five. Other, less consistent symptoms may include neurological, cutaneous (skin), and a variety of other conditions. Neurological Neurological symptoms of A-T include: • Progressive cerebellar ataxia (although ataxia may appear static between the ages of two and five) • Cerebellar dysarthria (slurred speech) • Difficulty swallowing, causing choking and drooling • Progressive apraxia (lack of control) of eye movements • Muscle weakness and poor reflexes • Initially normal intelligence, sometimes with later regression to mildly retarded range Cutaneous Cutaneous symptoms include: • Progressive telangiectases of the eye and skin develop between two to ten years of age • Atopic dermatitis (itchy skin) • Café au lait spots (pale brown areas of skin) • Cutaneous atrophy (wasting away) • Hypo- and hyperpigmentation (underpigmented and overpigmented areas of skin) • Loss of skin elasticity • Nummular eczema (coin-shaped inflammatory skin condition) Other symptoms Other manifestations of A-T include: • Susceptibility to neoplasms (tumors or growths) • Endocrine abnormalities • Tendency to develop insulin-resistant diabetes in ado- lescence • Recurrent sinopulmonary infection (involving the sinuses and the airways of the lungs) • Characteristic loss of facial muscle tone • Absence or dysplasia (abnormal development of tissue) of thymus gland • Jerky, involuntary movements • Slowed growth • Prematurely graying hair Diagnosis For a doctor who is familiar with A-T, the diagnosis can usually be made on purely clinical grounds and often on inspection. But because most physicians have never seen a case of A-T, misdiagnoses are likely to occur. For example, physicians examining ataxic children fre- quently rule out A-T if telangiectases are not observed. However, telangiectases often do not appear until the age of six, and sometimes appear at a much older age. In addition, a history of recurrent sinopulmonary infections might increase suspicion of A-T, but about 30% of patients with A-T exhibit no immune system deficiencies. The most common early misdiagnosis is that of static encephalopathy—a brain dysfunction, or ataxic cerebral palsy—paralysis due to a birth defect. Ataxia involving the trunk and gait is almost always the present- ing symptom of A-T. And although this ataxia is slowly and steadily progressive, it may be compensated for— and masked—by the normal development of motor skills between the ages of two and five. Thus, until the pro- gression of the disease becomes apparent, clinical diag- nosis may be imprecise or inaccurate unless the patient has an affected sibling. Once disease progression becomes apparent, Friedreich ataxia (a degenerative disease of the spinal cord) becomes the most common misdiagnosis. However, Friedreich ataxia usually has a later onset. In addition, the spinal signs involving posterior and lateral columns along the positive Romberg’s sign (inability to maintain balance when the eyes are shut and feet are close together) distinguish this type of spinal ataxia from the cerebellar ataxia of A-T. Distinguishing A-T from other disorders (differential diagnosis) is ultimately made on the basis of laboratory tests. The most consistent laboratory marker of A-T is an elevated level of serum alpha-fetoprotein (a protein that stimulates the production of antibodies) after the age of two years. Prenatal diagnosis is possible through the measurement of alpha-fetoprotein levels in amniotic fluid and the documentation of increased spontaneous chro- mosomal breakage of amniotic cell DNA. Diagnostic support may also be offered by a finding of low serum IgA, IgG and/or IgE. However, these immune system findings vary from patient to patient and are not abnor- mal in all individuals. The presence of spontaneous chromosome breaks and rearrangements in lymphocytes in vitro (test tube) and in cultured skin fibroblasts (cells from which con- nective tissue is made) is also an important laboratory marker of A-T. And finally, reduced survival of lympho- cyte (cells present in the blood and lymphatic tissues) and fibroblast cultures, after exposure to ionizing radiation, will confirm a diagnosis of A-T, although this technique is performed in specialized laboratories and is not rou- tinely available to physicians. When the mutated A-T gene (ATM) has been identi- fied by researchers, it is possible to confirm a diagnosis by screening the patient’s DNA for mutations. However, 126 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Ataxia-telangiectasia in most cases the large size of the ATM gene and the large number of possible mutations in patients with A-T seri- ously limit the usefulness of mutation analysis as a diag- nostic tool or method of carrier identification. Treatment and management There is no specific treatment for A-T because gene therapy has not become an option as of year 2000. Also, the disease is usually not diagnosed until the individual has developed health problems. Treatment is therefore focused on the observed conditions, especially if neo- plams are present. However, radiation therapy must be minimized to avoid inducing further chromosomal dam- age and tumor growth. Supportive therapy is available to reduce the symp- toms of drooling, twitching, and ataxia, but individual responses to specific medications vary. The use of sun- screens to retard skin changes due to premature aging can be helpful. In addition, early use of pulmonary physio- therapy, physical therapy, and speech therapy is also important to minimize muscle contractures (shortening or tightening of muscles). Although its use has not been formally tested, some researchers recommend the use of antioxidants (such as vitamin E) in patients with A-T. Antioxidants help to reduce oxidative damage to cells. Prognosis A-T is an incurable disease. Most children with A-T depend on wheelchairs by the age of ten because of a lack of muscle control. Children with A-T usually die from respiratory failure or cancer by their teens or early 20s. However, some patients with A-T may live into their 40s, although they are extremely rare. Resources BOOKS Vogelstein, Bert, and Kenneth E. Kinzler. The Genetic Basis of Human Cancer. New York: McGraw-Hill, 1998. PERIODICALS Brownlee, Shanna. “Guilty Gene.” U.S. News and World Report. (July 3, 1995): 16. Kum Kum, Khanna. “Cancer Risk and the ATM Gene.” Journal of the American Cancer Institute 92, no. 6 (May 17, 2000): 795–802. Stankovic, Tatjana, and Peter Weber, et al. “Inactivation of Ataxia Tlangiectasia Mutated Gene in B-cell Chronic Lymphocytic Leukaemia.” Lancet 353 (January 2, 1999): 26–29. Wang, Jean. “New Link in a Web of Human Genes.” Nature 405, no. 6785 (May 25, 2000): 404–405. