Autoimmune disease -

Immune system disorder, any of various failures in the body’s defense mechanisms against infectious organisms. Disorders of
immunity include immune deficiency diseases, such as AIDS, that arise because of a diminution of some aspect of the immune
response. Other types of immune disorders, such as allergies and autoimmune disorders, are caused when the body develops an
inappropriate response to a substance—either to a normally harmless foreign substance found in the environment, in the case of
allergies, or to a component of the body, in the case of autoimmune diseases. Lymphocytes (white blood cells of the immune
system) can become cancerous and give rise to tumours called leukemias, lymphomas, and myelomas.This article discusses various
immune deficiencies, allergies, autoimmune disorders, and lymphocyte cancers. For additional information on leukemias,
lymphomas, and myelomas, see the article cancer. A discussion of how the immune system works to prevent disease is found in
the article immune system.

Immune Deficiencies

Immune deficiency disorders result from defects that occur in immune mechanisms. The defects arise in the components of the
immune system, such as the white blood cells involved in immune responses (T and B lymphocytes and scavenger cells) and the
complement proteins, for a number of reasons. Some deficiencies are hereditary and result from genetic mutations that are passed
from parent to child. Others are caused by developmental defects that occur in the womb. In some cases immune deficiencies result
from damage inflicted by infectious agents. In others drugs used to treat certain conditions, or even the diseases themselves, can
depress the immune system. Poor nutrition also can undermine the immune system. Limited contact with natural environmental
factors, particularly with microorganisms found in biodiverse settings, also has been associated with increased risk of allergies,
autoimmune disorders, and chronic inflammatory diseases.

Hereditary and congenital deficiencies

Immune deficiencies resulting from hereditary and congenital defects are rare, but they can affect all major aspects of the immune
system. Luckily many of those conditions can be treated. In the rare hereditary disorder called X-linked infantile
agammaglobulinemia, which affects only males, B lymphocytes are unable to secrete all classes of immunoglobulins. (An
immunoglobulin is a type of protein, also called an antibody, that is produced by B cells in response to the presence of a foreign
substance called an antigen.) The disease can be treated by periodic injections of large amounts of immunoglobulin G (IgG). The
congenital, but not hereditary, T-cell deficiency disease called DiGeorge syndrome arises from a developmental defect occurring in
the fetus that results in the defective development of the thymus. Consequently the infant has either no mature T cells or very few.
In the most severe cases—i.e., when no thymus has developed—treatment of DiGeorge syndrome consists of transplantation of a
fetal thymus into the infant. The group of disorders called severe combined immunodeficiency diseases result from a failure of
precursor cells to differentiate into T or B cells. Bone marrow transplantation can successfully treat some of those diseases. The
immune disorder called chronic granulomatous disease results from an inherited defect that prevents phagocytic cells from
producing enzymes needed to break down ingested pathogens. Treatments include administration of a wide spectrum of
antibiotics.

Deficiencies caused by infection

Damage to lymphocytes that is inflicted by viruses is common but usually transient. During infectious mononucleosis, for example,
the Epstein-Barr virus infects B cells, causing them to express viral antigens. T cells that react against these antigens then attack the
B cells, and a temporary deficiency in the production of new antibodies lasts until the overt viral infection has been overcome.
Because antibodies already present in the blood are slowly broken down, failure to make new ones is important only if the
infection persists for a long time, as it does occasionally. A much more serious viral infection is that caused by the human
immunodeficiency virus (HIV), which is responsible for the fatal immune deficiency disease AIDS. HIV selectively infects helper T
cells and prevents them from producing cytokines and from functioning in cell-mediated immunity. Persons with AIDS may be
unable to overcome infections by a variety of microbes that are easily disposed of by persons uninfected with HIV. Severe
infections by certain parasites, such as trypanosomes, also cause immune deficiency, as do some forms of cancer, but it is uncertain
how that comes about. For example, Hodgkin disease, which attacks the lymphatic system, makes the patient more susceptible to
infection.

Deficiencies caused by drug therapy

In countries with advanced medical services, immune deficiency often results from the use of powerful drugs to treat cancers. The
drugs work by inhibiting the multiplication of rapidly dividing cells. Although the drugs act selectively on cancer cells, they also
can interfere with the generation and multiplication of cells involved in immune responses. Prolonged or intensive treatment with
such drugs impairs immune responses to some degree. Although the immune impairment is reversible, the physician must seek a
balance between intentional damage to the cancer cells and unintentional damage to the immune system.

Medically induced suppression of the immune system also occurs when powerful drugs, which are designed to interfere with the
development of T and B cells, are used to prevent the rejection of organ or bone marrow transplants or to damp down serious
autoimmune responses. Although use of such drugs has greatly improved the success of transplants, it also leaves patients highly
susceptible to microbial infections. Fortunately, most of those infections can be treated with antibiotics, but the immunosuppressive
drugs have to be used with great care and for as short a period as possible.

Deficiencies caused by malnutrition

In countries where the diet, especially that of growing children, is grossly deficient in protein, severe malnutrition ranks as an
important cause of immune deficiency. Antibody responses and cell-mediated immunity are seriously impaired, probably because
of atrophy of the thymus and the consequent deficiency of helper T cells. The impairment renders children particularly susceptible
to measles and diarrheal diseases. Fortunately, the thymus and the rest of the immune system can recover completely if adequate
nutrition is restored.

Deficiencies associated with limited environmental exposure

The failure of regulatory T cells as a result of reduced exposure to microorganisms in the natural environment during early
childhood has been associated with the development of certain allergic conditions, autoimmune disorders (e.g., type I diabetes and
multiple sclerosis), and inflammatory bowel diseases. While the mechanism underlying T cell failure in this context remains
unclear, it is known that normally harmless microorganisms that coevolved with humans can help prevent the body from
generating inappropriate immune responses. This idea was first proposed in the late 1980s by American immunologist David P.
Strachan in his hygiene hypothesis. The hypothesis suggested that small family size and increased personal hygiene reduced
childhood exposure to infections and thereby resulted in the development of allergic disorders. Building on the hygiene
hypothesis, scientists later proposed that the continued increase in the prevalence of allergic disorders and chronic inflammatory
diseases in urban populations in the 21st century was linked to diminished contact with biodiverse environments and the
microorganisms they contain.

Autoimmune Disorders

The mechanism by which the enormous diversity of B and T cells is generated is a random process that inevitably gives rise to
some receptors that recognize the body’s own constituents as foreign. Lymphocytes bearing such self-reactive receptors, however,
are eliminated or rendered impotent by several different mechanisms, so that the immune system does not normally generate
significant amounts of antibodies or T cells that are reactive with the body’s components (self antigens). Nevertheless, an immune
response to self, called autoimmunity, can occur, and some of the ways that self-directed immune responses cause damage have
been mentioned in the section Allergies.Understanding and identifying autoimmune disorders is difficult given that all humans
have many self-reactive antibodies in the blood but most show no sign of disease. Consequently the identification of autoantibodies
is not a sufficient diagnostic tool for determining the presence of an autoimmune disorder. There is a difference between an
autoimmune response and disease: in the former case the autoantibodies do not cause dysfunction, but in the latter case they do.

