Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology
Mendelian Genetics: Patterns Of Inheritance And Single-Gene Disorders
Autosomal recessive single-gene diseases occur only in individuals with two mutant alleles of the disease-associated gene. Remember, for any given gene, a person inherits one allele from his or her mother and one allele from his or her father. Therefore, individuals with an autosomal recessive single-gene disease inherit one mutant allele of the disease-associated gene from each of their parents. In pedigrees of families with multiple affected generations, autosomal recessive single-gene diseases often show a clear pattern in which the disease "skips" one or more generations.
Phenylketonuria (PKU) is a prominent example of a single-gene disease with an autosomal recessive inheritance pattern. PKU is associated with mutations in the gene that encodes the enzyme phenylalanine hydroxylase (PAH); when a person has these mutations, he or she cannot properly manufacture PAH, so he or she is subsequently unable to break down the amino acid phenylalanine, which is an essential building block of dietary proteins. As a result, individuals with PKU accumulate high levels of phenylalanine in their urine and blood, and this buildup eventually causes mental retardation and behavioral abnormalities.
The PKU-associated enzyme deficiency was determined biochemically in the 1950s—long before the PAH-encoding gene was mapped to human chromosome 12 and cloned in 1983. Specifically, Dr. Willard Centerwall, whose child was mentally handicapped, developed the first diagnostic test for PKU in 1957. Called the "wet diaper" test, Centerwall's test involved adding a drop of ferric chloride to a wet diaper; if the diaper turned green, the infant was diagnosed with PKU. The wet diaper test was used to reliably test infants at eight weeks after birth; by this time, however, infants who were affected by PKU had already often suffered irreversible brain damage.
Thus, in 1960, Dr. Robert Guthrie, whose niece suffered from PKU and whose son was also mentally handicapped, established a more sensitive method for detecting elevated phenylalanine levels in blood, which permitted a diagnosis of PKU within three days after birth. Guthrie's test used bacteria that were unable to make their own phenylalanine as messengers to report high blood levels of phenylalanine in an infant's blood sample obtained via heel prick. With Guthrie's method, the phenylalanine-deficient bacteria were grown in media together with a paper disk spotted with a drop of the infant's blood. If the phenylalanine levels in the blood were high, the bacteria would grow robustly, and a diagnosis of PKU could be made. Through the ability to discover that their child had PKU at such an early age, parents became able to respond immediately by feeding their child a modified diet low in proteins and phenylalanine, thereby allowing more normal cognitive development. Guthrie's test continues to be used today, and the practice of obtaining an infant's blood sample via heel prick is now used in numerous additional diagnostic tests.
Several other human diseases, including cystic fibrosis, sickle-cell anemia, and oculocutaneous albinism, also exhibit an autosomal recessive inheritance pattern. Cystic fibrosis is associated with recessive mutations in the CFTR gene, whereas sickle-cell anemia is associated with recessive mutations in the beta hemoglobin (HBB) gene. Interestingly, although individuals homozygous for the mutant HBB gene suffer from sickle-cell anemia, heterozygous carriers are resistant to malaria. This fact explains the higher frequency of sickle-cell anemia in today's African Americans, who are descendants of a group that had an advantage against endemic malaria if they carried HBB mutations. Finally, oculocutaneous albinism is associated with autosomal recessive mutations in the OCA2 gene. This gene is involved in biosynthesis of the pigment melanin, which gives color to a person's hair, skin, and eyes.
DNA Deletion And Duplication And The Associated Genetic Disorders
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Anorexia And Bulimia: Cracking The Genetic Code
Not so long ago, doctors and therapists blamed anorexia, bulimia, and other eating disorders on overly controlling parents. When they first gained attention in the late 1970s and early 1980s, the diseases were often seen as psychosomatic -- the willful behavior of often-spoiled, privileged teenagers.
Today, a growing body of research indicates that you can indeed get anorexia from your parents, but not in the way previously thought. Eating disorders appear to be as strongly genetically linked as many other major psychiatric disorders, like schizophrenia, depression, bipolar disorder, or obsessive-compulsive disorder.
"I know a woman in Massachusetts who lost three sisters to an eating disorder. One of our board members has three generations of eating disorders in her family," says Lynn Grefe, CEO of the National Eating Disorders Association. "I meet elderly women who have had eating disorders who whisper to me, 'My mother cooked all day long, but she never ate.'"