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 127 Attention deficit hyperactivity disorder ORGANIZATIONS A-T Children’s Project. 668 South Military Trail, Deerfield Beach, FL 33442. (800) 5-HELP-A-T. Ͻhttp://www.atcp .orgϾ. A-T Medical Research Foundation. 5241 Round Meadow Rd., Hidden Hills, CA 91302. Ͻhttp://pathnet.medsch.ucla .edu/people/faculty/gatti/gatsign.htmϾ. National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020. Fax: (763) 553- 0167. naf@ataxia.org. Ͻhttp://www.ataxia.orgϾ. National Organization to Treat A-T. 4316 Ramsey Ave., Austin, TX 78756-3207. (877) TREAT-AT. Ͻhttp://www. treat-at .orgϾ. Genevieve T. Slomski, PhD I Attention deficit hyperactivity disorder Definition Attention deficit hyperactivity disorder, or ADHD, is a behavioral disorder, characterized by poor attention, inability to focus on specific tasks, and excessive activity. ADHD is thought to have a strong genetic component, although studies are still ongoing to determine what role specific genes play in ADHD. Description Attention deficit hyperactivity disorder (ADHD) was first described by a pediatrician, Dr. George Still, in 1902. At the time, he gave an account of 43 children who exhibited such symptoms as aggressiveness, defiance, and limited attention spans. He stated that he felt these symptoms indicated a lack of “moral control” in these children and others exhibiting similar characteristics. Until the 1950s, it was felt that the symptoms of ADHD were caused by either infections, toxins, or trauma to the head. During that time, ADHD was referred to as “minimal brain damage,” or minimal brain dysfunc- tion.” In the 1960s and 1970s, when more was learned about brain functioning, scientists and doctors changed the name of the disorder to “hyperkinetic reaction to childhood” in response to the recognition of the promi- nent role of hyperactivity with the disorder. It was also during this time that the use of stimulants such as amphetamines began to be used to treat children diag- nosed with the disorder. The term “attention deficit dis- order,” and finally, attention deficit hyperactivity disorder, was applied to the disorder in the 1980s and 1990s. From the time it was first clinically described by Dr. Still, the diagnosis of ADHD has included certain basic characteristics, such as easy distractibility, hyperactivity, impulsivity, and a short attention span, especially when related to specific tasks. Early in its history, ADHD was thought of as a purely childhood disorder; however, it is now recognized that ADHD can continue well into adult- hood. Current studies indicate that ADHD affects between six and nine million adults in the United States and is seen in both males and females, with males having the condition about twice as often as females. Genetic profile There is good evidence to suggest that genetic fac- tors play an important role in ADHD. From early studies to the present, it has been recognized that ADHD tends to run in families. Multiple studies have shown that patients who have first or second degree relatives with ADHD are at higher risk for developing ADHD then patients who do not have close relatives with the condition. It has also been shown that children who are adopted are at higher risk for ADHD if their biologic parents have the condi- tion, rather than their adoptive parents. Children whose parents have ADHD have a 50% chance of developing the condition. While genetics certainly plays a role in ADHD, the specific genes responsible for the condition have yet to be identified. In 1993, a study reported that ADHD was seen in 40% of adults and 70% of children in a rare thyroid autosomal dominant disorder located on chromosome 3. However, later studies have been unable to confirm this initial study. More convincing research points to a particular form of a gene called DRD4-7, which codes for dopamine transport in the brain. Dopamine is one of several very important brain neurotransmitters, and a certain type, or allele of DRD4-7 is thought to decrease the amount of dopamine in the brain. Studies have shown that about 30% of patients with ADHD have this certain DRD4-7 allele. In people who do not have ADHD, this allele is only seen about 15% of the time. Demographics Studies on the occurrence of ADHD within different ethnic, racial, and sociological groups is somewhat lim- ited. Early studies pointed to families on the lower end of the socioeconomic scale and minority racial groups as having a higher incidence of ADHD. However, later stud- ies have not bore these studies out, and in fact there was obvious ethnic and racial bias built into these initial studies. More recent studies have focused on possible enviro- mental factors in the development of ADHD. Childhood exposure to certain toxins, such as lead, alcohol, and cig- arette smoke, seemed to be linked to a higher occurrence of ADHD. Other studies point to childhood hypersensi- tivity to certain food additives as a contributing factor in the development of ADHD. Nutritional deficiencies in iron, zinc, and essential fatty acids have also been impli- cated in ADHD, but studies in this area are limited. Signs and symptoms ADHD is a condition defined by behaviors rather than specific chemical or genetic abnormalities. Therefore, there are very specific signs and symptoms that must be seen in a patient for a diagnosis of ADHD to be given. According to the DSM-IV (the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), patients must show six of the following symptoms for a period of six months in order to be properly diagnosed with ADHD: failure to pay attention to details or making careless mistakes on a regular basis; difficulty sustaining attention to work or play activities; failure to listen when spoken to; failure to complete chores and assignments; difficulty in organizing tasks and activities; chronic for- getfulness; chronic restlessness or fidgeting; losing or forgetting important things; avoidance of tasks or work which requires sustained mental effort. It should be emphasized that since ADHD is based on certain behav- iors, these behaviors can vary even in patients diagnosed with ADHD. Diagnosis Currently, there are no accepted or proven genetic studies to prove the existence of ADHD. The