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

Dentatorubral-pallidoluysian atrophy

Demographics

DRPLA has been reported to occur most often in the Japanese population, although it has been described in other ethnic groups including those in Europe and North America. The prevalence of DRPLA in the Japanese population is estimated to be 2–7 in 1,000,000, which is similar to the prevalence of Huntington disease in this population. A CAG repeat size of 17 or higher (usually 20–35) is more common in healthy Japanese individuals than Caucasians, which may explain why DRPLA is more common in the Japanese. In other words, a larger repeat size in a parent increases the possibility that the DNA will become unstable and expand when transmitted to the next generation. Even though DRPLA is rare in the United States, a large African-American family in North Carolina has DRPLA, where the condition is also called the Haw River syndrome.

Signs and symptoms

The cardinal features of DRPLA are involuntary movements (usually in the face, neck, tongue and hands) and dementia (inability to clearly think; confusion; poor judgement; failure to recognize people, places, and things; personality changes) regardless of the age of onset. A history of ataxia, epilepsy, and mental retardation in children, combined with a positive family history, are often the presenting signs of this condition in an individual under 20 years of age. Seizures are always present in patients under 20, but are not as common in patients age 20–40, and rarely seen in patients with onset after 40. Adult onset DRPLA (after 20) presents with ataxia, choreoathetosis, dementia, and psychiatric disturbances.

Diagnosis

A diagnosis of DRPLA exists when there is a positive family history of the disease, characteristic clinical findings, and DNA testing that reveals an expansion in the CAG repeat of the DRPLA gene. Genetic testing to examine the CAG repeats in the DRPLA gene can be performed from a small blood sample. A few reports have described DRPLA as sporadic (occuring by chance) in some families. Upon closer examination, the asymptomatic fathers had a mildly expanded CAG repeat size. Therefore, it is always important to evaluate both parents of an affected individual even if they appear to have no symptoms of DRPLA. Testing of asymptomatic children is not appropriate since it takes away the child’s right to want to know, or not know this information, raises the possibility of stigmatization (labeling someone a certain way and making assumptions about them) within a family, as well as the threat of educational and employment discrimination. Children with symptoms, however, usually benefit from having a diagnosis established.

For pregnancies at 50% risk, prenatal diagnosis is available via either CVS (chorionic villus sampling) or amniocentesis. CVS is a biopsy of the placenta performed in the first trimester of pregnancy under ultrasound guidance. Ultrasound is the use of sound waves to visualize the developing pregnancy. The genetic makeup of the placenta is identical to the fetus (developing baby) and therefore the DRPLA gene can be studied from this tissue. There is approximately a 1 in 100 chance for miscarriage with CVS. Amniocentesis is a procedure done under ultrasound guidance where a long thin needle is inserted into the mother’s abdomen, into the uterus, to withdraw a couple of tablespoons of amniotic fluid (fluid surrounding the developing baby) to study. The DRPLA gene can be studied using cells from the amniotic fluid. Other genetic tests, such as a chromosome analysis, may also be performed on either a CVS or amniocentesis. A small risk of miscarriage (1 in 200 to 1 in 400) is associated with amniocentesis.

Treatment and management

There is currently no cure for DRPLA; treatment is supportive. Epilepsy is treated with anti-seizure medication.

Prognosis

Patients with DRPLA have progressive disease, which means symptoms become worse over time.

Resources

WEBSITES

International Network of Ataxia Friends (INTERNAF).http://www.internaf.org .

National Ataxia Foundation. http://www.ataxia.org .

WE MOVE (Worldwide Education and Awareness for Movement Disorders). http://www.wemove.org .

Catherine L. Tesla, MS, CGC

Deoxyribonucleic acid see DNA

I Depression

Definition

Depression is the general name for a family of illnesses known as depressive disorders. Depression is an illness that affects not only the mood and thoughts, but also the physical functions of affected individuals. Depressive disorders usually result from a combination of genetic, environmental, and psychological factors.

Depression

Depression

Description

Everyone feels sadness, grief, or despair at some point in their lives. However, unlike these normal, transient emotional states, a depressive disorder is not a temporary bout of “feeling down” but rather a serious disease that should be recognized and treated as a medical condition. Without treatment, a depressive disorder can persist and its symptoms can go on for weeks, months, or years. The three most common types of depression are dysthymia or dysthymic disorder, major depression, and bipolar disorder.

