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

Deletion 22q11 syndrome

K E Y T E R M S

Cleft palate—A congenital malformation in which there is an abnormal opening in the roof of the mouth that allows the nasal passages and the mouth to be improperly connected.

Conotruncal heart abnormality—Congenital heart defects particularly involving the ventricular (lower chambers) outflow tracts of the heart includes subarterial ventricular septal defect, pulmonic valve atresia and stenosis, tetralogy of Fallot and truncus arteriosus.

Velo—Derived from the latin word velum, meaning palate and back of the throat.

Deletion 22q11 syndrome is an extremely variable syndrome. The main features are congenital heart defects, distinctive facial features, and palate (roof of the mouth) problems. Other problems include immune system abnormalities, thyroid problems, kidney abnormalities, and learning difficulties including mild developmental delay. Very rarely do individuals have all of the problems associated with this syndrome. Most individuals with deletion 22q11 syndrome have only a few of the associated features. Some individuals with 22q11 deletion syndrome are very mildly affected and others are more severely affected. The reason for the wide variability in this syndrome is not known.

Genetic profile

Deletion 22q11 syndrome is a genetic disorder caused by a deletion of chromosomal material from the long arm of chromosome 22. A series of genes are located in this region. Individuals with deletion 22q11 syndrome may have some or all of these genes deleted. This syndrome is sometimes called a microdeletion syndrome or a contiguous gene syndrome. Contiguous refers to the fact that these genes are arranged next to each other. The size of the deletion can be large or small, which may explain why some individuals with deletion 22q11 syndrome are more severely affected than others. The exact genes responsible for this syndrome are not known.

Deletion 22q11 syndrome is an autosomal dominant disorder. Genes always come in pairs and in an autosomal dominant disorder only one gene needs too be missing or altered for an individual to have the disorder. About 10–15% of the time, the deletion on the long arm of chromosome 22 that causes this syndrome is inherited from a parent. If a parent has deletion 22q11 syndrome, then there is a 50% chance that he or she will pass the

deletion on to each of his or her children who will also be affected with 22q11 syndrome. For reasons that are not understood, it is possible for a parent with mild features of deletion 22q11 syndrome to have a child with severe features of the syndrome.

Although deletion 22q11 syndrome is an autosomal dominant disorder, over 85–90% of individuals with this disorder are the only individuals in their family with this disorder. When this is the case, the chromosome deletion that causes deletion 22q11 syndrome is called de novo. A de novo deletion is one that occurs for the first time in the affected individual. The causes of de novo chromosome deletions are not known. Parents of a child with deletion 22q11 syndrome due to a de novo deletion are very unlikely to have a second child with deletion 22q11 syndrome.

Demographics

The 22q11 deletion syndrome is one of the most common chromosomal deletion syndromes. It is estimated that approximately 1 in 2000 to 1 in 6000 individuals has a deletion of chromosome 22q11. Approximately 130,000 individuals in the United States have deletion 22q11 syndrome. Because of the extreme variability of this syndrome, it is possible that individuals with milder features are under diagnosed and the exact incidence of this disorder is not known. As more physicians become familiar with this syndrome, it is likely that more individuals will be correctly diagnosed.

Individuals with deletion 22q11 syndrome are diagnosed based upon physical findings. Of infants born with congenital heart defects, 5% will be found to have a deletion of chromosome 22q11. Of infants with a cleft palate, approximately 5–8% of them will be found to a have a 22q11 deletion.

Signs and symptoms

Deletion 22q11 syndrome is a multisystem disorder. It is also sometimes referred to as velocardiofacial syndrome. This name reflects the organ systems that are most commonly affected in deletion 22q11 syndrome. Velo is from the Latin velum which means “palate” and back of the throat, cardio refers to the heart, and facial refers to the distinctive facial features of individuals with deletion 22q11 syndrome. While it may seem unusual that these three separate areas are affected, a possible explanation lies in the early development of the embryo. Very early in development, the cells that will become the heart, face, and thyroid lie next to each other in a region called the neural crest. As the embryo continues to develop, these cells migrate, or move, to become organs (the heart, face, and palate). It is believed that the dele-

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tion of chromosomal material from chromosome 22q causes a problem in the migration of these cells leading to the variability of features or problems seen in deletion 22q11 syndrome.

In addition to the heart, palate, and face, many other organ systems can also be affected including the kidneys, the immune system, the brain, the throat, the skeletal system, the skin, the genitourinary system, and the endocrine (hormone) system. It is not possible to cover every possible feature of deletion 22q11 syndrome but the following is an overview of the most common features.

The characteristic facial features seen in individuals with deletion 22q11 syndrome include a long face with narrow palpebral fissures (the opening for the eyes), a prominent nasal bridge (the arch of the nose between the eyes), a slightly bulbous nasal tip, a long nose, small ears with thick helical folds, and a small jaw. None of these features individually is abnormal but the combination of features is characteristically seen in individuals with deletion 22q11 syndrome. These features may not be present or as easily noticeable in African-American individuals with deletion 22q11 syndrome.