Basic processes underlying autoimmunity

Immunologists cannot always explain why the mechanisms that normally prevent the development of autoimmunity have failed in
a particular autoimmune disorder. They have, however, advanced a number of explanations for such failures.

Alteration of self antigens

Various mechanisms can alter self components so that they seem foreign to the immune system. New antigenic determinants can
be attached to self proteins, or the shape of a self antigen can shift—for a variety of reasons—so that previously unresponsive
helper T cells are stimulated and can cooperate with preexisting B cells to secrete autoantibodies. Alteration of the shape of a self
protein has been shown to occur in experimental animals and is the most probable explanation for the production of the
rheumatoid factors that are characteristic of rheumatoid arthritis. Infectious organisms also can alter self antigens, which may
explain why viral infection of specialized cells—such as those in the pancreas that secrete insulin or those in the thyroid gland that
make thyroid hormones—often precedes the development of autoantibodies against the cells themselves and against their
hormonal products.

Release of sequestered self antigens

Intracellular antigens and antigens found on tissues that are not in contact with the circulation normally are segregated effectively
from the immune system. Thus, they may be regarded as foreign if they are released into the circulation as a result of tissue
destruction caused by trauma or infection. After sudden damage to the heart, for example, antibodies against heart muscle
membranes regularly appear in the blood.

Cross-reaction with foreign antigens

This mechanism comes into play when an infectious agent produces antigens so similar to those on normal tissue cells that the
antibodies stimulated to react against the foreign antigen also recognize the similar self antigen; hence, the two antigens are said to
be cross-reactive. Autoantibodies stimulated by external antigens in this way can cause serious damage. For example, the
streptococci that cause rheumatic fever make antigens that are cross-reactive with those on heart muscle membranes, and the
antibodies that react with the bacteria also bind to the heart muscle membrane and cause damage to the heart. Another instance of
an autoimmune disorder that arises from cross-reactivity is Chagas disease. The trypanosomes that cause the disease make
antigens that are cross-reactive with antigens on the surface of the specialized nerve cells that regulate the orderly contraction of
muscles in the bowel. Antibodies directed against the trypanosomes also interact with these nerve cells and disrupt normal bowel
functioning.

Genetic factors

Several autoimmune diseases clearly run in families. Careful studies (for example, those comparing the incidence in identical twins
with that in fraternal twins) have shown that the increased incidence of such autoimmune diseases cannot be explained by
environmental factors. Rather, it stems from a genetic defect that is passed from one generation to the next. Such disorders include
Graves disease, Hashimoto disease, autoimmune gastritis (including pernicious anemia), type I (insulin-dependent) diabetes
mellitus, and Addison disease. These diseases are more common in persons who bear particular MHC antigens on their cells. The
possession of these antigens does not imply that a person will contract such diseases, only that he or she is more likely to do so.
Researchers generally agree that the interaction of many genes is needed before a person develops such autoimmune diseases. For
example, type I diabetes is believed to result from at least 14 genes.Another interesting feature that appears to relate to the
inheritance of autoimmune disorders is gender. Most human autoimmune diseases afflict far more women than men. Women are
affected more often than men with most of the better-known disorders, including myasthenia gravis, systemic lupus erythematosis,
Graves disease, rheumatoid arthritis, and Hashimoto disease. The reason for this is not fully understood, but researchers think it
probably is related to hormonal effects on immune responses.

Examples of autoimmune disorders

The spectrum of autoimmune disorders is wide, ranging from those that involve a single organ to others that affect several
different organs as a secondary consequence of the presence of immune complexes in the circulation. It is not possible in this article
to discuss them all. The following disorders have been chosen to illustrate some of the very different complications that can arise
from autoimmunity.

Autoimmune diseases of the thyroid gland

Hashimoto disease and Graves disease are two of the most common autoimmune disorders of the thyroid gland, the hormone-
secreting organ (located in the throat near the larynx) that plays an important role in the development and maturation of all
vertebrates. The thyroid is composed of closed sacs (follicles) lined with specialized thyroid cells. These cells secrete thyroglobulin,
a large protein that acts as a storage molecule from which thyroid hormones are made and released into the blood. The rate at
which this occurs is regulated by thyroid-stimulating hormone (TSH), which activates the thyroid cells by combining with TSH
receptors found on the thyroid cell membrane. Hashimoto disease involves swelling of the gland (a condition called goiter) and a
loss of thyroid hormone production (hypothyroidism). The autoimmune process underlying this disorder is thought to be
instigated by helper T cells that react with thyroid antigens, although the mechanism is not completely understood. Once activated,
the self-reactive T cells stimulate B cells to secrete antibodies against several target antigens, including thyroglobulin.Graves
disease is a type of overactive thyroid disease (hyperthyroidism) involving excess production and secretion of thyroid hormones.
The disease arises with the development of antibodies that are directed against the TSH receptor on the thyroid cells and that can
mimic the action of TSH. When bound to the receptor, the antibodies stimulate excessive secretion of thyroid hormones.In both
Hashimoto disease and Graves disease, the thyroid gland becomes infiltrated with lymphocytes and is partially destroyed. If the
gland is completely destroyed, a condition called myxedema may ensue, involving a swelling of tissues, especially those around
the face.

Autoimmune hemolytic anemia

A number of autoimmune disorders are grouped under the rubric autoimmune hemolytic anemia. All result from the formation of
autoantibodies against red blood cells, an event that can lead to hemolysis (destruction of red blood cells). The autoantibodies
sometimes appear after infection with the bacterium Mycoplasma pneumoniae, a rather uncommon cause of pneumonia. In that
case the autoantibodies are directed against certain antigens that are present on red cells, and they are probably induced by a
similar antigen in the microbes (an example of the cross-reaction of antigens). Autoantibodies directed against a different antigen of
red blood cells are often produced in persons who have been taking the antihypertensive medication alpha methyldopa for several
months; the reason for autoantibody development in such cases is unknown. Other drugs, such as quinine, sulfonamides, or even
penicillin, very occasionally cause hemolytic anemia. In such cases it is thought that the drug acts as a hapten—that is, it becomes
bound to a protein on the surface of red blood cells, and the complex becomes immunogenic.

The autoantibodies that form against red blood cells are categorized into two groups on the basis of their physical properties.
Autoantibodies that bind optimally to red blood cells at 37 °C (98.6 °F) are categorized as warm-reacting. Warm-reacting
autoantibodies belong primarily to the IgG class and cause about 80 percent of all cases of autoimmune hemolytic anemia.
Autoantibodies that attach to red blood cells only when the temperature is below 37 °C are called cold-reacting. They belong
primarily to the IgM class. Cold-reacting autoantibodies are efficient at activating the complement system and causing the cell to
which they are bound to be destroyed. Nevertheless, as long as the body temperature remains at 37 °C, cold-reacting
autoantibodies dissociate from the cell, and hemolysis is not severe. However, when limbs and skin are exposed to the cold for
long periods of time, the temperature of circulating blood can be lowered, allowing cold-reacting autoantibodies to go to work.
Infection with M. pneumoniae is met by cold-reacting antibodies.