Depression is quite widespread and one of the leading causes of disability in the world. Commonly recognized symptoms of all types of depressive disorders are recurring feelings of sadness and guilt, changes in sleeping patterns such as insomnia or oversleeping, changes in appetite, decreased mental and physical energy, unusual irritability, the inability to enjoy once-favored activities, difficulty in working, and thoughts of death or suicide. If only these “down” symptoms are experienced, the individual may suffer from a unipolar depressive disorder such as dysthymia or major depression. If the depressed periods alternate with extreme “up” periods, the individual may have a bipolar disorder.

Dysthymia is a relatively mild depressive disorder that is characterized by the presence of two or more of the symptoms listed above. The symptoms are not severe enough to disable the affected individual, but are longterm (chronic), and may last for several years. Dysthymia is a compound word originating in Greek that means ill, or bad, (dys-) soul, mind, or spirit (thymia). Individuals affected with dysthymia often also experience episodes of major depression at some point in their lives.

In major depression, the affected individual has five or more symptoms and experiences one or more prolonged episodes of depression that last longer than two weeks. These episodes disrupt the ability of the affected individual to the point that the person is unable to function. Individuals experiencing an episode of major depression often entertain suicidal thoughts, the presence of which contribute to this disorder being quite serious. Major depression should not be confused with a grief reaction such as that associated with the death of a loved one. Some individuals affected by major depression may experience only a single bout of disabling depression in their lifetimes. More commonly, affected individuals experience recurrent disabling episodes throughout their lives.

Bipolar disorder, formerly called manic depression or manic-depressive illness, is not nearly as common as major depression and dysthymia. Bipolar disorder is associated with alternating periods of extreme excitement

(mania) and periods of extreme sadness (depression). The rate of the transition between cycles is usually gradual, but the mood swings may also be severe and dramatically rapid. When in the depressive state, the bipolar disorder affected individual may show any or all of the common symptoms of depression. In the manic state, the bipolar disorder affected individual may feel restless and unnaturally elated, have an overabundance of confidence and energy, and be very talkative. Mania can distort social behavior and judgment, causing the affected individual to take excessive risks and perhaps make imprudent decisions that can have humiliating or damaging consequences. Without medical treatment, bipolar disorder may progress into psychosis.

Depressive disorders are believed to be related to imbalances in brain chemistry, particularly in relation to the chemicals that carry signals between brain cells (neurotransmitters) as well as the hormones released by parts of the brain. Serotonin and neuroepinephrine are two important neurotransmitters. Disruption of the brain’s circuits in areas involved with emotions, appetite, sexual drive, and sleep is a likely cause of the dysfunctions associated with depressive disorders. Thus, some of the newest treatments for depression are drugs that are known to have an effect on brain chemistry.

Genetic profile

Depression is known to be genetically linked because it often runs in families and has been studied in identical twins, but the specific gene markers for depression remain elusive. As of early 2000, the National Institutes of Mental Health has begun enrolling patients in what will become the largest clinical psychiatric genetic study ever attempted to investigate how recurrent depression is transmitted across generations. This study is primarily focused on major depression and dysthymia.

In familial cases of bipolar disorder, the most widely implicated genetic regions are those of chromosome 18 and chromosome 21. However, other researchers have mapped bipolar disorder to chromosomes 11p, Xq28, 6p, and many others. From this evidence, it is possible that bipolar disorder is a multi-gene (polygenic) trait requiring a combination of 3 or more genes on separate chromosomes for the condition to be expressed. Further research is also ongoing to determine the genetic marker, or markers, for bipolar disorder.

It is understood that there are also many non-genetic factors that cause depression, including stressful environmental conditions, certain illnesses, and precipitating conditions such as the loss of a close relationship. Alcohol abuse and the use of sedatives, barbiturates, narcotics, or other drugs can cause depression due to their effect on brain chemistry.

Demographics

It is estimated that the likelihood of experiencing an episode of major depression during one’s lifetime is 5 percent. Approximately 9.5% of the American population, or 19 million people, are affected by depression in any given year. Depression occurs worldwide, but more Americans are diagnosed with depression than inhabitants of any other country. These lower occurrences of diagnosis in other parts of the world might indicate a higher incidence of depression in Americans than in all other peoples, but it may also be the result of the stigma, or shame, often associated with the diagnosis of a psychological disorder. Depression is not generally linked to any particular race of people.