Approximately 70% of individuals with deletion 22q11 syndrome have palate abnormalities. These may include complete cleft palate (an opening of the bones and skin of the roof of the mouth) or submucous cleft palate (an opening of only the bones of the roof of the mouth covered by skin). Other individuals with deletion 22q11 syndrome have more subtle palate and throat abnormalities, including velopharyngeal insufficiency, a problem in the coordination between the tongue, palate, and throat muscles. All of these problems can lead to feeding problems in infancy and speech problems such as hypernasal speech.

Cardiac defects, or congenital heart defects, are some of the more serious symptoms of deletion 22q11 syndrome and affect about 75% of individuals with the syndrome. There is a wide range of cardiac defects seen in deletion 22q11 syndrome. Some are minor and may require no treatment, some are correctable by surgery, and others are invariably fatal. The most common heart defects seen in individuals with deletion 22q11 syndrome are truncus arteriosus, interrupted aortic arch, tetralogy of Fallot, ventricular septal defects (VSDs), pulmonary stenosis, and patent ductus arteriosus. Many of these heart defects are known as conotruncal heart defects. Conotruncal refers to the type of embryonic cells that were involved in the development of these regions of the heart.

Immune problems are another of the serious problems associated with this syndrome. Because of the underdevelopment of the thymus gland, individuals with deletion 22q11 syndrome can have reduced amounts of

the cells necessary to fight infections—T cells. Because of this reduction in T cells, individuals with deletion 22q11 syndrome are more prone to getting infections and less able to fight them off. The degree of immune deficiency can be variable with some individuals having life threatening infections and others having much milder problems.

Growth problems may be seen in children with deletion 22q11 syndrome. Infants with deletion 22q11 syndrome are often diagnosed as having failure to thrive. This may be due to feeding problems due to their palate abnormalities but they can also have gastroesophageal reflux and vomiting problems. It also appears that individuals with deletion 22q11 syndrome have generalized growth problems. Most adult individuals with deletion 22q11 syndrome have short stature.

Individuals with deletion 22q11 syndrome may also have specific learning disabilities and possibly mild developmental delay. The learning disabilities are specific. Most individuals with learning disabilities have a discrepancy between their performance IQ score (higher) and their verbal IQ score (lower) that indicates a nonverbal learning disability. Simple IQ testing may not reveal this learning disability and it is important to evaluate the IQ score components separately. Individuals with deletion 22q11 syndrome seem to do better at verbal learning and do well in subjects such as reading. They have more trouble with abstract concepts such as math.

Individuals with deletion 22q11 syndrome are also at risk to develop psychological problems and mental illness. Deletion 22q11 syndrome has been associated with higher rates of bipolar affective disorder, manic-depres- sive illness, and schizoaffective disorder when compared to individuals who do not have deletion 22q11 syndrome. Other mood disorders, such as depression, also occur at a higher incidence in individuals with deletion 22q11 syndrome. Most of these disorders appear during adolescence or adulthood. Some individuals with deletion 22q11 syndrome are mildly mentally retarded. Others have learning disabilities and some are diagnosed as having attention deficit hyperactivity disorder.

Endocrine problems are also commonly seen. The endocrine system is the hormone-producing system of the body and is composed of glands such as the thyroid and parathyroid. Individuals with deletion 22q11 syndrome may be missing one or more of these glands or they have underactive glands. An underactive thyroid is called hypothyroidism and an underactive parathyroid is called hypoparathyroidism. Because the parathyroids help to regulate the level of calcium in the body, individuals with deletion 22q11 syndrome can also have problems with their calcium levels. Low levels of calcium can lead to seizures.

syndrome 22q11 Deletion

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Individuals with deletion 22q11 syndrome may also have kidney problems such as a cystic kidney, missing (aplastic) kidney, or malformed kidney. They may also have limb differences such as such as extra fingers or ribs and problems with the vertebrae in the back that might lead to scoliosis.

Diagnosis

The diagnosis of deletion 22q11 syndrome is usually made by a physician familiar with the syndrome and based upon a physical examination of the individual and a review of his or her medical history. It is often made in infants after a heart problem is diagnosed. In children without significant heart problems, the possibility of a diagnosis may first be raised by preschool teachers or by other medical professionals such as plastic surgeons and speech therapists. These medical professionals may be seeing the child for one of the features of deletion 22q11 syndrome and may be the first ones to become suspicious about the diagnosis. In rare cases, the diagnosis is made in a parent after they have had an affected child.

While a diagnosis may be made based upon physical examination and medical history, the diagnosis can now be confirmed by a DNA test.