Pernicious anemia and autoimmune gastritis

Pernicious anemia stems from a failure to absorb vitamin B12 (cobalamin), which is necessary for the proper maturation of red
blood cells. It is characteristically accompanied by a failure to secrete hydrochloric acid in the stomach (achlorhydria) and is in fact
a symptom of severe autoimmune gastritis. To be absorbed by the small intestine, dietary vitamin B12 must form a complex with
intrinsic factor, a protein secreted by the parietal cells in the stomach lining. Pernicious anemia results when autoantibodies against
intrinsic factor bind to it, preventing it from binding to vitamin B12 and thus preventing the vitamin from being absorbed into the
body. The autoantibodies also destroy the acid-secreting parietal cells, which leads to autoimmune gastritis.

Rheumatoid arthritis
Rheumatoid arthritis is a chronic inflammatory disease that affects connective tissues throughout the body, particularly the
synovial membranes that line the peripheral joints. Rheumatoid arthritis is one of the most common autoimmune diseases. Its
cause is not known, but a variety of altered immune mechanisms probably contribute to the disorder, especially in more severe
cases.

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One theory suggests that the inflammatory process of the disease is initiated by autoimmune reactions that involve one or more
autoantibodies, referred to collectively as rheumatoid factor. The autoantibodies react with the tail region of the Y-shaped IgG
molecule—in other words, rheumatoid factor is anti-IgG antibodies. Immune complexes form between rheumatoid factor and IgG
and apparently are deposited in the synovial membrane of joints. The deposition triggers a type III hypersensitivity reaction,
activating complement and attracting granulocytes, which causes inflammation and pain in the joints. The granulocytes release
enzymes that break down cartilage and collagen in the joints, and this eventually can destroy the smooth joint surface that is
needed for ease of movement. If immune complexes in the blood are not effectively removed by the liver and spleen, they can
produce systemic effects similar to those precipitated by serum sickness.The devastating effects of rheumatoid arthritis also have
been seen in patients, especially younger ones, in whom no rheumatoid factor is detected, and thus other mechanisms of initiation
of the disorder probably exist.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a syndrome characterized by organ damage that results from the deposition of immune
complexes. The immune complexes form when autoantibodies are made against the nucleic acids and protein constituents of the
nucleus of cells. Such autoantibodies, called antinuclear antibodies, do not attack healthy cells, since the nucleus lies within the cell
and is not accessible to antibodies. Antigen-antibody complexes form only after the nuclear contents of a cell are released into the
bloodstream during the normal course of cell death or as a result of inflammation. The resultant immune complexes are deposited
in tissues, causing injury. Certain organs are more commonly involved than others, including the kidneys, joints, skin, heart, and
serous membranes around the lungs.

Multiple sclerosis

Multiple sclerosis is an autoimmune disease that results in the gradual destruction of the myelin sheath that surrounds nerve
fibres. It is characterized by progressive degeneration of nerve function, interjected with periods of apparent remission. The
cerebrospinal fluid of persons with multiple sclerosis contains large numbers of antibodies directed against myelin basic protein
and perhaps other brain proteins. Infiltrating lymphocytes and macrophages may exacerbate the destructive response. The reason
the immune system launches an attack against myelin is unknown, but several viruses have been suggested as initiators of the
response. A genetic tendency toward the disease has been noted; susceptibility to the disorder is indicated by the presence of the
major histocompatibility complex (MHC) genes, which produce proteins found on the surface of B cells and some T cells.

Type I (insulin-dependent) diabetes mellitus

Type I diabetes mellitus is the autoimmune form of diabetes and often arises in childhood. It is caused by the destruction of cells of
the pancreatic tissue called the islets of Langerhans. Those cells normally produce insulin, the hormone that helps regulate glucose
levels in the blood. Individuals with type I diabetes have high blood glucose levels that result from a lack of insulin. Dysfunction of
islet cells is caused by the production of cytotoxic T cells or autoantibodies that have formed against them. Although the initiating
cause of this autoimmune response is unknown, there is a genetic tendency toward the disease, which also involves class II MHC
genes. It can be treated with injections of insulin; however, even when treated, type I diabetes may eventually lead to kidney
failure, blindness, or serious circulation difficulties within the extremities.

Other autoimmune disorders

Mechanisms similar to those that produce autoimmune hemolytic anemia can result in the formation of antibodies against
granulocytes and platelets, although autoimmune attacks against these blood cells occur less frequently. Antibodies against other
types of cells occur in a number of autoimmune diseases, and those self-reactive responses may be primarily responsible for the
damage incurred. In myasthenia gravis, a disease characterized by muscle weakness, autoantibodies react against receptors on
muscle cells. Normally the receptors bind to acetylcholine, a neurotransmitter released from nerve endings. When acetylcholine
binds to an acetylcholine receptor on the surface of muscle cells, it stimulates the muscle to contract. The autoantibodies in
myasthenia gravis bind to the acetylcholine receptors without activating them. The antibodies prevent muscle contraction either by
blocking acetylcholine from binding to its receptor or by destroying the receptors outright. This renders the muscle less responsive
to acetylcholine and ultimately weakens muscle contraction.A different example is provided by Goodpasture syndrome, a disorder
in which autoantibodies form against the basement membrane of the blood vessels in the kidney glomeruli and in the air sacs of
the lung. The autoantibodies cause severe kidney damage and lung hemorrhage.

Cancers Of The Lymphocytes

Tumours arising from lymphocytes are given various names: they are called leukemias if the cancer cells are present in large
numbers in the blood, lymphomas if they are mainly concentrated in lymphoid tissues, and myelomas if they are B-cell tumours
that secrete large amounts of immunoglobulin. The following sections describe how cancers of the lymphocytes arise and how
immunological techniques are being used to determine the prognosis and treatment of B- and T-cell tumours.
Genetic causes of cancer

Most cancers result from a series of random genetic accidents, or mutations, that occur to genes involved in controlling cell growth.
One general group of genes implicated in cancer initiation and growth are called oncogenes. The unaltered, healthy form of an
oncogene is called a proto-oncogene. Proto-oncogenes stimulate cell growth in a controlled manner that involves the interplay of a
number of other genes. However, should a proto-oncogene become mutated in some way, it may become hyperactive, leading to
uncontrolled cellular proliferation and the exaggeration of some normal cellular activities. A proto-oncogene can become mutated
in a number of ways. According to one mechanism, called chromosomal translocation, part of one chromosome is severed from its
normal position and reattached (translocated) onto another chromosome. If a proto-oncogene appears on the piece of the
chromosome that is moved, it may be separated from the region that normally regulates it. In this manner the proto-oncogene
becomes unregulated and turns into an oncogene. Chromosomal translocation of proto-oncogenes is involved in a number of B-cell
tumours, including Burkitt lymphoma and chronic myelogenous leukemia. T-cell leukemia also results from a chromosomal
translocation.