In the United States, women experience depression at a rate that is almost twice that of men. This may be partially explained by the greater willingness of women to seek psychological treatment, but this does not explain the entire discrepancy. Many physical events specific to women, such as menstruation, pregnancy, miscarriage, the post partum period, and menopause are recognized as factors contributing to depression in women. Women in the United States may face environmental stresses with a higher frequency than men. Most single parent households are headed by women; women still provide the majority of child and elder care, even in two-income families; and women are generally paid less than men, so financial concerns may be greater.

Particular demographic problems associated with depression are depression in the elderly and depression in children and adolescents. A common belief is that depression is normal in elderly people. This is not the case, although increasing age and the absence of interpersonal relationships are associated with higher rates of depression. Because of this misconception, depressive disorders in the elderly population often go undiagnosed and untreated. Similarly, many parents often ignore the symptoms of a depressive disorder in their children, assuming that these symptoms are merely a phase that the child will later outgrow.

Signs and symptoms

Individuals affected with depressive disorders display a wide range of symptoms. These symptoms vary in severity from person to person and vary over time in a single affected individual.

Symptoms that characterize a depressive state are: feelings of hopelessness, guilt, or worthlessness; a persistent sad or anxious mood; restlessness or irritability; a loss of interest in activities that were once considered pleasurable; difficulty concentrating, remembering, or making decisions; sleep disorders, including insomnia,

K E Y T E R M S

Bipolar disorder—Formerly called “manic depression,” this psychological disorder is characterized by periods of mania followed by periods of depression.

Cognitive/behavioral therapies—Psychological counseling that focuses on changing the behavior of the patient.

Dysthymia—A psychological condition of chronic depression that is not disabling, but prevents the sufferer from functioning at his or her full capacity.

Electroconvulsive therapy—A psychological treatment in which a series of controlled electrical impulses are delivered to the brain in order to induce a seizure within the brain.

Grief reaction—The normal depression felt after a traumatic major life occurrence such as the loss of a loved one.

Interpersonal therapies—Also called “talking therapy,” this type of psychological counseling is focused on determining how dysfunctional interpersonal relationships of the affected individual may be causing or influencing symptoms of depression.

Major depression—A psychological condition in which the patient experiences one or more disabling attacks of depression that last two or more weeks.

Polygenic—A trait, characteristic, condition, etc. that depends on the activity of more than one gene for its emergence or expression.

Psychodynamic therapies—A form of psychological counseling that seeks to determine and resolve the internal conflicts that may be causing an individual to be suffering from the symptoms of depression.

Psychotherapy—Psychological counseling that seeks to determine the underlying causes of a patient’s depression. The form of this counseling may be cognitive/behavioral, interpersonal, or psychodynamic.

early morning awakening, and/or oversleeping; constant fatigue; eating disorders, including weight loss or overeating; suicidal thoughts and/or tendencies; and persistent physical symptoms that do not respond to the normal treatments of these symptoms, such as headaches, digestive problems, and chronic pain.

Depression

Depression

Clinical depression can be detected by a CAT scan. These two images demonstrate the difference between normal brain activity and depressed brain activity. (Photo Researchers, Inc.)

Symptoms that characterize a manic state are: increased energy accompanied by a decreased need for sleep, a loss of inhibitions accompanied by inappropriate social behavior, excessive enthusiasm and verve, increased talking, poor judgment, a feeling of invincibility, grandiose thinking and ideas, unusual irritability, and increased sexual desire.

Diagnosis

Depression is notoriously difficult to diagnose because its symptoms are not readily apparent to the medical professional unless the patient first recognizes and admits to them. Once the individual seeks help for his or her symptoms, the first step in the diagnosis of a depressive disorder is a complete physical examination to rule out any medical conditions, viral infections, or currently used medications that may produce the effects also seen in depression. Alcohol or other drug abuse as

a possible cause of the observed symptoms should also be investigated. Once a physical basis for these symptoms is eliminated, a complete psychological exam should be undertaken. This examination consists of a mental status examination; a complete history of both current and previously experienced symptoms; and a family history.