Sometimes the 22q11 deletion is large enough that it can be seen during a karyotype analysis. A karyotype is a microscopic analysis of an individual’s chromosomes. However, many 22q11 deletions are too small to be seen by microscopic examination and another specific technique called fluorescent in situ hybridization testing, or FISH testing, can determine whether genetic material is missing. A FISH test will be positive (detect a deletion) in over 95% of individuals with deletion 22q11 syndrome. A negative FISH test for deletion 22q11 syndrome means that no genetic material is missing from the critical region on chromosome 22. Research testing on these individuals usually reveals that up to 5% of individuals with deletion 22q11 syndrome will have a smaller deletion that is not picked up by the routine FISH test.

Prenatal testing (testing during pregnancy) for deletion 22q11 syndrome is possible using the FISH test on a DNA sample obtained by chorionic villus sampling (CVS) or by amniocentesis. Chorionic villus sampling is a prenatal test that is usually done at 10–12 weeks of pregnancy and involves removing a small amount of tissue from the placenta. Amniocentesis is a prenatal test that is usually performed at 16–18 weeks of pregnancy and involves removing a small amount of the amniotic fluid that surrounds the fetus. DNA is obtained from these samples and tested to see if the

deletion responsible for deletion 22q11 syndrome is present. While prenatal testing is possible, it is not routinely performed. Typically, the test is done only if there is a family history of deletion 22q11 syndrome or if a congenital heart defect has been seen on a sonogram (ultrasound).

A sonogram uses sound waves to provide an image of a fetus. During the second trimester of pregnancy, it becomes possible to evaluate the fetal heart. If a heart defect is detected, DNA testing may be offered to the parents (along with other tests) to determine the cause of the heart defect. Unfortunately, congenital heart defects are common and there are many other syndromes that also cause congenital heart defects.

Treatment and management

Because of the incredible variability seen in deletion 22q11 syndrome, there is no one plan of treatment for all affected individuals. The treatment and management of an individual with deletion 22q11 syndrome depends on his or her age and symptoms. Because deletion 22q11 syndrome is a multisystem disorder, it is important to have multiple evaluations. Individuals with deletion 22q11 syndrome may see geneticists, plastic surgeons, immunologists, cardiologists, rheumatologists, endocrinologists, ophthalmologists, neurosurgeons, pediatricians, audiologists, and specialists in feeding, speech, and child development.

It is important that all individuals with deletion 22q11 syndrome have a cardiac evaluation by a cardiologist. An evaluation may include special tests such as a chest x ray, electrocardiogram, and echocardiogram (ultrasound of the heart). Some cardiac defects do not require treatment and others may require surgery.

Because of the wide variety of cleft palate and velopharyngeal problems, all individuals with deletion 22q11 syndrome should be evaluated by a cleft palate team. Cleft palate teams may include a plastic surgeon, ENT (ear, nose, and throat) specialist, genetic counselor, and other staff. Because of the effect of cleft palate abnormalities on speech, all children with deletion 22q11 should have a speech evaluation and speech therapy if necessary. A referral to a feeding specialist may also be helpful if there is a cleft problem or other medical problem that interferes with feeding.

Because of the possibility and serious nature of immune problems, individuals with deletion 22q11 syndrome should have an immune evaluation. This can be done by an immunologist and usually requires blood tests to check immune function.

Individuals with deletion 22q11 syndrome should also have an endocrinology examination to check the

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function of their thyroid, parathyroid, and pituitary glands. They may also see an endocrinologist if they are having growth problems.

Neurologists can help with issues such as seizures and other neurology problems. Psychiatrists can help with psychiatric illness and problems arising from having a chronic illness.

Individuals with deletion 22q11 syndrome should be seen by a geneticist to confirm the diagnosis and to discuss issues such as the inheritance of deletion 22q11 syndrome, the recurrence risks and the availability of prenatal diagnosis. Geneticists can also help arrange the necessary medical consults.

Prognosis

The prognosis for individuals with deletion 22q11 syndrome is highly dependant on the medical complications of the specific individual. Because this is such a variable syndrome, it is impossible to give one prognosis. The cardiac defects associated with deletion 22q11 syndrome are a major variable in determining prognosis. Those with serious heart defects have a guarded prognosis. Individuals with deletion 22q11 syndrome with minor or treatable cardiac defects have a good prognosis. Good medical care and treatment of problems allows most individuals with deletion 22q11 syndrome to have a normal life span.

While the physical features and medical complications of deletion 22q11 syndrome can affect prognosis, the degree of intellectual and psychological can also have an effect. Those individuals with normal IQ and no mental illness have a good prognosis. Those with learning disabilities can benefit from specific educational interventions. Individuals with developmental delay need more help but can do well in sheltered environments. Individuals with mental illness may or may not do well. Some individuals benefit from psychiatric counseling and medication.

The range of abilities among individuals with deletion 22q11 syndrome is very wide and the ultimate functioning of an individual is dependent on his or her abilities.