Malignant transformation of lymphocytes

At any stage in its development, from stem cell to mature form, a lymphocyte may undergo malignant (cancerous) transformation.
The transformed cell is no longer constrained by the processes that regulate normal development, and it proliferates to produce a
large number of identical cells that make up the tumour. These cells retain the characteristics of the transformed cell’s particular
developmental stage, and because of this cancers can be distinguished according to the stage at which transformation took place.
For example, B cells that become cancerous in the early stages of development give rise to such conditions as chronic myelogenous
leukemia and acute lymphocytic leukemia, whereas malignant transformation of late-stage B cells—i.e., plasma cells—can result in
multiple myeloma. Regardless of what stage of the cell becomes cancerous, malignant cells outgrow and displace other cells that
continue to develop normally.

Treatment of cancers through identification of antigens

Both T and B cells have surface antigens that are characteristic of different stages in their life cycle, and antibodies have been
prepared that identify the antigens. Knowledge of the specific type and stage of maturation of the tumour cells helps physicians
determine the prognosis and course of treatment for the patient. This is important because different types of tumours respond to
different therapies and because the chances of effecting a cure vary from type to type. Advances made in drug treatments have
dramatically improved the outlook for children with acute lymphoblastic leukemia, the most prevalent of the childhood leukemias.
Similarly, most cases of Hodgkin disease, a common type of lymphoma that mainly strikes adults, can be cured by drugs,
radiation, or a combination of both. Myelomas primarily arise in older individuals. These tumours grow fairly slowly and are
usually diagnosed by virtue of the characteristic immunoglobulin they secrete, which may be produced in such large amounts that
they cause secondary damage such as kidney failure.

Disease introduction-
Disease, any harmful deviation from the normal structural or functional state of an organism, generally associated with certain
signs and symptoms and differing in nature from physical injury. A diseased organism commonly exhibits signs or symptoms
indicative of its abnormal state. Thus, the normal condition of an organism must be understood in order to recognize the
hallmarks of disease. Nevertheless, a sharp demarcation between disease and health is not always apparent.The study of
disease is called pathology. It involves the determination of the cause (etiology) of the disease, the understanding of the
mechanisms of its development (pathogenesis), the structural changes associated with the disease process (morphological
changes), and the functional consequences of those changes. Correctly identifying the cause of a disease is necessary to
identifying the proper course of treatment.Humans, other animals, and plants are all susceptible to diseases of some sort.
However, that which disrupts the normal functioning of one type of organism may have no effect on the other types.

Major Distinctions
The normal state of an organism represents a condition of delicate physiological balance, or homeostasis, in terms of chemical,
physical, and functional processes, maintained by a complex of mechanisms that are not fully understood. In a fundamental
sense, therefore, disease represents the consequences of a breakdown of the homeostatic control mechanisms. In some
instances the affected mechanisms are clearly indicated, but in most cases a complex of mechanisms is disturbed, initially or
sequentially, and precise definition of the pathogenesis of the ensuing disease is elusive. Death in humans and other mammals,
for example, often results directly from heart or lung failure, but the preceding sequence of events may be highly complex,
involving disturbances of other organ systems and derangement of other control mechanisms.The initial cause of the diseased
state may lie within the individual organism itself, and the disease is then said to be idiopathic, innate, primary, or “essential.” It
may result from a course of medical treatment, either as an unavoidable side effect or because the treatment itself was ill-
advised; in either case the disease is classed as iatrogenic. Finally, the disease may be caused by some agent external to the
organism, such as a chemical that is a toxic agent. In this case the disease is noncommunicable; that is, it affects only the
individual organism exposed to it. The external agent may be itself a living organism capable of multiplying within the host and
subsequently infecting other organisms; in this case the disease is said to be communicable.
Noncommunicable disease
Noncommunicable diseases generally are long-lasting and progress slowly, and thus they are sometimes also referred to as
chronic diseases. They can arise from environmental exposures or from genetically determined abnormalities, which may be
evident at birth or which may become apparent later in life. The World Health Organization (WHO) has identified four major
types of noncommunicable disease: cancer, cardiovascular disease (e.g., heart attack, stroke), chronic respiratory disease (e.g.,
asthma), and diabetes mellitus. WHO estimates that, combined, these four groups of conditions account for 82 percent of all
deaths from noncommunicable disease.Noncommunicable diseases that arise from inherited genetic abnormalities often leave
an individual ill-equipped to survive without some form of treatment. Examples of inherited disease include cystic fibrosis, Down
syndrome, and inborn errors of metabolism, which are present at birth. Examples of inherited diseases that emerge in
adulthood include Huntington disease and certain forms of cancer (e.g., familial breast cancer involving inherited mutations in
either of the genes BRCA1 or BRCA2).

Metabolic defects
Metabolic defects offer useful insight into understanding the impact of noncommunicable disease on the function of the human
body. In humans, for example, the lack of an enzyme known as phenylalanine hydroxylase, which is necessary for the
metabolism of the common amino acid phenylalanine, leads to the disease phenylketonuria (PKU), which appears at a few
weeks of age and, if not treated, is often associated with the onset of intellectual disability. Other metabolic defects may make
their appearance only relatively late in life. Examples of this situation are the diseases gout and type 2 (late-onset, or adult-type)
diabetes. Gout results from an accumulation within the tissues of uric acid, an end product of nucleic acid metabolism. Late-
onset diabetes results from an impaired release of insulin by the pancreas and a reduction in responsiveness of body tissues to
insulin that lead to the inability to metabolize sugars and fats properly.Alternatively, the metabolic fault may be associated with
aging and the concomitant deterioration of control mechanisms, as in the loss of calcium from bone in the condition known as
osteoporosis. That these late-developing metabolic diseases also have a genetic basis—that is, that there is an inherited
tendency for the development of the metabolic faults involved—seems to be definitely the case in some instances but remains
either incompletely understood or uncertain in others.

Environmental hazards
Metabolic abnormalities also may result from the effects of external environmental factors, a relationship that has been
suggested by the apparent confinement of certain diseases to sharply delimited geographic areas. Notable examples are goitre
and mottled enamel of the teeth in humans. The development of goitre is attributable to iodine deficiency in the diet, which
leads to compensatory growth of the thyroid gland in a vain effort to overcome the deficiency. The disease tends to occur in
inland areas where seafood consumption is minimal and dietary supplementation of iodine—through such items as table salt—
does not occur. Mottled enamel of teeth results from consumption of excessive amounts of fluoride, usually in water supplies.
Conversely, dental caries (tooth decay) is found to occur to a greater extent in areas in which water supplies are deficient in
fluoride. Analogous conditions in herbivorous domesticated animals result from deficiencies in trace elements, such as zinc and
selenium, in the soil of pastures and, therefore, also in plants making up the diet. Similarly, plant growth suffers from soil
deficiencies of essential elements, particularly nitrogen, potassium, and phosphorus. These conditions can be corrected by
adding salts to the diets of domesticated animals and by applying fertilizers to soil.There also are diseases resulting from toxic
substances added to the environment in sufficient amounts to produce symptoms of greater or lesser severity. Although human
disorders of this nature are best known, untoward effects of such contamination of the environment occur also in plants and
animals. The problems caused by environmental toxic agents are largely, if not entirely, anthropogenic. Occupational diseases,
for example, are associated with factors that are present in the work environment or are otherwise encountered in the course of
work. Examples of occupational diseases include asbestosis, silicosis, and byssinosis, which affect the respiratory tract and which
are caused by inhalation of, respectively, asbestos, silica, and cotton dust. Also important in this regard are metal poisoning,
particularly involving mercury, lead, or arsenic; poisoning with solvents used in industrial processes; and exposure to ionizing
radiation. Of greater importance to the population at large are the diseases that result from exposure to insecticides and
atmospheric pollutants. Such diseases usually, though not invariably, are of a chronic nature; they require prolonged exposure
to the noxious agent and develop slowly. Environmental diseases of all kinds, however, also may predispose the individual to
other diseases; for example, respiratory diseases such as silicosis render the sufferer more susceptible to tuberculosis.