The mental status examination is used to determine if a more severe psychotic condition is evident. This mental status examination will also determine whether the depressive disorder has caused changes in speech or thought patterns or memory that may indicate the presence of a depressive disorder. The complete psychological exam also includes a complete history of the symptoms being experienced by the affected individual. This history includes the onset of the symptoms, their duration, and whether or not the affected individual has had similar symptoms in the past. In the case of past symptoms, a treatment history should be completed to assess whether these symptoms previously responded to treatment, and if so, which treatments were effective. The final component of the complete psychological exam is the family history. In cases where the affected individual has had similarly affected family members a treatment history should also be completed, as much as possible, for these family members.

Treatment and management

Treatment of depression is on a case-by-case basis that is largely dependent on the outcome of the psychological examination. Some mildly affected individuals respond fully to psychotherapy and do not require medication. Some individuals affected with moderate or severe depression benefit from antidepressant medication. Most affected individuals respond best to a combination of antidepressant medication and psychotherapy: the medication to provide relatively rapid relief from the symptoms of depression and the psychotherapy to learn effective ways to manage and cope with problems and issues that may cause the continuation of symptoms or the onset of new symptoms of depression.

Various types of antidepressant medications are available for the treatment of depressive disorders. Many individuals affected with depression will go through a variety of antidepressants, or antidepressant combinations, before the best medication and dosage for them is identified. Almost all antidepressant medications must be taken regularly for at least two months before the full therapeutic effects are realized. A full course of medication is generally no shorter than 6 to 9 months to prevent recurrence of the symptoms. In individuals affected with bipolar disorder or chronic major depression, medication

may have to be continued throughout the remainder of their lives. These time-related conditions often pose problems in the management of individuals affected with depressive disorder. Many individuals with a depressive disorder discontinue their medications before the fully prescribed course for a variety of reasons. Some affected individuals feel side effects of the medications prior to feeling any benefits; others do not feel that the medication is helping because of the delay between the initiation of the treatment and the feelings of symptom relief; and many feel better prior to the full course and so cease taking the medication.

The three most commonly prescribed antidepressant drug classes consist of the older tricyclics (TCAs) and the two relatively new drug classes: the selective serotonin reuptake inhibitors (SSRIs) and the monoamine oxidase inhibitors (MAOIs). The most common TCAs are amitriptyline (Elavil), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), doxepin (Sinequan, Adapin), imipramine (Tofranil, Janimine), nortriptyline (Pamelor, Aventyl), protriptyline (Vivactil), and trimipramine (Surmontil). The most common SSRIs are: citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). The most common MAOIs are: phenelzine (Nardil) and tranylcypromine (Parnate).

Many antidepressant medications cause side effects such as agitation, bladder problems, blurred vision, constipation, drowsiness, dry mouth, headache, insomnia, nausea, nervousness, or sexual problems. Most of these side effects wear off as the treatment course progresses. The tricyclics cause more severe side effects than the newer SSRIs or MAOIs.

St. John’s wort is an herbal remedy that has been widely used to treat depressive disorders. In Germany, this herbal remedy is used more than any other antidepressant. As of early 2001, no scientific studies have been completed on the long-term effects of St John’s wort in the treatment of depression. In 2000, the National Institutes of Health (NIH) completed patient enrollment in a three-year clinical study to study this herbal treatment of depression. The results of this study should be available in late 2003 or in 2004.

In the most severely affected individuals, or where antidepressant medications either have not worked or cannot be taken, electroconvulsive therapy (ECT) may be considered. In the ECT procedure, electrodes are put on specific locations on the head to deliver electrical stimulation to the brain. This electrical stimulation is designed to trigger a brief seizure within the brain. These seizures generally last approximately 30 seconds and are not consciously felt by the patient. ECT has

been much improved in recent years; it is no longer the electro-shock treatment of nightmares, and its deleterious effects on long-term memory have been reduced. ECT treatments are generally administered several times a week as necessary to control the symptoms being experienced.

Several short-term (10 to 20 week) psychotherapies have also been demonstrated to be effective in the treatment of depressive disorders. These include interpersonal and cognitive/behavioral therapies. Interpersonal therapies focus on the interpersonal relationships of the affected individual that may both cause and heighten the depression. Cognitive/behavioral therapies focus on how the affected individual may be able to change his or her patterns of thinking or behaving that may lead to episodes of depression. Psychodynamic therapies, which generally are not short-term psychotherapies, seek to treat the individual affected with depressive disorder through a resolution of internal conflicts. Psychodynamic therapies are generally not initiated during major depression episodes or until the symptoms of depression are significantly improved by medication or one of the shortterm psychotherapies.

