Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

Attention deficit hyperactivity disorder

K E Y T E R M S

Allele—One of two or more alternate forms of a gene.

Autosomal dominant—A pattern of genetic inheritance 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.

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 adulthood. 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 factors 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 condition, 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 limited. 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 studies 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 enviromental factors in the development of ADHD. Childhood exposure to certain toxins, such as lead, alcohol, and cigarette smoke, seemed to be linked to a higher occurrence of ADHD. Other studies point to childhood hypersensitivity 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 implicated 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 forgetfulness; 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 behaviors, 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 characteristics are listed above under signs and symptoms.

Treatment and management

The treatment and management of ADHD has significantly changed over time. Before the 1950s, behavioral therapy, such as teaching patients with ADHD how to improve their organizational skills and focus on tasks,

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was the mainstay of treatment. However, with the development of medications specifically for psychiatric problems, 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 functioning in patients with the condition in about 75–90% of patients. It is thought that the stimulants work by increasing 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 medications 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 children 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 without 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 medication 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.

Students diagnosed with myopia have a difficult time concentrating for long periods of time. (Field Mark Publications)

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 outcomes 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 pharmacological 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 Hyperactivity 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.

http://www.add.org .

Edward R Rosick, DO, MPH, MS

disorder hyperactivity deficit Attention

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Autism

I Autism

Definition

Autism is a potentially severe neurological condition affecting social functioning, communication skills, reasoning, and behavior. It is considered a “spectrum disorder,” meaning that the symptoms and characteristics of autism can present themselves in a variety of combinations, ranging from extremely mild to quite severe.

Description

Autism is a neurological disorder that affects a persons ability to communicate and form relationships. Individuals with autism have deficits in social interaction, communication, and understanding. Some individuals 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 different 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 identified 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 intensity, all individuals with autism have deficits in three key areas—social interaction, communication, and reasoning. 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 verbally 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 developing speech, individuals with autism have problems understanding 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 themselves due to overstimulation. Other characteristic behaviors 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 discovered. 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 development of autism. Multifactorial conditions tend to run in families, but the pattern of inheritance is not as predictable as with single gene disorders. The chance of recurrence is also less than the risk for single gene disorders and is usually derived from empiric or long-term studies of a large number of families.

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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 concordant (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 factors 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 component, then the recurrence risk should equal the incidence 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 families 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 subsequent 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.

K E Y T E R M S

Asperger syndrome—A term used to describe high-functioning individuals with autism. These individuals usually have normal IQ and some language 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 isolated 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, phenylalanine 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 disorder is more common among individuals of northern European descent.

Fragile X syndrome is a mental retardation syndrome 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.

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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 underlying genetic syndrome as the cause of their disorder. Many studies are underway to try and determine the etiology or cause of autism.

Demographics

The exact incidence of autism is not known. Because the diagnostic criteria for autism has changed and broadened over the years, studies done to determine the incidence 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 normal IQ to a severally affected child with mental retardation 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 headbanging

•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 difficult 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 developmental pediatrician, speech therapist, psychologist, geneticist and other health professionals. Medical tests may be done to rule out other possible causes and may include a hearing 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

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behaviors in three key areas—impairment in social interaction, 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 nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction

•Failure to develop peer relationships appropriate 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 developmental 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 parents are also used to elicit information about early behavior and development. Sometimes these interviews may be supplemented by review of family movies and photographs.

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

Autism

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are generally long and intensive. While treatments vary and there is considerable controversy about some treatments, there is uniform agreement that early and intensive 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 determine the child’s level of cognitive development and interviews with parents and caregivers, as well as observation 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 therapy 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, auditory integration training, dietary interventions, medications, 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 professionals, 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 general, the ultimate prognosis of an individual with autism is dependant on their overall IQ, the communicative abilities and the extent of their behavioral problems.

Individuals with autism without mental retardation can develop independent living skills. Often these individuals 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 living arrangements in settings equipped to deal with their

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. [phone]. Fax: [phone]. [e-mail].

