TUESDAY, AUGUST 24, 2010


KLMNO


Health


E5 Blood test could have revealed disorder far earlier mystery continued from E1


years, wreaking havoc on fami- lies who struggle to figure out what is wrong.


Looking for answers Adam was born four weeks


early, and doctors told Driscoll and her husband, Toby, a math professor, that was the reason he had trouble feeding as a new- born. He seemed unable to suck but then learned to do it, his mother recalled, noting a recur- ring pattern. “From early on it seemed like we had to teach him,” Driscoll said, recalling how she taught him to pick up blocks and use a shape-sorting toy, grasping his hand and guiding it. His limbs seemed somewhat floppy, but doctors ruled out cer- ebral palsy. His experienced pediatrician dismissed Driscoll’s increasingly urgent questions about Adam’s development. “It’s not like he won’t be walking and talking when he goes to college,” she re- called the doctor telling her. But by 15 months, the age at which her older son walked, Ad- am showed no sign of taking steps. He wasn’t talking or even babbling. The staffers at his day- care center were also concerned, and the pediatrician referred him to an early intervention pro- gram. A nurse came to the Driscolls’ home to observe Adam. To his parents’ dismay, she pronounced Adam developmentally on track and said he was “just about ready to walk”; in fact, he did not take his first steps for eight more months, when he was nearly 2. Social problems were also emerging. In day care Adam “hated to have other kids ap- proach him. He wanted to be alone,” his mother said. And he seemed terrified by swings or the slide.


When he was nearly 21⁄2 his


family attended a Christmas par- ty at the home of a developmen- tal pediatrician with whom Dris- coll worked. The doctor later told Driscoll that she was struck by Adam’s behavior: First he hid be- hind the sofa and had to be coaxed out. Then he sat quietly all night beside his parents, nev- er running around and playing like the other children. At Driscoll’s request, the devel- opmental pediatrician evaluated Adam, ruling out autism. He was given a diagnosis of an unspeci- fied motor and speech delay and enrolled in a special-ed day-care center. There he made significant gains, but by then Driscoll had become convinced something more global was wrong. “I felt that everything going on had to be tied together,” she said. “There were too many problems in too many domains.” Specialists working with Adam and his reg- ular pediatrician counseled pa- tience.


But a physical therapist agreed with Driscoll and urged her to


ing puberty, which can boost lev- els of the male sex hormone dur- ing a critical growth phase, fuel- ing the development of bigger muscles and more facial and body hair, which tends to be sparse. As teenagers, they may experience breast development; most are tall. Bean said that the diagnosis can be difficult to make before puberty, because Klinefelter’s mimics other problems. “It’s not something I see frequently” as a neurologist, he said, unless a child has significant motor prob- lems.


Driscoll said her initial reac-


tion after Adam’s diagnosis was to breathe “a huge sigh of relief. It explained everything and it’s not going to kill him. I realized the path was pretty clear” about what needed to be done. “But,” she added, “it was a bit of a punch in the gut, too,” be- cause the diagnosis will affect Adam for the rest of his life. Dris- coll said her family also grapples with the stigma that accompa- nies a genetic disorder, “espe- cially one involving sex chromo- somes,” and with misinforma- tion. When people learn that Adam possesses two X chromo- somes, they often ask his mother if he is gay. (Studies have found that Klinefelter’s patients are no more likely to be gay than the general population.) Heart defects often accompa-


PHOTOS BY DOUG KAPUSTIN FOR THE WASHINGTON POST Jen Driscoll works with her son, Adam, as he practices his writing skills. Tests have shown his intelligence to be above average.


see S. Charles Bean, a pediatric neurologist at the Nemours/Al- fred I. duPont Hospital for Chil- dren in Wilmington, where Dris- coll was then employed. “If any- body can figure it out, it’s Chuck Bean,’” the physical therapist told Driscoll.


During an intensive, 90-min-


ute evaluation in November 2007, Bean took a detailed his- tory, watched Adam walk and eat, and played games with him. Then he ordered blood tests for several metabolic and genetic disorders. He told Driscoll he suspected Adam had fragile X syndrome, the most common cause of inherited mental im- pairment, which is responsible for a range of problems, from learning disabilities to mental retardation.


Driscoll thought fragile X was


less likely than a mild form of muscular dystrophy. Two weeks later, the results came back from the lab. “You’re not going to believe this one,” she recalled Bean telling her. They were both wrong.