Prognosis

Over 80% of individuals affected with a depressive disorder have demonstrated improvement after receiving the appropriate combination of treatments. A significant tragedy associated with depression is the failure of many affected individuals to realize that they have a treatable medical condition. Some affected individuals who do not receive treatment may recover completely on their own, but most will suffer needlessly. A small number of individuals with depressive disorder do not respond to treatment.

Resources

BOOKS

Appleton, William. Prozac and the New Antidepressants: What You Need to Know About Prozac, Zoloft, Paxil, Luvox, Wellbutrin, Effexor, Serzone, and More. New York: Plume, 2000.

Beck, Aaron, and Brian Shaw. Cognitive Theory of Depression.

New York: Guilford Press, 1987.

Papolos, Demitri, and Janice Papolos. Overcoming Depression, 3rd ed. New York: Guilford Press, 1997.

PERIODICALS

Cytryn, L. “The cutting edge of sadness.” Psychiatric Times (October 1996).

Kelsoe, G. “An update on the search for genes for bipolar disorder.” Psychiatric Times (September 1996).

Nemeroff, C. “The neurobiology of depression.” Scientific American (June 1998): 42–9.

Depression

Diabetes

ORGANIZATIONS

National Depressive and Manic Depressive Association. 730 N. Franklin, Suite 501, Chicago, IL 60610-7204. (800) 8263632 or (312) 642-7243. http://www.ndmda.org .

National Foundation for Depressive Illness, Inc. PO Box 2257, New York, NY 10016. (212) 268-4260 or (800) 239-1265.http://www.depression.org .

National Institute of Mental Health. 6001 Executive Blvd., Rm. 8184, MSC 9663, Bethesda, MD 20892-9663. (301) 4434513. Fax: (301) 443-4279. http://www.nimh.nih.gov/ publicat/index.cfm .

WEBSITES

About.com—Depression. http://depression.about.com/health/ depression . (12 February 2001).

Medical Health InfoSource—Depression. http://www

.mhsource.com/depression/overview.html . (12 February 2001).

Paul A. Johnson

I Diabetes

Definition

Diabetes mellitus describes a group of diseases in which there is an elevated level of the sugar glucose, the body’s main source of energy for cellular functions, in the blood. The level of glucose, as well as other “fuel” molecules, is increased due to a disorder in the production or function of the hormone insulin. A range of health problems occurs primarily due to the damaging effects of elevated levels of glucose on blood vessels.

Description

To understand diabetes, it is important to understand how the hormone insulin functions in the breakdown and utilization of glucose. Insulin acts in two ways. It is necessary for the transport of glucose and other fuel molecules into the cells. It also regulates several pathways in metabolism that are important in the utilization of these fuel molecules. Insulin is made and released by specialized cells of the organ known as the pancreas. These beta cells of the pancreas release insulin when blood levels of glucose, amino acids, fatty acids, and ketones are high. These are all breakdown products of food, and an increase in their level in the blood signals that a person has recently eaten. The insulin acts to mobilize each of these fuel molecules so they can be used as energy to support cellular functions needed to maintain the body.

There are two main types of diabetes mellitus: type I and type II diabetes. While there are similarities, type

I and type II diabetes differ in several aspects related to cause, symptoms, treatment, and associated risk factors. In addition, there are other less common forms of diabetes.

Type I diabetes

Also called insulin-dependent diabetes mellitus (IDDM), this is the most severe form of diabetes, in which shots of insulin are necessary on a daily basis. IDDM is thought to be an autoimmune condition in which one’s own immune system attacks and destroys the insulin-producing cells of the pancreas. Insulin production is low or absent, and onset is generally in childhood or early adulthood. Affected individuals tend to be thin and prone to events in which ketones can become so high in the blood as to be potentially life-threatening, a complication called ketosis.

Type II diabetes

The most common type of diabetes, non-insulin dependent diabetes mellitus (NIDDM or type II), is the milder form of diabetes. Symptoms can generally be controlled with diet or oral medications that decrease blood sugar levels. True NIDDM does not develop into the insulin-dependent type of diabetes. In NIDDM, blood sugar levels become elevated because of resistance to the effects of insulin, which is usually present at normal levels. In other words, there may be plenty of insulin available, but the cells are not sensitive to insulin’s effects. This results in the inability of insulin to move glucose to the inside of cells where it can be used. NIDDM typically develops after age 40, although it can occur at any age. Affected individuals tend to be obese and are not prone to ketosis.