Autism Society of America. 7910 Woodmont Ave. Suite 300, Bethesda, MD 20814-3015. [phone] or (800) 3-AUTISM. http://www.autism-society.org .

Cure Autism Now (CAN) Foundation. 5455 Wilshire Blvd. Suite 715, Los Angeles, CA 90036-4234. (500) 888AUTISM. Fax: [phone]. [e-mail]://www.cureautismnow.org .

National Alliance for Autism Research (NAAR). 414 Wall Street Research Park, Princeton, NJ 08540. (609) 4309160 or [phone] CA: [phone]. Fax: [phone]. http://www.naar.org .

WEBSITES

The Autism Society of America.

http://www.autism-society.org .

OASIS Online Asperger Syndrome Information Society.

http://www.udel.edu/bkirby/asperger/ . www.autism-resources.com. Information and links regarding

the developmental disabilities autism and Asperger’s syndrome. http://www.autism-resources.com .

The Autism/PDD Network. http://www.autism-pdd.net/ .

The National Institute of Mental Health.

http://www..nimh.nih.gov/publicat/autism.cfm .

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

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I Azorean disease

Definition

Azorean disease causes progressive degeneration of the central nervous system. Affected individuals experience 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 spinocerebellar 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 muscle 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 sensation 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 degradation 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 dominant 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 overduplication of a CAG trinucleotide sequence. The location 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 repetitions may increase, a phenomenon known as genetic anticipation. In addition, there appears to be a strong relationship 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 parents, 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 difficulty in walking and slurred speech. There is wide variation 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 stumbling,

•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.

disease Azorean

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K E Y T E R M S

Ataxia—A deficiency of muscular coordination, especially when voluntary movements are attempted, such as grasping or walking.

Genetic anticipation—The tendency for an inherited disease to become more severe in successive generations.

Homozygous—Having two identical copies of a gene or chromosome.

Nucleotides—Building blocks of genes, which are arranged in specific order and quantity.

Trinucleotide—A sequence of three nucleotides.

Eyes and vision

People with Azorean disease may experience double vision, bulging eyes, difficulty in looking upward, difficulty in opening the eyes, a fixed or staring gaze, or involuntary eye movements from side to side.

Other symptoms

Other symptoms reported in people with Azorean disease include difficulty in speech such as slurring, loss of feeling in arms or legs, frequent urination, infections of the lungs, diabetes, weight loss, and difficulty sleeping.

Diagnosis

Azorean disease can be diagnosed after observation of typical symptoms and a medical history that establishes a familial pattern to the disease. Brain imaging studies such as computerized tomography (CT) and magnetic resonance imaging (MRI) may be employed. Blood tests can show increased levels of blood sugar and uric acid. Genetic studies that reveal the presence of the increased number of CAG trinucleotide repeats in the affected individual will provide definite confirmation of the diagnosis of Azorean disease.

The symptoms of Azorean disease are similar to other degenerative neurological conditions such as

Parkinson disease, Huntington disease, and multiple sclerosis. Careful diagnosis is required in order to distinguish Azorean disease from these other conditions.

Treatment and management

Treatment for Azorean disease is based on management of the symptoms. As of 2001 there is no treatment that stops or reverses the effects of the disease itself. A multidisciplinary team of specialists in neurology, oph-

thalmology, and endocrinology is often called for. Medications that specifically treat movement disorders, such as dopamine agonists, may help alleviate some of the symptoms of Azorean disease. Some experimental drugs and treatments under development for other neurological disorders may also benefit patients with Azorean disease.

Since Azorean disease is an inherited disorder, genetic counseling is recommended for people with a family history of the disease.

Prognosis

The prognosis for individuals with Azorean disease varies depending on the age of onset and severity of the symptoms. The muscular degeneration caused by the disease usually results in eventual confinement to a wheelchair. After onset of the symptoms, life expectancy ranges from 10 to 30 years.

Resources

PERIODICALS

Gaspar, C. et al. “Ancestral Origins of the Machado-Joseph Disease Mutation: A Worldwide Haplotype Study.”

American Journal of Human Genetics (February 2001): 523-8.