‘A punch in the gut’


Adam had Klinefelter syn- drome, also known as XXY syn- drome. The disorder, which is not hereditary, occurs very early in fetal development when boys randomly acquire an extra X sex chromosome rather than one X and one Y. Named for Harry


Klinefelter, the physician who first described it in 1942, the syn- drome affects one in 500 to 1,000 males, according to the Genetics Home Reference. In addition to being one of the most common chromosomal disorders, it is also one of the most stigmatized; ear- ly studies were conducted among prison inmates, and researchers erroneously linked the disorder with criminal behavior and low IQ, a legacy that has been hard to shake.


“Early on it got a very bad


press,” said Samango-Sprouse, a neurodevelopmental specialist who works with children who have sex chromosome disorders. That linkage, she suspects, pre- vents some doctors from consid- ering it as a possible diagnosis in children.


XXY syndrome varies in sever-


ity, although it almost always causes infertility because it im- pairs the production of testoster- one. Males who do not have the extra X chromosome on all their cells may have mild cases and never know they have the prob- lem until it is discovered during an infertility workup. Boys who are more severely affected may struggle with physical, social and language development. As ba- bies, they tend to be shy and un- demanding.


If the disorder is diagnosed


Jen and Toby Driscoll play with Adam. “We feel tremendously lucky that we’ve gotten him diagnosed this young,” she said.


early, boys can be treated with supplemental testosterone dur-


ny XXY syndrome, but a cardiol- ogist found no such problems in Adam. He is continuing to re- ceive physical therapy and test- ing showed his intelligence is above average. The Driscolls have told Adam about his diagnosis, explaining that he has an extra chromo- some, “like an instruction book that was printed twice.” She doesn’t want Adam to think the problems are his fault, as did some men she has met whose disorder was not diagnosed until adulthood but had been told as children that they were lazy, dumb or mentally ill. Adam, she says, is persistent


and determined to surmount his difficulties. A few weeks ago, the little boy who used to hate play- ing with other children invited 10 classmates to his first-ever party to celebrate his seventh birthday. Had Adam’s condition been di- agnosed earlier, Driscoll believes her family would have been spared years of unnecessary anxiety and frustration. “We feel tremendously lucky that we’ve gotten him diagnosed this young,” she said. “But I worry about the other kids” whose baf- fling problems could be ex- plained by a blood test.


If you have a Medical Mystery that has been solved, e-mail medicalmysteries@washpost.com. To read previous mysteries, go to www.washingtonpost.com/health.


Studies seek ways to predict onset of Alzheimer’s alzheimer’s continued from E1


ers, the biological indicators of the disease. New brain-scanning techniques, tests for “suspect” genes and measures of certain telltale proteins in spinal fluid probably won’t benefit patients for years, but they’re giving re- searchers a more sophisticated picture of the disease’s pathology. At the Banner Alzheimer’s In-


stitute in Phoenix, researchers Eric Reiman and Pierre Tariot are leading the Alzheimer’s Preven- tion Initiative, a collaborative ef- fort by scientists, academics and the pharmaceutical industry. “We want to help launch the era of Alzheimer’s prevention research,” Reiman says. “It’s a true collabo- ration between stakeholders, the people afflicted, the families and people at risk.” The institute is developing two studies, to begin in 2012, that will treat apparently healthy people who show the highest genetic risk for developing the disease. “They will be more or less free of symp- toms when we begin,” Tariot says. The researchers will use brain imaging and cognitive tests to track the impact of experimental drugs. “The hypothesis is that if we give pre-symptomatic people these treatments we should be able to see some evidence of the effects,” Tariot says. One study, to take place in the region around Medellin, Colom- bia, will focus on 2,000 members of 25 extended families who share


help prevent onset. Reiman says they have not yet decided which drugs will be tested.


Ethical questions


Studies led by Eric Reiman, left, and Pierre Tariot will track the impact of experimental drugs on people at risk of Alzheimer’s.


a common ancestry and whose members carry a gene that leads some to develop Alzheimer’s while they’re still in their 40s. Though early-onset Alzheimer’s is rare, the underlying mecha- nisms are thought to be quite similar to those that appear when the disease typically emerges, usually in the 70s and 80s. For the second study, to be con-


ducted in the United States, re- searchers will screen 50,000 peo- ple ages 60 to 80 to see if they car- ry two copies of a gene, ApoE4, that evidence suggests is linked to Alzheimer’s. Of those who do, Reiman expects 400 to be en- rolled in the study. Half the participants in each study will receive an experimen- tal drug and half will receive pla- cebos; then they will be mon- itored for two years. If the drug doesn’t seem to have a protective effect, the investigators will try another drug, looking for one to