Impaired glucose tolerance (IGT)

Impaired glucose tolerance is a symptom characterized by lab test results that indicate elevated blood glucose levels. The results are not abnormal enough to be called “diabetes.” However, IGT may be an early sign of NIDDM, and is certainly a risk factor for developing NIDDM.

MODY

Maturity-onset diabetes of the young (MODY) is a rare form of NIDDM, in which onset is usually significantly earlier than in NIDDM. This form of diabetes shows a dominant inheritance pattern, unlike other forms of diabetes that are considered to be multifactorial (caused by a combination of multiple genetic and environmental factors). MODY is variable clinically within and between families.

Gestational diabetes

Also called diabetes of pregnancy, this form of the disease is often limited to the time during which a woman is pregnant. Management of glucose levels in affected women during pregnancy is very important, because high glucose levels can have serious, negative effects on the developing fetus. Gestational diabetes usually disappears after delivery. However, history of gestational diabetes increases a woman’s risk of developing NIDDM in the future and of having gestational diabetes again in future pregnancies. Risk factors for gestational diabetes are similar to those for NIDDM.

Genetic profile

Like many common diseases, diabetes is caused by a combination of multiple environmental and genetic risk factors. The exact set of environmental and genetic factors that causes diabetes in any one individual is usually not known.

There are several known or suspected environmental factors that increase risk of developing diabetes and/or worsening complications. Environmental risk factors for developing IDDM are less well understood than for other types of diabetes. Infection by certain viruses has been implicated as a triggering event that can lead to the autoimmune reaction that causes disease in individuals with genetic susceptibility. Risk factors that are entirely or partially environmental have been implicated in NIDDM. These include obesity, low physical activity, poor dietary habits (high fat, salt, sugar intake), and alcohol and tobacco use. Cardiovascular risk factors— increased cholesterol and blood pressure, as well as others—also increase the chance for NIDDM to develop. Impaired glucose tolerance is a risk factor and can sometimes progress to NIDDM. For women, past history of gestational diabetes or delivery of a baby who was large- for-gestational-age also increases the chance of developing NIDDM. Ethnic background has a role in disease susceptibility for all types of diabetes, due to both genetic and environmental factors that may in part be affected by cultural practices.

Multiple genetic factors, both between individuals and often within a single affected individual, increase susceptibility to IDDM and NIDDM. Genetic factors are thought to be most important in individuals with a family history of the disease.

Heritability is the term that describes the genetic component causing a disease. It is a measure of the extent to which disease expression is the result of underlying genetic factors. One indication of the relative contribution of heritability in the causation of a particular disease is concordance.

Concordance describes the rate of similarity in disease expression between identical twins that share the same genetic material. As a general rule, the higher the concordance between identical twins, the greater the contribution of genetic factors to disease development. For example, the concordance for all types of diabetes ranges from 45-96%, indicating this percentage of diabetes can be attributed to genetic factors, with the remaining due to environmental factors. The specific genetic factors involved and their relative contributions toward diabetes development vary depending on the type of diabetes.

IDDM

Type I diabetes occurs when one’s own immune system attacks and destroys the body’s insulin-producing cells. There is a general population risk of 1/500 for developing IDDM. This risk increases when there is a family history or the presence of known genetic risk factors. The concordance for IDDM is generally thought to be less than 50%, suggesting that environmental factors must be present to trigger the development of the disease in individuals with genetic susceptibility. Even given this relatively low concordance, several genetic factors have been identified as established or suspected causes of IDDM susceptibility.

HLA ASSOCIATIONS HLA stands for human leukocyte antigens (also called major histocompatibility complex). HLA describes a group of proteins—geneti- cally-determined and unique in each individual—that are important in helping the immune system distinguish ‘self’ from ‘non-self’ (foreign). Given their role in immunity, it seems intuitive that HLA types would be involved in susceptibility to this autoimmune form of diabetes. However, it is not yet clear if it is the HLA types themselves, or another closely linked gene, that increases risk.