Communicable disease
Communicable, or contagious, diseases are those transmitted from one organism to another. Infectious diseases are diseases
caused in the host by infection with living, and therefore replicating, microorganisms, such as animal parasites, bacteria, fungi,
or viruses. Practically, these two classes of disease are the same, because infectious diseases generally are communicable, or
transmissible, from one host to another, and the causative agent, therefore, is disseminated, directly or indirectly, through the
host population. Such spread is an ecological phenomenon, the host serving as the environment in which the parasite lives;
complexity arises when the parasite occurs in more than one host species. Infectious diseases are a leading cause of death in
children and young adults worldwide. Lower respiratory infections, diarrheal diseases, and tuberculosis are among the most
common and deadliest types of infectious diseases. Since the latter part of the 20th century, however, death rates from
infectious disease have dropped considerably, because of increases in vaccination and other methods of disease prevention and
because of improvements in treatment and in the control of disease spread. Notable progress included the near elimination of
polio from the world by the early 2000s and substantial declines in AIDS-related deaths by 2015. As a result, by the second
decade of the 21st century, many infectious diseases, particularly those of childhood, were being replaced by noncommunicable
diseases of adulthood.

Host-parasite relationships
In the context of communicable disease, the host-parasite relationship must be considered not only with respect to the
individual host-parasite interaction but also in terms of the interrelationship between the host and parasite populations, as well
as those of any other host species involved. Most pathogenic bacteria are obligate parasites; that is, they are found only in
association with their hosts. Some, such as staphylococci and streptococci, can proliferate outside the body of the host in
nutritive materials infected from host sources. Within the tissues of the host, these organisms set up local infections that spread
throughout the body. Still other bacteria, such as the glanders bacillus (Burkholderia mallei) and the gonococci, meningococci,
and pneumococci, are more closely adapted parasites, capable of multiplying outside the body of the host only under the
artificial conditions of the laboratory. All these microorganisms have complete cell structures and metabolic capabilities. A
greater degree of dependence on the host is shown by rickettsiae and viruses. Rickettsiae are microorganisms that have the cell
structure of bacteria. They exhibit a small degree of metabolic activity outside cells, but they cannot grow in the absence of host
tissue. The ultimate in parasitism, however, is that of the viruses, which have no conventional cell structure and consist only of a
nucleic acid (either DNA or RNA) wrapped in a protective protein coat. Viruses are obligatory intracellular parasites, capable of
multiplying only within the cells of the host, and they have no independent metabolic activity of their own. The genetic
information that directs the synthesis of virus materials and certain enzymes enters the host cell, parasitizes its chemical
processes, and directs them toward the synthesis of new virus elements. These various degrees of parasitism suggest that the
host-parasite relationship is subject to continuing evolutionary change. The adaptation of the microorganism to its parasitic
existence, in this view, is accompanied by progressive loss in metabolic capability, with eventual complete physiological
dependence of the parasite on the host.

Parasite specificity
The condition of obligate parasitism is associated with a degree of specificity of the parasite with regard to the host; i.e., the
parasite generally is more closely adapted to one species of host than to all others. Microorganisms adapted to plant hosts, with
only rare exception, are unable to infect animal hosts, and conversely microorganism parasites of animals rarely occur in plants.
A number of host species may be susceptible to infection with a given parasite, and the pattern of host susceptibility need not
correspond with taxonomic relationships, including hosts varying as widely as vertebrates and invertebrates. The ability to
produce consistently fatal disease in a host is often of negative survival value to the parasite, because it is quite likely to
eliminate quickly all available hosts. Consistent with this, there is a tendency for disease resulting from infection to be less
severe when adaptation of the parasite to the host has become close. A change in severity of a disease, presumably resulting
from adaptation, has been observed in the case of the spirochete that causes syphilis, with the disease in humans being less
severe today than it was in the 16th century. However, ecological studies of parasitism indicate that it is incorrect to assume
that all host-parasite relationships will evolve toward reduced antagonism and that a resultant disease state eventually will be
ameliorated. (For further information see community ecology.) Disease produced in related host species may be either
milder or more severe than in the definitive host. In certain cases, adaptation is so close that the parasite is unable to infect any
other hosts under natural conditions; this is true of many microorganisms producing disease in humans. On the other hand,
natural infection of secondary hosts may occur, leading to severe or fatal disease. Rabies, for example, is a fatal disease in
almost all animal hosts. In some species, such as the bat, however, the virus may persist for long periods as an asymptomatic
infection.

Host resistance
The specificity of pathogenic microorganisms with regard to their hosts is an expression not only of differences in microbial
character but also of differing host resistance. The ability of a microorganism to produce disease can be evaluated only in terms
of the host reaction, and, conversely, the resistance, or immunity, of the host can be judged only with regard to its effect on the
microorganism. In short, the two are but different facets of the same phenomenon, and either may be evaluated by holding the
other constant and varying it.

Inheritance of resistance
That there exists genetic control of resistance is suggested by the mere fact of host specificity, and such control has been
demonstrated amply by experimental studies on both plant and animal hosts. The former, for example, had wide practical
application in the development, by selective breeding, of strains and races of plants of economic importance, especially grains,
that are resistant to a wide variety of plant diseases.

In general, resistance developed by selective breeding is only partially specific; that is, the observed resistance to infection with
pathogenic microorganisms, and to the toxins of such organisms, is manifested toward groups of related microorganisms
producing similar diseases, not to single organisms alone. Although resistance to disease has been found in a few instances to be
a function of a single gene, in most cases several genes are involved.

Epidemiology
The interaction of host and parasite populations constitutes the subject matter of epidemiology (the term being more inclusive
than suggested by its relation to the word epidemic). In most instances the epidemiology of infectious disease is characteristic of
that disease and is an outgrowth of biological properties of the parasite and the host, including host specificity and the
behaviour of the host species as populations.Aside from the saprophytic microorganisms that occasionally produce disease,
most pathogenic microorganisms are adapted sufficiently closely to their hosts that they cannot compete successfully in the
physical, chemical, and biological environment outside the host tissues. Exceptions to this generalization occur in the cases of
microorganisms with life histories that include a resistant spore stage. This occurs with various fungi responsible for plant
disease, as well as certain parasites of animals. Among the latter are species of the fungus Coccidioides, which infect both
rodents and humans (producing desert fever in the latter), and the anthrax bacillus, which causes disease in cattle, sheep, and
other domesticated animals and occasionally infects humans as well. A disease of animals that can be transmitted to humans is
called a zoonosis.Survival of the parasite ordinarily requires that it be transmitted more or less directly from an infected host
organism to a susceptible one. The precise route of infection often is of primary importance, with some microorganisms
requiring direct access to internal tissue, some being able to initiate infection on mucous membranes of the nose and throat,
and others able to establish primary infections in the intestinal tract. These particular modes of infection generally occur by way
of, respectively, biting insects, coughing and sneezing, and contamination of food and water.