condition is diagnosed purely on certain behavioral characteristics that are long-term, excessive, and pervasive. These char- acteristics are listed above under signs and symptoms. Treatment and management The treatment and management of ADHD has sig- nificantly changed over time. Before the 1950s, behav- ioral therapy, such as teaching patients with ADHD how to improve their organizational skills and focus on tasks, 128 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Attention deficit hyperactivity disorder KEY TERMS Allele—One of two or more alternate forms of a gene. Autosomal dominant—A pattern of genetic inher- itance where only one abnormal gene is needed to display the trait or disease. Dopamine—A neurochemical made in the brain that is involved in many brain activities, including movement and emotion. was the mainstay of treatment. However, with the devel- opment of medications specifically for psychiatric prob- lems, the use of pharmacological agents has become a common treatment for ADHD. The use of stimulant medications has been proven to decrease the symptoms of ADHD and to improve func- tioning in patients with the condition in about 75–90% of patients. It is thought that the stimulants work by increas- ing the amount of dopamine in the brain of patients with ADHD, either by decreasing the rate at which the brain breaks down normally present dopamine, or by causing an increase in the production dopamine. Other medica- tions that are less frequently used to treat ADHD, such as antidepressants, also increase the amount of dopamine in the brain. There are currently many different types of stimulant medication that can be used to treat ADHD, although it is thought they all work through increasing dopamine in the brain. The three most commonly used stimulants are methylphenidate, or Ritalin, amphetamines such as Dexedrine or Adderall, or Pemoline, also called Cylert. All of the above stimulant medications share some common effects, as well as common side effects. In chil- dren with ADHD, use of stimulants causes a marked improvement in classroom behavior and performance, with an increase in goal-oriented organized behavior. There is a significant decrease in hyperactivity and impulsively, and most children report an improvement in their concentration abilities. Common side-effects of stimulants in both patients with ADHD and people with- out ADHD include decreased appetite, weight loss, insomnia, and in children, growth retardation. The first-line stimulant in the treatment of ADHD is generally Ritalin, due to less side-effects, proven value in the condition, and relative safety, even in overdose cases. Dexedrine or Adderall is initially used if a stronger med- ication is needed or if patients do not respond well to Ritalin. Cylert is less potent then either Ritalin or Adderall or Dexedrine, so is a good choice if patients are sensitive to the effects of stimulants. Cylert also has the advantage of being taken only once a day, versus two or three times a day for the other stimulants. Prognosis Long-term studies examining patients who have been diagnosed with ADHD are limited. Some early studies done in the 1960s examined adults who had been diagnosed with ADHD as children. There were reports of increased rates of alcoholism, drug abuse, and lower socioeconomic levels among those adults who had been diagnosed with ADHD as children. These studies also stated that at least 50% of these adults still reported symptoms of ADHD, such as hyperactivity, poor impulse control, and inability to concentrate. Later studies reported in the 1990s have confirmed some, but not all of the same results as earlier studies. A study done in Canada followed over 100 boys who were diagnosed with ADHD for fifteen years. The study found that there were lower educational and occupational out- comes for those with ADHD as compared with children without the condition. However, there was no increase seen in alcohol or drug abuse as was seen in earlier studies. Studies are currently being done following children with ADHD who are being treated with up-to-date phar- macological and behavioral therapy. It is hoped that with such treatment children with ADHD will have the same opportunities to achieve personal success as children without ADHD. Resources BOOKS Accardo, J. Pasquale, Thomas A. Blondis, Barbara Y. Whitman, and Mark A. Stein. eds. Attention Deficits and Hyperactivity in Children and Adults Marcel Dekker Inc., 2000. PERIODICALS Mercugliano, Marianne. “What is Attention-Deficit Hyper- activity Disorder?” The Pediatric Clinics of North America 46, no. 5 (October, 1999): 831-843. ORGANIZATIONS National Attention Deficit Disorder Association. 1788 Second St., Suite 200, Highland Park, IL 60035. (847) 432-ADDA. WEBSITES National Attention Deficit Disorder Foundation. Ͻhttp://www.add.orgϾ. Edward R Rosick, DO, MPH, MS GALE ENCYCLOPEDIA OF GENETIC DISORDERS 129 Attention deficit hyperactivity disorder Students diagnosed with myopia have a difficult time concentrating for long periods of time. ( Field Mark Publications ) I Autism Definition Autism is a potentially severe neurological condition affecting social functioning, communication skills, rea- soning, and behavior. It is considered a “spectrum disor- der,” meaning that the symptoms and characteristics of autism can present themselves in a variety of combina- tions, ranging from extremely mild to quite severe. Description Autism is a neurological disorder that affects a per- sons ability to communicate and form relationships. Individuals with autism have deficits in social interac- tion, communication, and understanding. Some individu- als with autism have unusual repetitive behaviors such as head banging, rocking, and hand-flapping. Up to 75-80% of individuals with autism are mentally retarded. Only a small portion of this group (15-20%) have severe mental retardation. Additionally, over one-third of individuals with autism will develop seizures in early childhood or adolescence. There is a wide degree of variability in the specific symptoms of autism. Because of this variability, autism is considered a spectrum disorder. There is no standard type or form of autism. Each individual is affected differently. This variability is reflected in some of the terms or names for autism. Asperger syndrome is a term used to describe individuals with autism with language skills. Pervasive developmental delay (PDD) is another term that is often used