There are several genes in the HLA gene family. Specific HLA-associations—consisting of variations of the HLA-DR gene—are thought to account for 60-70% of genetic susceptibility in IDDM. There is a significant understanding about the role of the HLA types, DR3 and DR4, in IDDM susceptibility.

HLA-DR alleles DR3 and DR4 are common in the general population. Almost half of all people in the United States have one or the other, which leads to a risk of 1/300 to 1/400 for developing IDDM. Two copies of DR3 or two copies of DR4—occuring in a very small percentage of the population—gives a risk of 1/150. Individuals having one copy each of DR3 and DR4 (1- 3% of the population) is a combination that results in a 1/40 risk for developing IDDM. While less than 1% of individuals with these HLA types will develop diabetes, DR3 and/or DR4 are present in about 95% of all individuals with IDDM. While these HLA types confer suscep-

Diabetes

Diabetes

Diabetes

Diabetics must give themselves insulin shots to maintain proper blood sugar levels. (Custom Medical Stock Photo, Inc.)

highly uniform. Therefore, all those who have genetic susceptibility can be considered to be exposed to a sufficient number environmental risk factors to trigger NIDDM.

GENES ASSOCIATED WITH NIDDM SUSCEPTIBILITY

Genetic susceptibility in NIDDM is highly heteroge- neous—meaning that variations in many different genes contribute to disease susceptibility. Although multiple susceptibility genes have been established or are suspected, major genes that confer a clearly high susceptibility do not play a major role—such as that seen with DR3 and DR4 in IDDM. NIDDM-associated genes include, but are not limited to, those found in the table.

MODY

This dominantly inherited form of type II diabetes has been shown to be caused by alterations in at least four distinct genes. The majority of cases of MODY are due to mutations in the glucokinase gene (GCK) on chromosome 7. GCK plays a role in the regulation of glucose levels. Another gene, whose precise location and function is yet to be determined, is the next most common cause of MODY cases. The gene, called MODY3, is located on chromosome 12. A minority of MODY cases can be attributed to a presumed mutation in a gene on chromosome 20 (MODY1), whose exact location and function is not yet known. It is thought that there must be one or more additional genes yet to be identified that account for MODY in the remaining families with a dominant inher-

itance pattern. Parents, siblings, and children of affected individuals have a 50% chance of inheriting the same MODY-related mutation.

NIDDM due to insulin gene mutations

In some families, NIDDM appears to be inherited in an autosomal dominant fashion. Late onset of the disease may occur together with characteristic lab values. Some such families have been shown to carry specific mutations in the insulin gene. Three mutations are known and produce altered forms of the insulin protein that apparently do not function as well as the usual type of insulin. These include Insulin Los Angeles, Insulin Wakayama, and Insulin Chicago. Although only present in about 0.5% of people with NIDDM, these mutations can lead to a dominant form of the disease. Other alterations in the insulin gene—including other point mutations and a variation outside the gene called the 5’ VNTR—may also contribute to NIDDM development or susceptibility in some populations.

Syndromes with NIDDM as a feature

As seen in IDDM, there are several distinct syndromes that have NIDDM as a potential feature. Aside from NIDDM, other characteristic features are present in each of these syndromes. The genetic basis for many of these conditions is known or suspected. These include syndromes with pancreatic disease (i.e. hemochromatosis and thalassemia) and syndromes due to mutations of the DNA of mitochondria—the cellular organelles that create energy. The latter includes MELAS syndrome, as well as a large deletion of mitochondrial DNA associated with diabetes and deafness. There are multiple syndromes with glucose intolerance resulting from or in association with a variety of other conditions. These include obesity, chromosomal imbalances, diseases of the endocrine system, or diseases of metabolism. As might be expected, mutations in the insulin receptor gene account for an increased risk for NIDDM. About 0.1% to 1% of the population carries such mutations, which leads to insulin resistance in some instances. Individuals who inherit two mutated copies of the insulin receptor gene may have extreme insulin resistance or diabetes. Some such individuals may have one of two rare syndromes. Donohue syndrome usually leads to death in the newborn period due to many serious complications resulting from very extreme insulin resistance. Rabson-Mendenhall syndrome is another very rare syndrome that affects multiple body systems and has been associated with the insulin receptor gene. Finally, mutations in this gene can lead to an inherited form of diabetes with acanthosis nigricans, a highly pigmented skin condition.