Resources

ORGANIZATIONS

National Institute on Deafness and Other Communication Disorders. 31 Center Dr., MSC 2320, Bethesda, MD 20814. http://www.nidcd.nih.gov .

Velo-Cardio-Facial Syndrome Educational Foundation. VCFS Educational Foundation, Inc., Upstate Medical University Hospital, 708 Jacobsen Hall (C.D.U.), 750 East Adams St., Syracuse, NY 13210.

Velo-Cardio-Facial Syndrome Research Institute. Albert Einstein College of Medicine, 3311 Bainbridge Ave., Bronx, NY 10467. [phone]. Fax: [phone]. [e-mail]. http://www.kumc.edu/gec/ vcfhome.html .

WEBSITES

McDonald-McGinn, Donna M., Beverly S. Emanuel, and Elaine H Zackai. “22q11 deletion syndrome.” Gene Clinics. (Updated 15 Sept. 1999). http://www.geneclinics.org/profiles/22q11deletion/index.html .

National Institute on Deafness and Other Communication Disorders. http://www.nidcd.nih.gov/health/pubs_vsl/ velocario.htm .

The VCFS Educational Foundation.http://www.vcfsef.org/ .

Kathleen Fergus, MS, CGC

Delta storage pool disease see Hermansky-

Pudlak syndrome

I Dementia

Definition

Dementia is not a specific disorder or disease. It is a syndrome (group of symptoms) associated with a progressive loss of memory and other intellectual functions that is serious enough to interfere with the tasks of daily life. Dementia can occur to anyone at any age from an injury or oxygen deprivation, although it is most commonly associated with aging.

Description

The definition of dementia has become more inclusive over the past several decades. Whereas earlier descriptions of dementia emphasized memory loss, the last two editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R in 1987 and DSM-IV in 1994) define dementia as an overall decline in intellectual function, including difficulties with language, simple calculations, planning and judgment, and motor (muscular movement) skills as well as loss of memory. Although dementia is not caused by aging itself—most researchers regard it as resulting from injuries, infections, brain diseases, tumors, or other disorders—it is quite common in older people. Common estimates are that over 15% of people in North America over the age of 65 suffer from dementia, and 40% of people over 80. Surveys indicate that dementia is the condition most feared by older adults in the United States.

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Dementia can be caused by nearly forty different diseases and conditions, ranging from dietary deficiencies and metabolic disorders to head injuries and inherited diseases. The possible causes of dementia can be categorized as follows:

•Primary dementia. These dementias are characterized by damage to or wasting away of the brain tissue itself. They include Alzheimer disease (AD), Pick’s disease, and frontal lobe dementia (FLD).

•Multi-infarct dementia (MID). Sometimes called vascular dementia, this type is caused by blood clots in the small blood vessels of the brain. When the clots cut off the blood supply to the brain tissue, the brain cells are damaged and may die.

•Lewy body dementia. Lewy bodies are areas of injury found on damaged nerve cells in certain parts of the brain. They are associated with Alzheimer and Parkinson disease, but researchers do not yet know whether dementia with Lewy bodies is a distinct type of dementia or a variation of Alzheimer or Parkinson disease.

•Dementia related to alcoholism or exposure to heavy metals (arsenic, antimony, bismuth).

•Dementia related to infectious diseases. These infections may be caused by viruses (HIV, viral encephalitis); spirochetes (Lyme disease, syphilis); or prions (Creutzfeldt-Jakob disease).

•Dementia related to abnormalities in the structure of the brain. These may include a buildup of spinal fluid in the brain (hydrocephalus); tumors; or blood collecting beneath the membrane that covers the brain (subdural hematoma).

Dementia may also be associated with depression, low levels of thyroid hormone, or niacin (vitamin B12) deficiency. Dementia related to these conditions is often reversible.

Genetic profile

Genetic factors play a role in several types of dementia, but the importance of these factors in the development of the dementia varies considerably. Alzheimer disease (AD) is known, for example, to have an autosomal (non-sex-related) dominant pattern in most earlyonset cases as well as in some late-onset cases, and to show different degrees of penetrance (frequency of expression) in late-life cases. Moreover, researchers have not yet discovered how the genes associated with dementia interact with other risk factors to produce or trigger the dementia. One non-genetic risk factor presently being investigated is toxic substances in the environment.

Early-onset Alzheimer disease

In early-onset AD, which accounts for 2–7% of cases of AD, the symptoms develop before age 60. It is usually caused by an inherited genetic mutation. Earlyonset AD is also associated with Down syndrome, in that persons with trisomy 21 (three forms of human chromosome 21 instead of a pair) often develop earlyonset AD.