interchangeably with autism. The dif- ferent terms for autism are partly due to the different individuals that first described this disorder. Autism was first described by Leo Kanner in 1943. He observed and described a group of children with a pattern of symptoms. These children had some unique abilities and did not seem to be emotionally disturbed or mentally retarded. He invented the category Early Infantile Autism (sometimes called Kanners syndrome) to describe these children. In a strange coincidence, Hans Asperger made the same discoveries in the same year. He also described children with a unique behavioral profile and used the term Autism to describe them. His original study was in German and was not translated into English until the late 1980s. Because the children that he identi- fied all had speech, the term Asperger syndrome is often used to label autistic children who have speech. While the affects of this disorder may vary in inten- sity, all individuals with autism have deficits in three key areas—social interaction, communication, and reason- ing. In addition to these neurologic problems, individuals with autism often exhibit bizarre repetitive movements such as hand flapping or head-banging. Other character- istics include a need for sameness or routine. While most individuals with autism have deficits, there are affected individuals that display unusual talents in areas such at math, music, and art. Some children have extraordinary talent in drawing and others learn to read before they learn to speak. These talents usually coexist with the other deficits of autism and are rare. They are usually referred to as savant skills. Social interaction is the ability to interact—both ver- bally and non-verbally with other humans. Individuals with autism have problems recognizing the social cues such as facial expressions and tone of voice. Individuals with autism are often described as “being in their own world.” This sense of isolation may arise from their inability to communicate effectively. They also lack the motivation for reciprocal communication. Individuals with autism also have communication and language problems. They may or may not develop speech. Those individuals with autism that do speak use language in unusual ways. They may echo the comments of others (echolalia) or use phrases inappropriately. People with autism often use pronouns such as “I” “me” and “you” incorrectly. In addition to problems develop- ing speech, individuals with autism have problems under- standing the purpose of speech. Individuals with autism can also have hyperacute senses. They may be very sensitive to bright lights, loud noises, or rough textures. The self-stimulating behaviors (head-banging, hand-flapping, rocking) sometimes seen in individuals with autism may be attempts to calm them- selves due to overstimulation. Other characteristic behav- iors can include throwing temper tantrums for no known reason and developing fixations or obsessive interests. The cause of autism is unknown. Originally, it was hypothesized that autism was a psychological problem caused by defective parenting. This hypothesis has been discredited as scientific information about neurological differences and biologic causes for autism have emerged. Genetic profile No single specific gene for autism has been discov- ered. Although the exact cause of autism is unknown, it is thought that autism is due to a combination of genetic and environmental causes. This combination of causative factors is often referred to as multifactorial inheritance. There are probably a number of different genes as well as unknown environmental factors involved in the develop- ment of autism. Multifactorial conditions tend to run in families, but the pattern of inheritance is not as pre- dictable as with single gene disorders. The chance of recurrence is also less than the risk for single gene disor- ders and is usually derived from empiric or long-term studies of a large number of families. 130 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Autism There are two separate genetic aspects of autism— studies that suggest a genetic component to autism and genetic syndromes that can cause autistic like behaviors. There are a number of scientific studies that suggest autism is partially due to genetic causes. Twin studies are used to determine the degree of heritability of a disorder. Identical twins have the exact same genes and fraternal (non-identical) twins have only half of their genes in common. By examining the rates of concordance (the number of twin pairs that both have autism) it is possible to determine if there is a genetic component to autism. Studies that looked at the incidence of twins with autism determined that identical twins are more likely to be con- cordant (both affected) with autism than fraternal twins. This means that individuals with the same genes both have autism more often than twins with only half of the same genes. This finding suggests that genes play a role in the development of autism. Identical twin pairs with autism reveal that there is a genetic component to autism. However, if autism was purely genetic, then all identical twins should be affected with autism (concordant). The fact that there are some identical twin pairs that are discordant for autism (one twin has autism and the other does not) means that other factors, possibly environmental, must also play a role in causing autism. These discordant identical twin pairs highlight the fact that there must be other factors besides genes that also influence the development of autism. There have been speculations as to what other fac- tors might influence or cause an individual to become autistic. These speculations include viral, immunologic (including vaccinations), and environmental factors. While there are many theories about possible causes for autism, as of 2001 no specific non-genetic causes have been found and there is no scientific evidence for any specific environmental factor being a causative agent. Much work is being done in this area. Other scientific studies that point to the role of genes in the cause of autism are studies that look at the recurrence risk for autism. A recurrence risk is the chance that the same condition will occur for a second time in the same family. If a disease has no genetic com- ponent, then the recurrence risk should equal the inci- dence of the disorder. If autism had no genetic component, then it would not be expected to occur twice in the same family. However, studies have shown that autism does have an increased recurrence risk. In fami- lies with an affected son, the recurrence risk to have another child with autism is 7%. In families with an autistic daughter, the recurrence risk is 14%. In families with two children with autism, the chance that a subse- quent child will also be affected is around 35%. The fact that the recurrence risks are increased in families with one child with autism indicates that there is some genetic component to autism. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 131 Autism KEY TERMS Asperger syndrome—A term used to describe high-functioning individuals with autism. These individuals usually have normal IQ and some lan- guage skills. Pervasive developmental disorder (PDD)—The term used by the American Psychiatric Association for individuals who meet some but not all of the criteria for autism. Savant skills—Unusual talents, usually in art, math or music, that some individuals with autism have in addition to the deficits of autism. Genetic syndromes with autistic behaviors While no specific gene has been found to cause iso- lated autism, there are some genetic syndromes in which the affected individual can have autistic behaviors. These genetic syndromes include untreated phenylketonuria (PKU), Fragile X syndrome, tuberous sclerosis, Rett syndrome and others. Phenylketonuria is an inborn error of metabolism. Individuals with PKU are missing an enzyme necessary to break down phenylalanine, an amino acid found in protein rich food. As these individuals eat protein, pheny- lalanine builds up in the bloodstream and nervous system eventually leading to mental retardation and autistic behaviors. The vast majority of infants in the US are tested at birth (newborn screening) and those affected with PKU are treated with a protein free diet. This disor- der is more common among individuals of northern European descent. Fragile X syndrome is a mental retardation syn- drome that predominantly (but not exclusively) affects males. Males with fragile X syndrome have long narrow faces, large cupped ears, enlarged testicles as adults and variable degrees of mental retardation. Some individuals with fragile X syndrome also display autistic behaviors. Tuberous sclerosis is a variable disease characterized by hypopigmented skin patches, tumors, seizures, and mental retardation in some affected individuals. Up to one-quarter (25%) of individuals with tuberous sclerosis have autism. Rett syndrome is a progressive neurological disorder that almost exclusively affects females. Girls with Rett syndrome develop normally until the age of 18 months and then undergo a period of regression with loss of speech and motor milestones. In addition, girls with Rett syndrome exhibit a nearly ceaseless hand washing or hand wringing motion. Girls with Rett syndrome also have mental retardation and can have autistic like behaviors. While individuals with these genetic syndromes can have autistic behaviors, it is important to remember that 70–90% of individuals with autism do not have an under- lying genetic syndrome as the cause of their disorder. Many studies are underway to try and determine the eti- ology or cause of autism. Demographics The exact incidence of autism is not known. Because the diagnostic criteria for autism has changed and broad- ened over the years, studies done to determine the inci- dence have yielded different estimates. Using the newer, more inclusive criteria, it is estimated that one in 500 individuals are affected with autism and that over half a million individuals in the United States fit the diagnostic criteria for autism, PDD, or Asperger syndrome. Boys are affected three times more often than girls, giving autism a 4:1 ratio of affected boys to affected girls. While boys may be affected more often, girls with autism tend to be more severely affected and have a lower IQ. The reasons for these differences are not known. Autism occurs in all racial, social and economic backgrounds. Signs and symptoms One of the most frustrating aspects of autism is the lack of physical findings in individuals with autism. Most individuals with autism have normal appearance and few, if any, medical problems. Because the specific cause of autism is unknown, there is no prenatal test available for autism. Autism is a spectrum disorder. A spectrum refers to the fact that individuals with a diagnosis of autism can have very different abilities and deficits. The spectrum of autism stretches from a socially isolated adult with nor- mal IQ to a severally affected child with mental retarda- tion and behavioral problems. The following is a partial list of behaviors seen in individuals with autism divided into main areas of concern. It is unlikely that any specific individual would exhibit all of the following behaviors. Most affected individuals would be expected to exhibit some but not all of the following behaviors. Communication: • Language delay or absence • Impaired speech • Meaningless repetition of words or phrases • Communicates with gestures rather than words • Concrete or literal understanding of words or phrases • Inability to initiate or hold conversations Social Interaction: • Unresponsive to people • Lack of attachment to parents of caregivers • Little or no interest in human contact • Failure to establish eye contact • Little interest in making friends • Unresponsive to social cues such as smiles or frowns Play: • Little imaginative play • Play characterized by repetition (e.g. endless spinning of car wheels) • No desire for group play • No pretend games Behaviors: • Repetitive motions such as hand flapping and head- banging • Rigid or flaccid muscle tone when held • Temper tantrums or screaming fits • Resistance to change • Hyperactivity • Fixates or develops obsessive interest in an activity, idea, or person • Over reaction to sensory stimulus such as noise, lights, and texture • Inappropriate laughing or giggling Diagnosis There is no medical test like a blood test or brain scan to diagnose autism. The diagnosis of autism is very diffi- cult to make in young children due to the lack of physical findings and the variable behavior of children. Because the primary signs and symptoms of autism are behavioral, the diagnosis usually requires evaluation by a specialized team of health professionals and occurs over a period of time. This team of specialists may include a developmen- tal