"I think what we're learning is that the genetic predisposition interacts with the culture to bring about anorexia and other eating disorders," she says.
"You're born with the gun, and society -- your cultural and environmental circumstances -- pulls the trigger," says Grefe.
In 1996, a private European foundation called the Price Foundation began to fund research into the genetics of anorexia and bulimia. During the next several years, an international group of scientists collected an astounding amount of data: first, on some 600 families with two or more members who have anorexia or bulimia, and later, on another group of 700 families with three members who have anorexia or bulimia along with 700 "control" women for comparison studies.
Their early results found a couple of "likely suspects": areas on chromosomes 1 and 10 that appear to be significantly linked with anorexia and bulimia. Follow-up studies of candidate genes have identified several genes that may increase a person's vulnerability to these disorders.
The research proved so promising that in 2002, the National Institute of Mental Health awarded a $10 million grant to this group of investigators. This is the first-ever U.S. Government-funded genetic study of anorexia. It aims to find regions of the human genome that contain genes influencing risk for anorexia. (Ten sites in the U.S., Canada, and Europe are now recruiting families for the study. You can find out more at https://www.Wpic.Pitt.Edu/research/angenetics/.)
"I don't think any of us feel that we're going to find a single gene that will account for anorexia nervosa and bulimia, such as with the gene for Huntington's disease," says Craig Johnson, PhD, director of the Eating Disorders Program at Laureate Psychiatric Clinic and Hospital in Tulsa, Oklahoma, and one of the study's co-investigators. "We're convinced that instead there will be a number of genes that, to small effect, line up to create susceptibility."
Many people have theorized that the current obsessive cultural focus on weight and thinness -- and on celebrities and their appearances -- is likely to promote anorexia and bulimia. But that doesn't entirely explain the conundrum of eating disorders, says Johnson.
"The overall prevalence of anorexia and bulimia, combined, is about 4%. But if they're largely caused by societal pressures, there should be a lot more of this. How many newsstand magazines can you pick up and read about someone's weight loss?" he asks. "Why can many girls go on a diet and walk away not dramatically affected, while four out of 100 wind up with psychiatric illnesses? The answer probably lies in neurochemistry and genetics."
The genetic research seems to indicate that some people -- mostly, though not all, female -- may have a latent vulnerability to eating disorders, which might never be "turned on" if they weren't exposed to particular influences, just as a predisposition to alcoholism can remain latent unless the person takes a drink.
"Since in our culture today, dieting behaviors are more intense, it's exposing that latent vulnerability more now than in previous generations," suggests Johnson.
Ultimately, of course, the investigators hope that this research might suggest new possibilities for treatment.
"The long-term goal is to identify those aspects of brain-related function that influence development, behavior, and personality, and help us refine the search for potentially more effective pharmacotherapies," says Michael Strober, MD, professor of psychiatry at the David Geffen School of Medicine at the University of California, Los Angeles. He is also director of the Eating Disorders Program at the Lynda and Stewart Resnick Neuropsychiatric Hospital at UCLA.
But while new medicines may help, Strober is quick to say he doubts anorexia and bulimia will ever be treated solely with medication. "More effective new medications will be important, but a combination of approaches is essential. The importance of psychotherapy should never be minimized."
Drug treatments based on the new research are probably a long way off. But in the meantime, study results may help improve current treatment approaches. "It potentially gives us a frame of reference for psychological treatment, allowing us to better target the therapeutic approaches that may help," says Strober.
Information about the inheritability of anorexia and bulimia will also be important in prevention. For example, it could help parents and doctors to intervene early with young people whose family history and psychological profile may put them at particularly high risk. Johnson says that studies have shown people at highest risk for anorexia or bulimia tend to have five personality traits:
Many experts also hope that the growing evidence for a genetic component to anorexia and bulimia will help make the case for better access to treatment of these disorders, and improved insurance coverage of such treatment.
"Whereas we have developing treatments for eating disorders that are more and more effective, the majority of people still struggle to access them," says Doug Bunnell, past president of the National Eating Disorders Association and clinical director of the Renfrew Center of Connecticut. "There aren't enough clinicians trained to do this, and not enough funding for a process of treatment that often takes a very long time."
"We need to understand the genetic influence involved in eating disorders, and its impact on psychological functioning," agrees Strober. "Bridging that gap of understanding will reduce stigma, inform the public, target the focus of therapy, and bring eating disorders rightly under the rubric of medical/psychological conditions as opposed to social phenomena."
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