Late-onset Alzheimer disease

Recent research indicates that late-onset Alzheimer disease is a polygenic disorder; that is, its development is influenced by more than one gene. It has been known since 1993 that a specific form of a gene for apolipoprotein E (APOE) on human chromosome 19 is a genetic risk factor for late-onset AD. In 1998 researchers at the University of Pittsburgh reported on another gene that controls the production of bleomycin hydrolase (BH) as a second genetic risk factor that acts independently of the APOE gene. In December 2000, three separate research studies reported that a gene on chromosome 10 that may affect the processing of amyloid-beta protein is also involved in the development of late-onset AD.

Multi-infarct dementia (MID)

While the chief risk factors for MID are high blood pressure, advanced age, and male sex, there is an inherited form of MID called CADASIL, which stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL can cause psychiatric disturbances and severe headaches as well as dementia.

Frontal lobe dementias

Researchers think that between 25% and 50% of cases of frontal lobe dementia involve genetic factors. Pick’s dementia appears to have a much smaller genetic component than FLD. It is not yet known what other risk factors combine with inherited traits to influence the development of frontal lobe dementias.

Familial British dementia (FBD)

FBD is a rare autosomal dominant disorder that was first reported in the 1940s in a large British family extending over nine generations. FBD resembles Alzheimer in that the patient develops a progressive dementia related to amyloid deposits in the brain. In 1999 a mutated gene that produces the amyloid responsible for FBD was discovered on human chromosome 13. Studies of this mutation may yield further clues to the development of Alzheimer disease as well as FBD itself.

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K E Y T E R M S

Age-associated memory impairment (AAMI)—A condition in which an older person suffers some memory loss and takes longer to learn new information. AAMI is distinguished from dementia in that it is not progressive and does not represent a serious decline from the person’s previous level of functioning.

Agnosia—Loss of the ability to recognize objects by use of the physical senses.

Amyloid—A waxy translucent substance composed mostly of protein, that forms plaques (abnormal deposits) in the brain.

Aphasia—Loss of previously acquired ability to speak, or to understand written or spoken language.

Apraxia—Impairment of the ability to make purposeful movements, but not paralysis or loss of sensation.

Creutzfeldt-Jakob disease—A degenerative disease of the central nervous system caused by a prion, or “slow virus.”

Delirium—A disturbance of consciousness marked by confusion, difficulty paying attention, delusions, hallucinations, or restlessness. It can be distinguished from dementia by its relatively sudden onset and variation in the severity of the symptoms.

Hematoma—An accumulation of blood, often clotted, in a body tissue or organ, usually caused by a break or tear in a blood vessel.

Huntington disease—A midlife-onset inherited disorder characterized by progressive dementia and loss of control over voluntary movements. It is sometimes called Huntington’s chorea.

Hydrocephalus—The excess accumulation of cerebrospinal fluid around the brain, often causing enlargement of the head.

Lewy bodies—Areas of injury found on damaged nerve cells in certain parts of the brain associated with dementia.

Multi-infarct dementia—Dementia caused by damage to brain tissue resulting from a series of blood clots or clogs in the blood vessels. It is also called vascular dementia.

Parkinson disease—A disease of the nervous system most common in people over 60, characterized by a shuffling gait, trembling of the fingers and hands, and muscle stiffness. It may be related in some way to Lewy body dementia.

Pick’s disease—A rare type of primary dementia that affects the frontal lobes of the brain. It is characterized by a progressive loss of social skills, language, and memory, leading to personality changes and sometimes loss of moral judgment.

Pseudodementia—A term for a depression with symptoms resembling those of dementia. The term dementia of depression is now preferred.

Creutzfeldt-Jakob disease

Although Creutzfeldt-Jakob disease is caused by a prion, researchers think that 5–15% of cases may have a genetic component.

Demographics

The demographic distribution of dementia varies somewhat according to its cause. Moreover, recent research indicates that dementia in many patients has overlapping causes, so that it is not always easy to assess the true rates of occurrence of the different types. For example, AD and MID are found together in about 15–20% of cases.

Alzheimer disease

AD is by far the most common cause of dementia in the elderly, accounting for 60–80% of cases. It is esti-

mated that 4 million adults in the United States suffer from AD. The disease strikes women more often than men, but researchers don’t know yet whether the sex ratio simply reflects the fact that women tend to live longer than men, or whether female sex is itself a risk factor for AD. One well-known long-term study of Alzheimer’s in women is the Nun Study, begun in 1986 and presently conducted at the University of Kentucky.

Multi-infarct dementia

MID is responsible for between 15% and 20% of cases of dementia (not counting cases in which it coexists with AD). Unlike AD, MID is more common in men than in women. Diabetes, high blood pressure, a history of smoking, and heart disease are all risk factors for MID. Researchers in Sweden have suggested that MID is underdiagnosed, and may coexist with other dementias more frequently than is presently recognized.

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Dementia with Lewy bodies

Dementia with Lewy bodies is now thought to be the second most common form of dementia after Alzheimer disease. But because researchers do not completely understand the relationship between Lewy bodies, AD, and Parkinson disease, the demographic distribution of this type of dementia is also unclear.