pediatrician, speech therapist, psychologist, geneticist and other health professionals. Medical tests may be done to rule out other possible causes and may include a hear- ing evaluation, chromosome analysis, DNA testing for specific genetic disorders and brain imaging (MRI, EEG or CT scan) to rule out structural brain anomalies. Once other medical causes have been excluded, the diagnosis for autism can be made using criteria from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This manual developed by the American Psychiatric Association lists abnormal 132 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Autism behaviors in three key areas—impairment in social inter- action, impairment in communication (language), and restrictive and repetitive patterns of behavior—that are usually seen in individuals with autism. If an individual displays enough distinct behaviors from the following list, then they will meet the diagnostic criteria for autism. Most individuals will not exhibit all of the possible behaviors listed and while individuals might exhibit the same behaviors, there is still a large degree of variability within this syndrome. DSM-IV criteria for autistic disorder A. A total of at least six items from (1), (2), and (3), with at least two from (1), and one from (2) and (3): 1. Qualitative impairment in social interaction, as manifested by at least two of the following: • Marked impairment in the use of multiple non- verbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to reg- ulate social interaction • Failure to develop peer relationships appropri- ate to developmental level • Markedly impaired expression of pleasure in other people’s happiness. 2. Qualitative impairments in communication as manifested by at least one of the following: • Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gestures or mime) • In individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others • Stereotyped and repetitive use of language or idiosyncratic language • Lack of varied spontaneous make-believe play or social imitative play appropriate to develop- mental level. 3. Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by as least one of the following: • Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus • Apparently compulsive adherence to specific nonfunctional routines or rituals • Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements) • Persistent preoccupation with parts of objects. B. Delays or abnormal functioning in at least one of the following areas, with onset prior to age three years: 1. social interaction, 2. language as used in social communication, or 3. symbolic or imaginative play. C. Not better accounted for by Rett’s Disorder or Childhood Disintegrative Disorder. Using these criteria, the diagnosis of autism is usually made in children around the age of two and a half to three originally seen for speech delay. Often these children are initially thought to have hearing impairments due to their lack of response to verbal cues and their lack of speech. While speech delay or absence might be the factor that initially brings a child with autism to the attention of medical or educational professionals, it soon becomes apparent that there are other symptoms in addition to the lack of speech. Children with autism are often described as “being in their own world.” This can be due to their lack of spontaneous play and their lack of initiative in communication. These deficits become more obvious when children with autism are enrolled in school for the first time. Their inability to interact with their peers becomes highlighted. Behaviors such as hand flapping, temper tantrums, and head banging also contribute to the diagnosis. Because the criteria to diagnose autism are based on observation, several appointments with healthcare providers may be necessary before a definitive diagnosis can be reached. The specialist usually closely observes ad evaluates the child’s language and social behavior. In addition to observation, structured interviews of the par- ents are also used to elicit information about early behav- ior and development. Sometimes these interviews may be supplemented by review of family movies and photo- graphs. Many parents find the process of diagnosing autism frustrating due to the amount of time it takes and the uncertainty of the diagnosis. Many health care providers hesitate to give a diagnosis of autism and use other terms as a means of protecting the family from what they perceive to be a devastating diagnosis. While meaning well, this strategy usually increases frustration and only ultimately delays the diagnosis. The delay in diagnosis can lead to a delay in treatment and in a worse case scenario a denial of services (especially if another term is used). Treatment and management There is no cure for autism. However, autism is not a static disorder. Behaviors can and do change over time and educational treatments can be used to focus on appropriate behaviors. The treatments available for individuals with autism depend upon their needs, but GALE ENCYCLOPEDIA OF GENETIC DISORDERS 133 Autism specific needs. Those individuals with autism that have severe behavioral problems will are also likely to need a supervised living arrangement. Resources BOOKS Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, (1994). Washington, DC: American Psychiatric Association, pp. 70-71. Hart, C. A Parent’s Guide to Autism, New York: Simon and Schuster, 1993. Siegel, Byrna. The World of the Autistic Child: Understanding and Treating Spectrum Disorders, Oxford University Press, 1998. ORGANIZATIONS Association for Science in Autism Treatment. 175 Great Neck Road, Suite 406, Great Neck, NY 11021. (516) 466-4400. Fax: (516) 466-4484. asat@autism-treatment.org. Autism Society of America. 7910 Woodmont Ave. Suite 300, Bethesda, MD 20814-3015. (301) 657-0881 or (800) 3-AUTISM. Ͻhttp://www.autism-society.orgϾ. Cure Autism Now (CAN) Foundation. 5455 Wilshire Blvd. Suite 715, Los Angeles, CA 90036-4234. (500) 888- AUTISM. Fax: (323) 549-0547. info@cureautismnow.org. Ͻhttp://www.cureautismnow.orgϾ. National Alliance for Autism Research (NAAR). 