Genetic Disease
Human genetic disease, any of the diseases and disorders that are caused by mutations in one or more genes.
With the increasing ability to control infectious and nutritional diseases in developed countries, there has come the
realization that genetic diseases are a major cause of disability, death, and human tragedy. Rare, indeed, is
the family that is entirely free of any known genetic disorder. Many thousands of different genetic disorders with
defined clinical symptoms have been identified. Of the 3 to 6 percent of newborns with a recognized birth defect, at
least half involve a predominantly genetic contribution. Furthermore, genetic defects are the major known cause of
pregnancy loss in developed nations, and almost half of all spontaneous abortions (miscarriages) involve a
chromosomally abnormal fetus. About 30 percent of all postnatal infant mortality in developed countries is due to
genetic disease; 30 percent of pediatric and 10 percent of adult hospital admissions can be traced to a predominantly
genetic cause. Finally, medical investigators estimate that genetic defects—however minor—are present in at least 10
percent of all adults. Thus, these are not rare events.
A congenital defect is any biochemical, functional, or structural abnormality that originates prior to or shortly after
birth. It must be emphasized that birth defects do not all have the same basis, and it is even possible for apparently
identical defects in different individuals to reflect different underlying causes. Though the genetic and biochemical
bases for most recognized defects are still uncertain, it is evident that many of these disorders result from a
combination of genetic and environmental factors.This article surveys the main categories of genetic disease, focusing
on the types of genetic mutations that give rise to them, the risks associated with exposure to certain environmental
agents, and the course of managing genetic disease through counseling, diagnosis, and treatment. For full explanation
of Mendelian and non-Mendelian genetics, genetic mutation and regulation, and other principles underlying genetic
disease, see the article heredity. The genetics of tumour development, briefly explained in this article, are covered at
length in the article cancer.

Classes Of Genetic Disease

Most human genetic defects can be categorized as resulting from either chromosomal, single-gene Mendelian, single-
gene non-Mendelian, or multifactorial causes. Each of these categories is discussed briefly below.

Diseases caused by chromosomal aberrations-About 1 out of 150 live newborns has a detectable chromosomal
abnormality. Yet even this high incidence represents only a small fraction of chromosome mutations since the vast
majority are lethal and result in prenatal death or stillbirth. Indeed, 50 percent of all first-trimester miscarriages and 20
percent of all second-trimester miscarriages are estimated to involve a chromosomally abnormal fetus.Chromosome
disorders can be grouped into three principal categories: (1) those that involve numerical abnormalities of
the autosomes, (2) those that involve structural abnormalities of the autosomes, and (3) those that involve the  sex
chromosomes. Autosomes are the 22 sets of chromosomes found in all normal human cells. They are referred to
numerically (e.g., chromosome 1, chromosome 2) according to a traditional sort order based on size, shape, and other
properties. Sex chromosomes make up the 23rd pair of chromosomes in all normal human cells and come in two
forms, termed X and Y. In humans and many other animals, it is the constitution of sex chromosomes that determines
the sex of the individual, such that XX results in a female and XY results in a male

Numerical abnormalities-Numerical abnormalities, involving either the autosomes or sex chromosomes, are
believed generally to result from meiotic nondisjunction—that is, the unequal division of chromosomes between
daughter cells—that can occur during either maternal or paternal gamete formation. Meiotic nondisjunction leads to
eggs or sperm with additional or missing chromosomes. Although the biochemical basis of numerical chromosome
abnormalities remains unknown, maternal age clearly has an effect, such that older women are at significantly
increased risk to conceive and give birth to a chromosomally abnormal child. The risk increases with age in an almost
exponential manner, especially after age 35, so that a pregnant woman age 45 or older has between a 1 in 20 and 1 in
50 chance that her child will have trisomy 21 (Down syndrome), while the risk is only 1 in 400 for a 35-year-old
woman and less than 1 in 1,000 for a woman under the age of 30. There is no clear effect of paternal age on numerical
chromosome abnormalities. Although Down syndrome is probably the best-known and most commonly observed of
the autosomal trisomies, being found in about 1 out of 800 live births, both trisomy 13 and trisomy 18 are also seen in
the population, albeit at greatly reduced rates (1 out of 10,000 live births and 1 out of 6,000 live births, respectively).
The vast majority of conceptions involving trisomy for any of these three autosomes are nonetheless lost to
miscarriage, as are all conceptions involving trisomy for any of the other autosomes. Similarly, monosomy for any of
the autosomes is lethal in utero and therefore is not seen in the population. Because numerical chromosomal
abnormalities generally result from independent meiotic events, parents who have one pregnancy with a numerical
chromosomal abnormality are generally not at markedly increased risk above the general population to repeat the
experience. Nonetheless, a small increased risk is generally cited for these couples to account for unusual situations,
such as chromosomal translocations or gonadal mosaicism, described below.

Structural abnormalities - Structural abnormalities of the autosomes are even more common in the population
than are numerical abnormalities and include translocations of large pieces of chromosomes, as well as smaller
deletions, insertions, or rearrangements. Indeed, about 5 percent of all cases of Down syndrome result not from classic
trisomy 21 but from the presence of excess chromosome 21 material attached to the end of another chromosome as the
result of a translocation event. If balanced, structural chromosomal abnormalities may be compatible with a normal
phenotype, although unbalanced chromosome structural abnormalities can be every bit as devastating as numerical
abnormalities. Furthermore, because many structural defects are inherited from a parent who is a balanced carrier,
couples who have one pregnancy with a structural chromosomal abnormality generally are at significantly increased
risk above the general population to repeat the experience. Clearly, the likelihood of a recurrence would depend on
whether a balanced form of the structural defect occurs in one of the parents.Even a small deletion or addition of
autosomal material—too small to be seen by normal karyotyping methods—can produce serious malformations
and mental retardation. One example is cri du chat (French: “cry of the cat”) syndrome, which is associated with the
loss of a small segment of the short arm of chromosome 5. Newborns with this disorder have a “mewing” cry like that
of a cat. Mental retardation is usually severe.