Giving experimental therapies to healthy people raises ethical questions. But researchers, physi- cians and pharmaceutical exec- utives say the urgency of the problem justifies taking a certain amount of risk, which they will disclose to everyone participat- ing in the studies. “We need to be able to say,


‘Here is what we know and here is what we don’t know about this drug,’ ” Tariot says. New brain-imaging technolo- gies will help the researchers evaluate the drugs’ efficacy. For example, Avid Radiopharmaceu- ticals of Philadelphia has devel- oped a new dye, AV45, that binds with amyloid proteins, which cre- ate the plaques in the brain that are Alzheimer’s hallmarks. The dye makes the plaques visible on a PET scan. “This is a compound that sees


amyloid in the brain,” says Mi- chael Weiner of the Alzheimer’s Disease Neuroimaging Initiative, who was not involved with the dye’s development but intends to use it in future studies. “Another way of saying it is that it sees Alz- heimer’s in the brain.” Before the advent of amyloid imaging tech- nologies, the only way to see amy- loid plaques and therefore obtain a definitive Alzheimer’s diagnosis was to do an autopsy after the pa-


tient died. AV45 is not the first amyloid dye, but it represents an impor- tant advance because researchers can use it for about two hours be- fore it degrades. Earlier amyloid dyes were limited because their fleeting radioactivity — they were effective for only 20 minutes — meant they had to be made on- site and used immediately. “This tracer can be used much more broadly,” researcher Susan Landau of the University of Cali- fornia at Berkeley, says of AV45. Landau is leading a study that seeks to determine which bio- markers can best predict Alzhei- mer’s. Her work has shown that a particular PET scan, which meas- ures overall brain function, used in conjunction with memory tests, can distinguish which pa- tients with mild cognitive impair- ment (an early Alzheimer’s symp- tom) will go on to develop Alzhei- mer’s and which won’t. “Overall, in the field, there’s the hope that we will be able to pre- dict it before symptoms appear,” Landau says. To date, remedies for Alzhei-


mer’s remain frustratingly lim- ited. Once Alheimer’s symptoms appear, the disease has already disrupted the brain’s communica- tion system of neurons, synapses and neurotransmitters. The drugs so far approved by the Food and Drug Administration include acetylcholinesterase inhibitors such as Aricept, Razadyne and Exelon, which aim to reduce the


breakdown of acetylcholine, a key neurotransmitter. Another medi- cation, Namenda, works to re- duce the excessive amount of the neurotransmitter glutamate pro- duced by Alzheimer’s brains; too much glutamate results in cell death. These drugs don’t cure Alzhei-


mer’s; they only treat the symp- toms and are effective for a few years, if at all. Some patients re- port improved memory and cog- nitive function with the treat- ments; others see no improve- ment. More than 150 Alzheimer’s drugs are in development.


Building momentum As enthusiastic as researchers


are, they face a long road. Even if they determine which biomark- ers are best at predicting the dis- ease and discover drugs that slow the progress of those biomarkers, there’s no guarantee that the drugs will arrest the cognitive de- cline.


Recent experimental drugs


have been effective in removing amyloid from patients’ brains, for example, but produced no change in their symptoms. That has fueled debate whether the telltale amyloid plaques may be only a sign of the underlying disease, not its cause. “Amyloid plaques may be like


gravestones that signify the end stage of the disease,” Tariot says. “The toxicity may have occurred long before the plaques appear.” “Creating knowledge is a long


way from making drugs,” ac- knowledges Fillit of the Alzhei- mer’s Drug Discovery Founda- tion, which invests in start-up biotech firms, existing companies and academic research. It can cost $1.2 billion to bring a new drug to market, Fillit says. “We give this money for a very


specific purpose, and we want specific milestones,” Fillit said. “The only way out of this co- nundrum is to find new drugs.” In a report last year, the Alzhei-


mer’s Study Group, a panel co- chaired by former House speaker Newt Gingrich and former sena- tor Bob Kerrey, warned that the Alzheimer’s epidemic will prog- ress like the disease itself: slowly. But if we ignore it, the group said, it could have the same disastrous consequences as ignoring the levees in New Orleans or looking the other way as subprime loans subverted the financial system. The convergence of technologi- cal innovation and an enormous population at risk has made Alz- heimer’s a higher national priori- ty for researchers. “We’re excited about this


change of momentum,” Tariot said. “We’ve captured people’s imagination and attention.” health-science@washpost.com


James, a senior at the University of Nebraska at Lincoln, is a fellow of the News21 program at the Columbia University Graduate School of Journalism. http://columbia.news21.com.


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