414 Wall Street Research Park, Princeton, NJ 08540. (609) 430- 9160 or (888) 777-6227 CA: (310) 230-3568. Fax: (609) 430-9163. Ͻhttp://www.naar.orgϾ. WEBSITES The Autism Society of America. Ͻhttp://www.autism-society.orgϾ. OASIS Online Asperger Syndrome Information Society. Ͻhttp://www.udel.edu/bkirby/asperger/Ͼ. www.autism-resources.com. Information and links regarding the developmental disabilities autism and Asperger’s syn- drome. Ͻhttp://www.autism-resources.comϾ. The Autism/PDD Network. Ͻhttp://www.autism-pdd.net/Ͼ. The National Institute of Mental Health. Ͻhttp://www nimh.nih.gov/publicat/autism.cfmϾ. Kathleen Fergus, MS, CGC Autistic disorder see Autism Autosomal dominant hearing loss see Hereditary hearing loss and deafness Autosomal recessive hearing loss see Hereditary hearing loss and deafness 134 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Autism are generally long and intensive. While treatments vary and there is considerable controversy about some treat- ments, there is uniform agreement that early and inten- sive intervention allows for the best prognosis. A treatment plan is usually based upon an evaluation of the child’s unique abilities and disabilities. A child’s abilities are capitalized on in developing the treatment for their disabilities. Standardized testing instruments are used to deter- mine the child’s level of cognitive development and interviews with parents and caregivers, as well as obser- vation by health professionals, are used to gauge a child’s social, emotional, and communication skills. Once a clear picture of the child’s needs is developed, treatment is initiated. Studies have shown that individuals with autism respond well to a highly structured, specialized education program tailored to their individual needs. All treatments are best administered by trained professionals. Treatment may include speech and language therapy to develop and improve language skills. Occupational ther- apy may be used to develop fine motor skills and to teach basic self-help and functional skills such as grooming. Behavior modification, with positive reinforcement, plays a large role in the early treatment of some of the abnormal behaviors of individuals with autism. Other therapies may include applied behavioral analysis, audi- tory integration training, dietary interventions, medica- tions, music therapy, physical therapy, sensory integration, and vision therapy. In order to be effective, the treatments and therapies must be consistent and reinforced by the family. It is helpful if family members and caregivers also receive training in working with and teaching individuals with autism. A team approach involving healthcare profes- sionals, therapists, educators, and families is necessary for successful treatment of individuals with autism. Prognosis The prognosis for individuals with autism is variable but much brighter than it was a generation ago. In gen- eral, the ultimate prognosis of an individual with autism is dependant on their overall IQ, the communicative abil- ities and the extent of their behavioral problems. Individuals with autism without mental retardation can develop independent living skills. Often these indi- viduals do well and can become self-sufficient if they have good communication skills. Other individuals with autism develop some level of self-sufficiency but may never be able to live independently due to their severe communication or cognitive difficulties. Up to 60% of individuals with autism will require lifelong assistance. Individuals with autism and intellectual deficits (mental retardation) usually do not achieve the ability to function independently. They may require sheltered liv- ing arrangements in settings equipped to deal with their I Azorean disease Definition Azorean disease causes progressive degeneration of the central nervous system. Affected individuals experi- ence deterioration in muscle coordination and other physical symptoms, but intelligence and mental function remain unaffected by the disease. Description Azorean disease is an inherited disorder that causes impaired brain functioning, vision problems, and loss of muscle control. It is named for the Azores, the group of nine Portuguese islands where the disease is prevalent. Many of the reported cases have been found in the direct descendants of William Machado, an Azorean native who immigrated to the New England area of the United States, and Atone Joseph, a Portuguese sailor from the island of Flores who came to California in 1845. Other names for Azorean disease include Machado-Joseph disease, Joseph disease, and spin- ocerebellar ataxia type III. Azorean disease is classified into three types depending on the age of onset and the specific physical symptoms. In type I, the age of onset is usually before age 25 and the affected individuals experience extreme muscle stiffness and rigidity. In type II, the age of onset is typically in the mid-30s, and progressive loss of mus- cle coordination (ataxia) occurs, resulting in the inability to walk. In type III, the average age of onset is 40 or later, and the main symptoms are weakness and loss of sensa- tion in the legs. The symptoms of Azorean disease result from the loss of brain cells and the impairment of neurological connections in the brain and spinal cord. This degrada- tion of the central nervous system is believed to be caused by the production of a destructive protein from a mutated gene. Genetic profile Azorean disease is inherited as an autosomal domi- nant trait. This means that only one parent has to pass on the gene mutation in order for the child to be affected with the syndrome. Each gene in the human body is made up of units called nucleotides, abbreviated C (cytosine), A (adenine), T (thymine), and G (guanine). A sequence of three nucleotides is called a trinucleotide. Azorean syndrome is caused by a genetic mutation that results in the over- duplication of a CAG trinucleotide sequence. The loca- tion of the mutant gene in Azorean disease is 14q32, on the long arm of chromosome 14. This gene normally encodes the formation of a cellular protein called ataxin- 3. In the general population, there are between 13 and 36 repeats of the CAG sequence, but in those individuals with Azorean disease, there may be between 61 and 84 repeats. The increased number of repetitions causes the gene to encode an abnormal protein product that is believed to cause cell death in the brain and spinal cord. In successive generations, the number of the repeti- tions may increase, a phenomenon known as genetic anticipation. In addition, there appears to be a strong rela- tionship between the number of repetitions and the age at onset of Azorean disease: the more repetitions, the sooner the disease presents and the more serious the