Abnormalities of the sex chromosomes

About 1 in 400 male and 1 in 650 female live births demonstrate some form of sex chromosome abnormality, although
the symptoms of these conditions are generally much less severe than are those associated with autosomal
abnormalities. Turner syndrome is a condition of females who, in the classic form, carry only a single X chromosome
(45,X). Turner syndrome is characterized by a collection of symptoms, including short stature, webbed neck, and
incomplete or absent development of secondary sex characteristics, leading to infertility. Although Turner syndrome
is seen in about 1 in 2,500 to 1 in 5,000 female live births, the 45,X karyotype accounts for 10 to 20 percent of the
chromosomal abnormalities seen in spontaneously aborted fetuses, demonstrating that almost all 45,X conceptions are
lost to miscarriage. Indeed, the majority of liveborn females with Turner syndrome are diagnosed as  mosaics,
meaning that some proportion of their cells are 45,X while the rest are either 46,XX or 46,XY. The degree of clinical
severity generally correlates inversely with the degree of mosaicism, so that females with a higher proportion of
normal cells will tend to have a milder clinical outcome.
In contrast to Turner syndrome, which results from the absence of a sex chromosome, three alternative conditions
result from the presence of an extra sex chromosome: Klinefelter syndrome, trisomy X, and 47,XYY syndrome. These
conditions, each of which occurs in about 1 in 1,000 live births, are clinically mild, perhaps reflecting the fact that the Y
chromosome carries relatively few genes, and, although the X chromosome is gene-rich, most of these genes become
transcriptionally silent in all but one X chromosome in each somatic cell (i.e., all cells except eggs and sperm) via a
process called X inactivation. The phenomenon of X inactivation prevents a female who carries two copies of the X
chromosome in every cell from expressing twice the amount of geneproducts encoded exclusively on the X
chromosome, in comparison with males, who carry a single X. In brief, at some point in early development one X
chromosome in each somatic cell of a female embryo undergoes chemical modification and is inactivated so that gene
expression no longer occurs from that template. This process is apparently random in most embryonic tissues, so that
roughly half of the cells in each somatic tissue will inactivate the maternal X while the other half will inactivate the
paternal X. Cells destined to give rise to eggs do not undergo X inactivation, and cells of the extra-embryonic tissues
preferentially inactivate the paternal X, although the rationale for this preference is unclear. The inactivated X
chromosome typically replicates later than other chromosomes, and it physically condenses to form a Barr body, a
small structure found at the rim of the nucleus in female somatic cells between divisions (see photograph). The
discovery of X inactivation is generally attributed to British geneticist Mary Lyon, and it is therefore often called
“lyonization.”
The result of X inactivation is that all normal females are mosaics with regard to this chromosome, meaning that they
are composed of some cells that express genes only from the maternal X chromosome and others that express genes
only from the paternal X chromosome. Although the process is apparently random, not every female has an exact 1:1
ratio of maternal to paternal X inactivation. Indeed, studies suggest that ratios of X inactivation can vary.
Furthermore, not all genes on the X chromosome are inactivated; a small number escape modification and remain
actively expressed from both X chromosomes in the cell. Although this class of genes has not yet been fully
characterized, aberrant expression of these genes has been raised as one possible explanation for the phenotypic
abnormalities experienced by individuals with too few or too many X chromosomes. Klinefelter
syndrome (47,XXY) occurs in males and is associated with increased stature and infertility. Gynecomastia (i.e., partial
breast development in a male) is sometimes also seen. Males with Klinefelter syndrome, like normal females,
inactivate one of their two X chromosomes in each cell, perhaps explaining, at least in part, the relatively mild clinical
outcome.

Trisomy X (47,XXX) is seen in females and is generally also considered clinically benign, although menstrual
irregularities or sterility have been noted in some cases. Females with trisomy X inactivate two of the three X
chromosomes in each of their cells, again perhaps explaining the clinically benign outcome.
47,XYY syndrome also occurs in males and is associated with tall stature but few, if any, other clinical manifestations.
There is some evidence of mild learning disability associated with each of the sex chromosome trisomies, although
there is no evidence of mental retardation in these persons.
Persons with karyotypes of 48,XXXY or 49,XXXXY have been reported but are extremely rare. These individuals show
clinical outcomes similar to those seen in males with Klinefelter syndrome but with slightly increased severity. In
these persons the “n − 1 rule” for X inactivation still holds, so that all but one of the X chromosomes present in each
somatic cell is inactivated.

Diseases associated with single-gene Mendelian inheritance-

The term Mendelian is often used to denote patterns of genetic inheritance similar to those described for traits in
the garden pea by Gregor Mendel in the 1860s. Disorders associated with single-gene Mendelian inheritance are
typically categorized as autosomal dominant, autosomal recessive, or sex-linked. Each category is described briefly in
this section. For a full explanation of Mendelian genetics and of the concepts of dominance and recessiveness,  see the
article heredity.

Autosomal dominant inheritance
A disease trait that is inherited in an autosomal dominantmanner can occur in either sex and can be transmitted by
either parent. It manifests itself in the heterozygote(designated Aa), who receives a mutant gene (designated a) from
one parent and a normal (“wild-type”) gene (designated A) from the other. In such a case the pedigree (i.e., a pictorial
representation of family history) is vertical—that is, the disease passes from one generation to the next.
The figure illustrates the pedigree for a family with achondroplasia, an autosomal dominant disorder characterized by
short-limbed dwarfismthat results from a specific mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. In
pedigrees of this sort, circles refer to females and squares to males; two symbols directly joined at the midpoint
represent a mating, and those suspended from a common overhead line represent siblings, with descending birth
order from left to right. Solid symbols represent affected individuals, and open symbols represent unaffected
individuals. The Roman numerals denote generations, whereas
the Arabic numerals identify individuals within each
generation. Each person listed in a pedigree may therefore be
specified uniquely by a combination of one Roman and
one Arabic numeral, such as II-1.

Pedigree of a family with a history of achondroplasia, an

autosomal dominantly inherited disease. The solid symbols
signify affected individuals.Encyclopædia Britannica, Inc.
 An individual who carries one copy of a dominant mutation (Aa) will produce two kinds of germ cells—eggs or
sperm—typically in equal proportions; one half will bear the mutant gene (A), and the other will bear the normal gene
(a). As a result, an affected heterozygote has a 50 percent chance of passing on the disease gene to each of his or her
children. If an individual were to carry two copies of the dominant mutant gene (inherited from both parents), he or
she would be homozygous (AA). The homozygote for a dominantly inherited abnormal gene may be equally affected
with the heterozygote. Alternatively, he or she may be much more seriously affected; indeed, the homozygous
condition may be lethal, sometimes even in utero or shortly after birth. Such is the case with achondroplasia, so that a
couple with one affected partner and one unaffected partner will typically see half of their children affected, whereas
a couple with both partners affected will see two-thirds of their surviving children affected and one-third unaffected,
because 1 out of 4 conceptions will produce a homozygous fetus who will die before or shortly after birth.Although
autosomal dominant traits are typically evident in multiple generations of a family, they can also arise from new
mutations, so that two unaffected parents, neither of whom carries the mutant gene in their somatic cells, can conceive
an affected child. Indeed, for some disorders the new mutation rate is quite high; almost 7 out of 8 children with
achondroplasia are born to two unaffected parents. Examples of autosomal dominant inheritance are common among
human traits and diseases. More than 2,000 of these traits have been clearly identified; a sampling is given in the table.