Other dementias

FLD, Pick’s disease, Huntington disease, Parkinson disease, HIV infection, alcoholism, head trauma, etc. account for about 10% of all cases of dementia. In FLD and Pick’s dementia, women appear to be affected slightly more often than men.

Signs and symptoms

DSM-IV specifies that certain criteria must be met for a patient to be diagnosed with dementia. One criterion is significant weakening of the patient’s memory with regard to learning new information as well as recalling previously learned information. In addition, the patient must be found to have one or more of the following disturbances:

•Aphasia. Aphasia refers to loss of language function. A person with dementia may use vague words like “it” or “thing” a lot because they can’t recall the exact name of an object; they may echo what other people say, or repeat a word or phrase over and over. People in the later stages of dementia may stop speaking at all.

•Apraxia. Apraxia refers to loss of the ability to perform intentional movements even though the person is not paralyzed, has not lost their sense of touch, and knows what they are trying to do. For example, patients with apraxia may stop brushing their teeth, or have trouble tying their shoelaces.

•Agnosia. Agnosia refers to loss of the ability to recognize objects even though the person’s sight and sense of touch are normal. People with severe agnosia may fail to recognize family members or their own face reflected in a mirror.

•Problems with abstract thinking and complex behavior. This criterion refers to the loss of the ability to make plans, carry out the steps of a task in the proper order, make appropriate decisions, evaluate situations, show good judgment, etc. For example, a patient might light a stove burner under a saucepan before putting food or water in the pan, or be unable to record checks and balance his or her checkbook.

DSM-IV also specifies that these disturbances must be severe enough to cause problems in the person’s daily

life, and that they must represent a decline from a previously higher level of functioning.

The following sections will focus on the signs and symptoms that are used to differentiate among the various types of dementia during a diagnostic evaluation.

Alzheimer disease

Dementia related to AD often progresses slowly; it may be accompanied by irritability, wide mood swings, and personality changes in the early stage. In secondstage AD, the patient typically gets lost easily, is completely disoriented with regard to time and space, and may become angry, uncooperative, or aggressive. In final-stage AD, the patient is completely bedridden, has lost control over bowel and bladder functions, and may be unable to swallow or eat. The risk of seizures increases as the patient progresses from early to endstage Alzheimer disease. Death usually results from an infection or malnutrition.

Multi-infarct dementia

In MID, the symptoms are more likely to occur after age 70. In the early stages, the patient retains his or her personality more fully than a patient with AD. Another distinctive feature of this type of dementia is that it often progresses in a stepwise fashion; that is, the patient shows rapid changes in functioning, then remains at a plateau for awhile rather than showing a continuous decline. The symptoms of MID may also have a “patchy” quality; that is, some of the patient’s mental functions may be severely affected while others are relatively undamaged. Other symptoms of MID include exaggerated reflexes, an abnormal gait (manner of walking), loss of bladder or bowel control, and inappropriate laughing or crying.

Dementia with Lewy bodies

This type of dementia may combine some features of AD, such as severe memory loss and confusion, with certain symptoms associated with Parkinson disease, including stiff muscles, a shuffling gait, and trembling or shaking of the hands. Visual hallucinations may be one of the first symptoms of dementia with Lewy bodies.

Frontal lobe dementias

The frontal lobe dementias are gradual in onset. Pick’s dementia is most likely to develop in persons between 40 and 60, while FLD typically begins before the age of 65. The first symptoms of the frontal lobe dementias often include socially inappropriate behavior (rude remarks, sexual acting-out, lack of personal

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hygiene, etc.). Patients are also often obsessed with eating and may put non-food items in their mouths as well as making frequent sucking or smacking noises. In the later stages of frontal lobe dementia or Pick’s disease, the patient may develop muscle weakness, twitching, and delusions or hallucinations.

Creutzfeldt-Jakob disease

The dementia associated with Creutzfeldt-Jakob disease occurs most often in persons between 40 and 60. It is typically preceded by a period of several weeks in which the patient complains of unusual tiredness, anxiety, loss of appetite, or difficulty concentrating. This type of dementia also usually progresses much more rapidly than other dementias, usually over a span of a few months.

Diagnosis

In some cases, a patient’s primary physician may be able to diagnose the dementia; in many instances, however, the patient will be referred to a neurologist or a specialist in geriatric medicine. The differential diagnosis of dementia is complicated because of the number of possible causes; because more than one cause may be present; and because dementia can coexist with other conditions such as depression and delirium. Delirium is a temporary disturbance of consciousness marked by confusion, restlessness, inability to focus one’s attention, hallucinations, or delusions. In elderly people, delirium is frequently a side effect of surgery, medications, infectious illnesses, or dehydration. Delirium can be distinguished from dementia by the fact that delirium usually comes on fairly suddenly (in a few hours or days) and may vary in severity—it is often worse at night. Dementia develops much more slowly, over a period of months or years, and the patient’s symptoms are relatively stable. It is possible for a person to have delirium and dementia at the same time. Another significant diagnostic distinction in elderly patients is the distinction between dementia and age-associated memory impairment (AAMI). Older people with AAMI have a mild degree of memory loss; they do not learn new information as quickly as younger people, and they may take longer to recall a certain fact or to balance their checkbook. But they do not suffer the degree of memory impairment that characterizes dementia, and they do not get progressively worse.