BOOKS

Hamilton, Patricia Birdsong. A Balancing Act: Living with Spinal Cerebellar Ataxia. Coral Springs, FL: Scripts Publishing, 1998.

Klockgether, Thomas (ed). Handbook of Ataxia Disorders. New York: Marcel Dekker, Inc., 2000.

ORGANIZATIONS

Ataxia MJD Research Project, Inc. 875 Mahler Rd., Suite 161, Burlingame, CA 94010-1621. [phone]. Fax: [phone]. http://www.ataxiamjd.org .

International Joseph Disease Foundation, Inc. PO Box 2550, Livermore, CA 94551-2550. [phone]. (925) 3711288. http://www.ijdf.net .

MJD Family Network Newsletter. c/o Mike and Phyllis Cote, 591 Federal Furnace Rd., Plymouth, MA 02360-4761.

National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. [phone]. Fax: [phone]. [e-mail]. http://www.ataxia.org .

WEBSITES

“Entry 109150: Machado-Joseph Disease; MJD.” OMIM— Online Mendelian Inheritance in Man. http://www.ncbi

.nlm.nih.gov/htbin-post/Omim/dispmim?109150

Machado/Joseph’s Disease. http://www.lusaweb.com/ machado.html (April 20 2001).

MJD Family Support Group. http://groups.yahoo.com/group/ MJDFamily/join (April 20 2001).

Paul A. Johnson

136	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

B

I Bardet-Biedl syndrome

Definition

Bardet-Biedl syndrome (BBS) is a condition that primarily affects vision, kidney function, limb development, growth, and intelligence.

Description

BBS expresses itself differently from person to person, even among members of the same family. However, certain features frequently appear.

Genetic profile

BBS is a genetically heterogeneous condition; this means that it has more than one known genetic cause. One of these causes is a mutation in the MKKS gene, located on chromosome 20. When working properly, this gene appears to produce a chaperonin, a factor needed to process proteins. Without the chaperonin, the proteins cannot work properly.

Using linkage analysis, researchers have connected some BBS cases to other chromosomes. Linkage analysis is a method of finding mutations based on their proximity to previously identified genetic landmarks. As of February 2001, the specific genes responsible for these BBS cases remain unknown. However, several potential locations of BBS genes have been recognized. These sites are named for the number of the chromosome on which they are found, the arm of the chromosome (“q” for long arm, “p” for short arm), region of the arm, and band within the region. For example, “11q13” 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 11q13, 15q22, or 16q21. In other families, researchers have linked BBS to either 2q31, 3p12, or 20p12. This last site is the location of the MKKS gene.

Regardless of the site involved, BBS displays an autosomal recessive inheritance pattern. This means that the condition occurs only when an individual inherits two defective copies of a BBS gene. If one copy is normal, the individual does not have BBS. This individual is called a carrier of BBS and can pass the gene on to the next generation.

Research indicates that people who inherit one abnormal BBS gene and one normal gene may be at risk for some of the health problems seen in BBS. Compared to the general population, these BBS gene carriers are more likely to develop high blood pressure, diabetes mellitus, and kidney disease, including kidney cancer.

Demographics

BBS affects people around the world. However, it is most common in the Middle East, especially in the Arab and inbred Bedouin populations of Kuwait. In these groups, it may affect as many as one in 13,500 individuals. The incidence is almost as high in Newfoundland, where as many as one in 16,000 individuals has BBS. Outside of these areas, researchers estimate that BBS affects only one in 160,000 people.

The specific genetic cause of BBS differs by family and geographic location. For example, in the Middle East, BBS appears to link to 16q21 or 3p12. However, in patients of European descent, BBS appears to link to 11q13 or 15q22.

Signs and symptoms

If the newborn with BBS has finger or toe abnormalities, these are apparent at birth. However, these defects have a variety of congenital causes, meaning they originated during development of the fetus and were not inherited. For this reason, medical care providers may not immediately suspect BBS. It becomes a consideration as the child develops and additional abnormalities emerge. In boys, genital abnormalities become evident soon after birth. In almost all patients, obesity and retinal degenera-

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