug, Warren hopes to see states like Georgia add fragile X testing to the newborn screening panel.


lthough Emory’s Department of Human Genetics is still young, in fact, two years younger than Cody Hardin, already it has reorganized the traditional approach to genetics. The conscious pairing of clinical care and basic science research in genetics is a marked departure from all but a handful of medical schools, according to Warren. The department has incorporated the former basic science genetics department, enfolded a long-standing medical genetics program, formerly in pediatrics, and gathered faculty scattered across campus to work together on patient care and translational genetics. The situation is good for both groups: clinicians gain access to expensive research tools, such as transgenic or knockout mice, which they can use to manipulate and study genes, and basic scientists are involved in clinical research with large numbers of patients and families.
     Since 2001, when Warren received the go-ahead to create what he saw as the ideal human genetics department, he has hired more than a dozen young professors, bringing the faculty total to 33. One of his senior recruitments, David Ledbetter, came to Emory from the University of Chicago, where he served as genetics chair. As director of the Division of Medical Genetics, Ledbetter is expanding Emory’s clinical genetic services selectively and strategically, building on areas where Emory has the basic science expertise to provide instant credibility and creating the infrastructure for more rapid translational research.
     The first clinical areas that are benefiting from basic science input include general pediatric genetics, adult genetics, and cancer genetics. For example, the department’s metabolic disorders program already serves as the referral center for Georgia’s newborn screening and is responsible for genetic disease screening in six metro hospitals. Now its clinical research protocols are growing as well, including enzyme replacement trials for metabolic diseases such as Fabry’s and Gaucher’s diseases. More evidence, says Ledbetter, of the power of interventional genetics. These lysosomal storage disorders are caused by a genetic defect that results in failure to produce an enzyme required to metabolize specific molecules. The subsequent accumulation of these molecules in the liver, spleen, or brain is debilitating, often lethal. A few years ago, however, scientists discovered that patients could be infused with the missing enzyme every week or 10 days. Emory participated in the clinical trial that resulted in FDA approval of the first and only enzyme in use and currently is testing a number of other enzymes for these and other diseases.
     The department is opening new specialty clinics too, for patients with Down syndrome and fragile X syndrome. The national Down Syndrome Project and a national Fragile X Syndrome Research Center are the largest programs of this kind in the nation. Pediatric medical geneticists Paul Fernhoff (who is medical director of the Division of Medical Genetics), Daniel Gruskin, or Margaret Adam are the first stop for children who attend these clinics to determine whether they have secondary medical problems that require further referrals. Next, a developmental pediatrician and geneticist assists parents in managing problems and guiding them to educational resources and therapies. Parents also receive counseling on recurrence risk. For Down syndrome patients, genetic specialists determine the specific type of the disorder—a significant finding for genetic counseling because some types are more easily inherited than others. With the high degree of recurrence of fragile X, genetic counselors involve the extended family. A majority of families, including the Hardins, enter research programs at Emory, doing what they can to move the science forward to clinical applications. They may not be the only beneficiaries. In an investigation of why some Down syndrome babies are born with congenital heart disease while others are not, for example, Stephanie Sherman is looking for DNA sequence differences in genes she knows are important for heart development. Her findings of possible mutations also may provide important clues, perhaps even prenatal testing, for congenital heart disease in general.

ragile X is the most common known cause of autism, accounting for 2% to 5% of cases. The only other known cause, accounting for 1% to 2% of cases, is duplication on chromosome 15, the same region involved in Prader-Willi syndrome. While Warren is the undisputed leader in fragile X research, Ledbetter is the scientist who discovered the genetic basis of Prader-Willi. Partnering with the autism center in Emory’s Department of Psychiatry and the private Marcus Institute, these researchers are applying their expertise to look for the unknown causes of autism and, ultimately, the point at which they can intervene.
     “Autism is clearly not caused by a single gene,” says Warren. “It may take gene mutation plus an environmental trigger.”
     To seek out such predisposing changes, the human genetics research group is taking advantage of the recently mapped human genome and high-throughput robotic technologies unavailable even two or three years ago. Ledbetter is a member of the steering committee of the Autism Genetic Resource Exchange, a gene bank with pedigrees, genomic scans, and/or DNA samples of almost 600 families with more than one member diagnosed with autism spectrum disorder. He and colleague Christa Martin take DNA from these patients, label it with fluorescent dyes, and compare it with the normal genome, looking for areas with duplications or deletions.
     Warren searches telltale genetic signs of autism using the magnifying glass of what is already known about genes that cause autism-like disorders when severely mutated. For example, the X chromosome is a good place to look, since five to nine times more males than females have autism and the X chromosome contains a large number of genes (including fragile X) that cause retardation if severely mutated. With the faculty and technology now in his laboratories, he is comparing this and other regions of a normal human genome to that of people with autism, looking for milder mutations.
     “And when we find those genes and what they do,” says Warren, “we will have our entrance into autism, exactly as we found one with fragile X. The next step will be to see where to intervene to compensate for the effect of those genes. Only this time, we will have the fragile X experience behind us, and it won’t take as long to know what to do.”


o accommodate its growth, the academic offices of human genetics have doubled their space on campus. The majority of Emory’s clinical and laboratory services in genetics are now clustered a mile away in a 24,000-square-foot building on North Decatur Road, modeled to fit the needs of families seen in the genetics program and the researchers who work with them. The facility allows easy access for patients and emphasizes patient privacy with a separate entrance to clinician and counselor offices. It includes a special foods store and demonstration kitchen for parents of children with metabolic diseases and genetics laboratories (biochemistry, molecular, and cytogenetics) that process more than 28,000 patient specimens each year from across the nation.
     Slated to join the genetics enterprise on North Decatur Road are the Center for Medical Genomics—where blood is drawn, studied, and stored for genetic studies—and an infusion center for patients with Fabry’s or Gaucher’s disease.
     “Genetics has always been a bit of a hybrid,” says Warren. Because of the many years during which genetic counseling was done largely by genetics professors, it is the only field in which PhDs apply for postgraduate training alongside MDs and are board-certified by the American Board of Medical Specialties.
     The hybrid model of genetics at Emory today is particularly important in a time when the integration of basic sciences and clinical care are absolute necessities for translating genetics. These bridges between the laboratory and the clinic, between PhDs and MDs, between doctors and patients, are the ones that bring promise to 6-year-olds like Cody Hardin.


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