symptoms are. Also, if the individual is homozygous for the mutated gene, meaning he or she inherits the gene from both par- ents, Azorean disease is more severe and the age of onset is as early as 16 years. Demographics Azorean disease is primarily found in people of Portuguese ancestry, particularly people from the Azores islands. In the Azores islands the incidence of Azorean disease is approximately one in every 4,000, while among those of Azorean descent, it is one in every 6,000. Azorean disease has also been identified in other ethnic groups, including Japanese, Brazilians, Chinese, Indians, Israelis, and Australian aborigines. Signs and symptoms The age of onset of Azorean disease is typically from the late teens to the 50s, although onset as late as the 70s has been reported. The first observable symptoms are dif- ficulty in walking and slurred speech. There is wide vari- ation in the range of observed symptoms, but they typically include problems with muscular coordination, eyes and vision, and other physical bodily functions such as speech and urination. Mental ability is not impaired by Azorean disease. Muscular symptoms Muscular symptoms observed in people with Azorean disease include: • difficulty in walking, including staggering or stum- bling, • weakness in arms or legs, • involuntary jerking or spastic motions, • cramping or twisting of the hands and feet, • facial tics and grimaces, • twitching or rippling of the muscles in the face. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 135 Azorean disease [...]... hydroxyurea” The Lancet 35 0 (19 97): 4 9 1- 492 ORGANIZATIONS Children’s Blood Foundation 33 3 East 38 th St., Room 830 , New York, NY 10 016 -2 745 ( 212 ) 29 7-4 33 6 cfg@nyh.med.cornell.edu Cooley’s Anemia Foundation, Inc 12 9-0 9 26th Ave #2 03, Flushing, NY 11 35 4 (800) 52 2-7 222 or ( 718 ) 3 2 1- 28 73 Ͻhttp://www.thalassemia.orgϾ March of Dimes Birth Defects Foundation 12 75 Mamaroneck Ave., White Plains, NY 10 605 (888) 66 3- 4 637 ... 11 q 13 means chromosome number 11 , long arm, region 1, band 3 In studies of families with BBS, researchers have found that a significant number of cases link either to 11 q 13, 15 q22, or 16 q 21 In other families, researchers have linked BBS to either 2q 31 , 3p12, or 20p12 This last site is the location of the MKKS gene GALE ENCYCLOPEDIA OF GENETIC DISORDERS Regardless of the site involved, BBS displays an autosomal... National Marfan Foundation 38 2 Main St., Port Washington, NY 11 05 0- 31 2 1 (800) 86 2-7 32 6 Ͻhttp://www.marfan orgϾ National Organization for Rare Disorders (NORD) PO Box 89 23, New Fairfield, CT 06 812 -8 9 23 (2 03) 74 6-6 518 or (800) 99 9-6 6 73 Fax: (2 03) 74 6-6 4 81 Ͻhttp://www rarediseases.orgϾ OTHER WEBSITES Godfrey, Maurice “Congenital Contractural Arachnodactyly.” GeneClinics Univeristy of Washington, Seattle Ͻhttp://www.geneclinics.orgϾ... (972) 99 4-9 902 or (800) 53 5 -3 6 43 contactcca@ccakids.com Ͻhttp://www.ccakids.comϾ FACES The National Craniofacial Assocation PO Box 11 082, Chattanooga, TN 37 4 01 (4 23) 266 -1 6 32 or (800) 33 2 237 3 faces@faces-cranio.org Ͻhttp://www.faces-cranio org/Ͼ WEBSITES “Cutis Gyrata Syndrome of Beare and Stevenson.” OMIM— Online Mendelian Inheritance in Man Ͻhttp://www.ncbi nlm.nih.gov/entrez/dispomim.cgi?id =12 37 90Ͼ... stores in Thalassemia Major” The New England Journal of Medicine 34 3, (2000): 32 7 -3 31 Mentzer, W C., et al “Prospects for research in hematologic disorders: sickle cell and thalassemia” The Journal of The American Medical Association 285 (20 01) : 64 0-6 42 Olivieri, N F The Beta Thalassemias” The New England Journal of Medicine 3 41 (19 99): 99 -1 0 9 Olivieri, N F., et al “Treatment of thalassemia major with... Suite 16 1, Burlingame, CA 94 010 -1 6 21 (650) 25 9 -3 984 Fax: (650) 25 9 -3 9 83 Ͻhttp://www.ataxiamjd.orgϾ International Joseph Disease Foundation, Inc PO Box 2550, Livermore, CA 945 5 1- 2550 (925) 4 6 1- 7550 (925) 3 711 288 Ͻhttp://www.ijdf.netϾ MJD Family Network Newsletter c/o Mike and Phyllis Cote, 5 91 Federal Furnace Rd., Plymouth, MA 0 236 0-4 7 61 National Ataxia Foundation 2600 Fernbrook Lane, Suite 11 9, Minneapolis,... elbow The skin of the palms of the hands and the soles of the feet often show deep ridging Affected individuals may have small, underdeveloped fingernails Children with Beare-Stevenson cutis gyrata syndrome may have breathing problems and narrowing of the roof of the mouth (cleft palate) The anus may be GALE ENCYCLOPEDIA OF GENETIC DISORDERS positioned more forward than normal The genitals are often... PO Box 3 010 5, Bethseda, MD 2082 4- 010 5 (3 01) 59 2-8 5 73 nhlbiinfo @rover.nhlbi.nih.gov Ͻhttp://www.nhlbi.nih.govϾ National Organization for Rare Disorders (NORD) PO Box 89 23, New Fairfield, CT 06 812 -8 9 23 (2 03) 74 6-6 518 or (800) 99 9-6 6 73 Fax: (2 03) 74 6-6 4 81 Ͻhttp://www rarediseases.orgϾ Parents may need to seek counseling or attend support groups that focus on the time demand and lifestyle changes of caring... Survey.” Journal of Medical Genetics 36 (19 99): 43 7-4 46 Foltin, Lynn “Researchers Identify Inherited Obesity, Retinal Dystrophy Gene.” Texas Medical Center News 22 (2000): 17 Hrynchak, P K “Bardet-Biedl Syndrome.” Optometry and Vision Science 77 (May 2000): 23 6-2 43 ORGANIZATIONS Foundation Fighting Blindness Executive Plaza 1, Suite 800, 11 35 0 McCormick Rd., Hunt Valley, MD 210 31 (888) 39 4 -3 937 Ͻhttp://www.blindness.orgϾ... egg and sperm The information contained in genes is responsible for the development of all the cells and tissues of the body Most genes occur in pairs: one copy of each pair is inherited from the egg cell produced by the mother and the other copy of each pair comes from the sperm cell of the father One of these genes (called FBN2) tells the body how to make fibrillin-2, a specific type of protein Proteins . Neck, NY 11 0 21. ( 516 ) 46 6-4 400. Fax: ( 516 ) 46 6-4 484. asat@autism-treatment.org. Autism Society of America. 7 910 Woodmont Ave. Suite 30 0, Bethesda, MD 20 814 -3 015 . (3 01) 65 7-0 8 81 or (800) 3- AUTISM 11 q 13 means chromosome number 11 , long arm, region 1, band 3. In studies of families with BBS, researchers have found that a significant number of cases link either to 11 q 13, 15 q22, or 16 q 21. . 94 010 -1 6 21. (650) 25 9 -3 984. Fax: (650) 25 9 -3 9 83. Ͻhttp://www.ataxiamjd.orgϾ. International Joseph Disease Foundation, Inc. PO Box 2550, Livermore, CA 945 5 1- 2550. (925) 4 6 1- 7550. (925) 3 7 1- 12 88.