Patient history

The doctor will begin by taking a full history, including the patient’s occupation and educational level as well as medical history. The occupational and educational his-

Colored positron emission of dementia in a patient with AIDS. (Photo Researchers, Inc.)

tory allows the examiner to make a more accurate assessment of the extent of the patient’s memory loss and other evidence of intellectual decline. In some cases the occupational history may indicate exposure to heavy metals or other toxins. A complete medical history allows the doctor to assess possibilities such as delirium, depression, alcohol-related dementia, dementia related to head injury, or dementia caused by infection. It is particularly important for the doctor to have a list of all the patient’s medications, including over-the-counter preparations, because of the possibility that the patient’s symptoms are related to side effects.

Mental status examination

A mental status examination (MSE) evaluates the patient’s ability to communicate, follow instructions, recall information, perform simple tasks involving movement and coordination, as well as his or her emotional state and general sense of space and time. The MSE includes the doctor’s informal evaluation of the patient’s

Dementia

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appearance, vocal tone, facial expressions, posture, and gait as well as formal questions or instructions. A common form that has been used since 1975 is the so-called Folstein Mini-Mental Status Examination, or MMSE. Questions that are relevant to diagnosing dementia include asking the patient to count backward from 100 by 7s, to make change, to name the current President, to repeat a short phrase after the examiner (e.g., “no ifs, ands, or buts”), to draw a clock face or geometric figure, and to follow a set of instructions involving movement (e.g., “Show me how to throw a ball” or “Fold this piece of paper and place it under the lamp on the bookshelf.”). The examiner may test the patient’s abstract reasoning ability by asking him or her to explain a familiar proverb (e.g. “People who live in glass houses shouldn’t throw stones”) or test the patient’s judgment by asking about a problem with a common-sense solution, such as what one does when a prescription runs out.

Neurological examination

A neurological examination includes an evaluation of the patient’s cranial nerves and reflexes. The cranial nerves govern the ability to speak as well as sight, hearing, taste, and smell. The patient will be asked to stick out the tongue, follow the examiner’s finger with the eyes, raise the eyebrows, etc. The patient is also asked to perform certain actions (e.g., touching the nose with the eyes closed) that test coordination and spatial orientation. The doctor will usually touch or tap certain areas of the body, such as the knee or the sole of the foot, to test the patient’s reflexes. Failure to respond to the touch or tap may indicate damage to certain parts of the brain.

Laboratory tests

Blood and urine samples are collected in order to rule out such conditions as thyroid deficiency, niacin (vitamin B12) deficiency, heavy metal poisoning, liver disease, HIV infection, syphilis, anemia, medication reactions, or kidney failure. A lumbar puncture (spinal tap) may be done to rule out neurosyphilis.

Diagnostic imaging

The patient may be given a CT (computed tomography) scan or MRI (magnetic resonance imaging) to detect evidence of strokes, disintegration of the brain tissue in certain areas, blood clots or tumors, a buildup of spinal fluid, or bleeding into the brain tissue. PET (positronemission tomography) or SPECT (single-emission computed tomography) imaging is not used routinely to diagnose dementia, but may be used to rule out Alzheimer disease or frontal lobe degeneration if a patient’s CT scan or MRI is unrevealing.

Treatment and management

Reversible and responsive dementias

Some types of dementia are reversible, and a few types respond to specific treatments related to their causes. Dementia related to dietary deficiencies or metabolic disorders is treated with the appropriate vitamins or thyroid medication. Dementia related to HIV infection often responds well to zidovudine (Retrovir), a drug given to prevent the AIDS virus from replicating. Multiinfarct dementia is usually treated by controlling the patient’s blood pressure and/or diabetes; while treatments for these disorders cannot undo damage already caused to brain tissue, they can slow the progress of the dementia. Patients with alcohol-related dementia often improve over the long term if they are able to stop drinking. Dementias related to head injuries, hydrocephalus, and tumors are treated by surgery.

It is important to evaluate and treat elderly patients for depression, because the symptoms of depression in older people often mimic dementia. This condition is sometimes called pseudodementia. In addition, patients who suffer from both depression and dementia often show some improvement in intellectual functioning when the depression is treated.

