Medicine: Tracing Fragile X Syndrome

Denver Housewife Jeannie Lancaster suspected that something was wrong with her son a few months after his birth. "He was always fussy and would never cuddle," she remembers. "When I would go to pick him up, he would arch away." By the time he was one, he had acquired the alarming habit of banging his head against the wall, and when he began to talk, he repeated the same sound or word over and over again. Says Lancaster, "I kept asking myself, 'What am I doing wrong?' " Professional counselors offered conflicting views. A pediatrician thought the boy might be autistic. School officials said he was emotionally disturbed. Further testing indicated he was mildly retarded.

It was only after Lancaster had given birth to a second son who showed some of the same mysterious symptoms that a family doctor began to suspect the cause. He had just returned from a medical seminar on a newly recognized disorder called Fragile X syndrome, which results from a weakness in the structure of the X sex chromosome (one of the 46 chromosomes -- complex molecules containing long segments of DNA -- in the nucleus of the human cell). The behavior of the Lancaster children seemed to fit the patterns described at the meeting, and tests at Denver's Children's Hospital soon confirmed that they both had the defective chromosome.

Virtually unknown to doctors five years ago, Fragile X has come to be recognized as a leading cause of mental retardation among newborns in the U.S., second only to Down's syndrome. It produces disabilities ranging from learning difficulties, especially in math, to mental retardation, often accompanied by such benign physical abnormalities as oversize ears, an elongated forehead, enlarged testes and double-jointedness. Recent research also suggests that Fragile X may be responsible for one out of ten cases of autism, a mysterious condition characterized by extreme withdrawal and refusal to communicate. At one time, autism was often blamed on cold, unfeeling parents.

Doctors diagnose Fragile X by using a microscope to examine X chromosomes isolated from white blood cells. The defective site is often clearly visible at the end of one of the chromosome's arms. Last year a more accurate diagnostic test was devised by Geneticist W. Ted Brown, of the New York State Institute for Basic Research in Developmental Disabilities (IBR) on Staten Island. Brown's team uses a technique in which snippets of DNA taken from the X chromosomes of people suspected of having the condition are compared with snippets from their normal relatives.

Because the defective site is on the X chromosome, females (who are born with two Xs, one inherited from each parent) are less often affected by the syndrome; their normal X chromosome can mask the effects of the faulty one. But males, who have one X and one Y sex chromosome, have no such backup and are therefore more susceptible. Still, for reasons that baffle scientists, not all females are protected, and some males are spared. "About 20% of males who inherit the gene are unaffected carriers, and about a third of all females who are carriers are affected," says Pediatrician Randi Hagerman, of Children's Hospital. "It's a crazy inheritance pattern."