Irreversible dementias

As of 2001, there are no medications or surgical techniques that can cure Alzheimer disease, the frontal lobe dementias, MID, or dementia with Lewy bodies. There are also no “magic bullets” that can slow or stop the progression of these dementias. Patients may be given medications to ease the depression, anxiety, sleep disturbances, and similar symptoms that accompany dementia, but most physicians prescribe relatively mild dosages in order to minimize the troublesome side effects of these drugs. Dementia with Lewy bodies appears to respond better to treatment with the newer antipsychotic medications than to treatment with such older drugs as haloperidol (Haldol).

Patients in the early stages of dementia can often remain at home with some help from family members or other caregivers, especially if the house or apartment can be fitted with safety features (handrails, good lighting, locks for cabinets containing potentially dangerous products, nonslip treads on stairs, etc.). Patients in the later stages of dementia, however, usually require skilled care in a nursing home or hospital.

Prognosis

The prognosis for reversible dementia related to nutritional or thyroid problems is usually good once the

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cause has been identified and treated. The prognoses for dementias related to alcoholism or HIV infection depend on the patient’s age and the severity of the underlying disorder.

The prognosis for the irreversible dementias is gradual deterioration of the patient’s functioning ending in death. The length of time varies somewhat. Patients with Alzheimer disease may live from two to 20 years with the disease, with an average of seven years. Patients with frontal lobe dementia or Pick’s disease live on average between five and 10 years after diagnosis. The course of Creutzfeldt-Jakob disease is much more rapid, with patients living between five and 12 months after diagnosis.

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC: American Psychiatric Association, 1994.

“Delirium and Dementia.” Section 5 in The Merck Manual of Geriatrics. Whitehouse Station, NJ: Merck Research Laboratories, 1995.

“Dementia.” The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

Lyon, Jeff, and Peter Gorner. Altered Fates: Gene Therapy and the Retooling of Human Life. New York and London: W. W. Norton & Co., Inc., 1996.

Morris, Virginia. How to Care for Aging Parents. New York: Workman Publishing, 1996. A good source of information about caring for someone with dementia as well as information about dementia itself.

ORGANIZATIONS

Alzheimer’s Association. 919 North Michigan Ave., Suite 1000, Chicago, IL 60611-1676. [phone].

Alzheimer’s Disease International. 45/46 Lower Marsh, London, SE1 7RG. UK ( 44 20) 7620 3011. [e-mail]. http://www.alz.co.uk. .

National Institute of Mental Health. 6001 Executive Blvd., Rm. 8184, MSC 9663, Bethesda, MD 20892-9663. (301) 4434513. Fax: [phone]. http://www.nimh.nih.gov/ publicat/index.cfm .

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. [phone] or [phone].http://www.ninds.nih.gov .

National Institute on Aging Information Center. PO Box 8057, Gaithersburg, MD 20898. [phone] or (301) 4961752.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. [phone] or [phone]. Fax: [phone]. http://www

.rarediseases.org .

WEBSITES

Alzheimer’s Disease Education and Referral (ADEAR).http://www.alzheimers.org .

National Institute of Mental Health (NIMH). http://www

.nimh.nih.gov .

National Institute of Neurological Disorders and Stroke (NINDS). http://www.ninds.nih.gov .

National Institute on Aging (NIA). http://www.nih.gov/nia . The Nun Study. http://www.coa.uky.edu/nunnet .

Rebecca J. Frey, PhD

I Dentatorubral-pallidoluysian

atrophy

Definition

Dentatorubral-pallidoluysian atrophy (DRPLA) is a disorder of ataxia (loss of balance), choreoathetosis (involuntary rapid, irregular, jerky movements or slow, writhing movements that flow into one another), and dementia (inability to clearly think; confusion, poor judgement; failure to recognize people, places, and things; personality changes) in adults, and ataxia, myoclonus (involuntary spasms of a muscle or muscle group), epilepsy (seizures), and loss of intellectual function (mental retardation) in children.

Description

DRPLA has also been referred to as Haw River syndrome and Natito-Oyanagi disease. The typical age of onset of DRPLA is 30, but it can present in people as young as one year of age and as late as 62 years of age, with differences in presentation between children and adults. In patients under the age of 20, DRPLA presents as seizures, ataxia, myoclonus, as well as progressive (worsening) mental deterioration. In patients over the age of 20, DRPLA is suspected when a person develops ataxia, choreoathetosis, dementia, and psychiatric disturbances (delusions, hallucinations). A positive family history (a relative with similar symptoms or one already diagnosed) confirms the diagnosis. DRPLA is sometimes initially thought to be Huntington disease.

A possible diagnosis of DRPLA can be devastating for a family to experience—their once healthy child, or young adult, will begin to have seizures, involuntary movements, loss of control over voluntary movement, and delusions—perhaps no longer being able to identify family members. Diagnosing DRPLA is complicated and requires a knowledgeable phyisician with expertise in both neurology and genetics. Usually an individual diagnosed with DRPLA already has a parent with the disease,

atrophy pallidoluysian-Dentatorubral

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