trait conspicuous signs

achondroplasia dwarfism, large head, short extremities, short fingers and toes

osteogenesis imperfecta bone fragility, deafness

Huntington disease involuntary movement, emotional disturbance, dementia

Marfan syndrome long, thin extremities and fingers; eye and cardiovascular problems

neurofibromatosis pigmented spots (café au lait) on skin, skin tumours, occasional brain or other internal tumours

Human disorders attributable to a single dominant gene

In many genetic diseases, including those that are autosomal dominant, specific mutations associated with the same
disease present in different families may be uniform, such that every affected individual carries exactly the same
molecular defect (allelic homogeneity), or they may be heterogeneous, such that tens or even hundreds of different
mutations, all affecting the same gene, may be seen in the affected population (allelic heterogeneity). In some cases
even mutations in different genes can lead to the same clinical disorder (genetic heterogeneity). Achondroplasia is
characterized by allelic homogeneity, such that essentially all affected individuals carry exactly the same mutation.
With regard to the physical manifestations (i.e., the phenotype) of some genetic disorders, a mutant gene may cause
many different symptoms and may affect many different organ systems (pleiotropy). For example, along with the
short-limbed dwarfism characteristic of achondroplasia, some individuals with this disorder also exhibit a long,
narrow trunk, a large head with frontal bossing, and hyperextensibility of most joints, especially the knees. Similarly,
for some genetic disorders, clinical severity may vary dramatically, even among affected members in the same family.
These variations of phenotypic expression are called variable expressivity, and they are undoubtedly due to the
modifying effects of other genes or environmental factors. Although for some disorders, such as achondroplasia,
essentially all individuals carrying the mutant gene exhibit the disease phenotype, for other disorders some
individuals who carry the mutant gene may express no apparent phenotypic abnormalities at all. Such unaffected
individuals are called “nonpenetrant,” although they can pass on the mutant gene to their offspring, who could be
affected.

Autosomal recessive inheritance
Nearly 2,000 traits have been related to single genes that are recessive; that is, their effects are masked by normal
(“wild-type”) dominant alleles and manifest themselves only in individuals homozygous for the mutant gene. A
partial list of recessively inherited diseases is given in the table. For example, sickle cell anemia, a severe hemoglobin
disorder, results only when a mutant gene (a) is inherited from both parents. Each of the latter is a carrier, a
heterozygote with one normal gene and one mutant gene (Aa) who is phenotypically unaffected. The chance of such a
couple producing a child with sickle cell anemia is one out of four for each pregnancy. For couples consisting of one
carrier (Aa) and one affected individual (aa), the chance of their having an affected child is one out of two for each
pregnancy.

trait conspicuous signs

albinism lack of pigment in skin, hair, and eyes, with significant visual problems

Tay-Sachs listlessness, seizures, blindness, death in early childhood

 trait conspicuous signs

disease

cystic fibrosis chronic lung and intestinal symptoms

phenylketonuria light pigmentation, mental retardation, seizures

thalassemia mild or severe anemia, enlarged spleen and liver, stunted growth, bone deformation

sickle cell anemia fatigue, shortness of breath, delayed growth, muscle and abdominal pain

Human disorders attributable to a single pair of recessive genes

Many autosomal recessive traits reflect mutations in key metabolic enzymes and result in a wide variety of disorders
classified as inborn errors of metabolism. One of the best-known examples of this class of disorders
is phenylketonuria(PKU), which results from mutations in the gene encoding the enzyme phenylalanine
hydroxylase (PAH). PAH normally catalyzes the conversion of phenylalanine, an amino acidprevalent in dietary
proteins and in the artificial sweetener aspartame, to another amino acid called tyrosine. In persons with PKU, dietary
phenylalanine either accumulates in the body or some of it is converted to phenylpyruvic acid, a substance that
normally is produced only in small quantities. Individuals with PKU tend to excrete large quantities of this acid, along
with phenylalanine, in their urine. When infants accumulate high concentrations of phenylpyruvic acid and
unconverted phenylalanine in their blood and other tissues, the consequence is mental retardation. Fortunately, with
early detection, strict dietary restriction of phenylalanine, and supplementation of tyrosine, mental retardation can be
prevented.
Since the recessive genes that cause inborn errors of metabolism are individually rare in the  gene pool, it is not often
that both parents are carriers; hence, the diseases are relatively uncommon. If the parents are related
(consanguineous), however, they will be more likely to have inherited the same mutant gene from a common
ancestor. For this reason, consanguinity is often more
common in the parents of those with rare, recessive inherited
diseases. The pedigree of a family in which PKU has
occurred is shown in the figure. This pedigree demonstrates
that the affected individuals for recessive diseases are
usually siblings in one generation—the pedigree tends to be
“horizontal,” rather than “vertical” as in dominant
inheritance.

Pedigree of a family in which the gene for phenylketonuria is

segregating. The half-solid circles and squares represent carriers of
phenylketonuria; the solid symbols signify affected individuals.Encyclopædia Britannica, Inc.

Sex-linked inheritance

In humans, there are hundreds of genes located on the X chromosome that have no counterpart on the Y chromosome.
The traits governed by these genes thus show sex-linked inheritance. This type of inheritance has certain unique
characteristics, which include the following: (1) There is no male-to-male (father-to-son) transmission, since sons will,
by definition, inherit the Y rather than the X chromosome. (2) The carrier female (heterozygote) has a 50 percent
chance of passing the mutant gene to each of her children; sons who inherit the mutant gene will be hemizygotes and
will manifest the trait, while daughters who receive the mutant gene will be unaffected carriers. (3) Males with the
trait will pass the gene on to all of their daughters, who will be carriers. (4) Most sex-linked traits are recessively
inherited, so that heterozygous females generally do not display the trait. The table lists some sex-linked conditions.
The figure shows a pedigree of a family in which a mutant gene for hemophilia A, a sex-linked recessive disease, is
segregating. Hemophilia A gained notoriety in early studies of human genetics because it affected at least 10 males
among the descendants of Queen Victoria, who was a carrier.

trait conspicuous signs

hemophilia A bleeding tendency with joint involvement

Duchenne muscular progressive muscle weakness

trait conspicuous signs

dystrophy

Lesch-Nyhan syndrome cerebral palsy, self-mutilation

fragile-X syndrome mental retardation, characteristic facies

Human disorders attributable to sex-linked recessive inheritance

Pedigree of a family with a history of hemophilia A, a sex-linked recessively inherited disease. Half-solid circles
represent female carriers (heterozygotes) of hemophilia A; the solid squares signify affected males
(hemizygotes).Encyclopædia Britannica, Inc.

Hemophilia A, the most widespread form of hemophilia,

results from a mutation in the gene encoding clotting factor
VIII. Because of this mutation, affected males cannot produce
functional factor VIII, so that their blood fails to clot properly,
leading to significant and potentially life-threatening loss of
blood after even minor injuries. Bleeding into joints
commonly occurs as well and may be crippling. Therapy
consists of avoiding trauma and of administering injections of
purified factor VIII, which was once isolated from outdated
human blood donations but can now be made in large
amounts through recombinant DNA technology.
Although heterozygous female carriers of X-linked recessive mutations generally do not exhibit traits characteristic of
the disorder, cases of mild or partial phenotypic expression in female carriers have been reported, resulting from
nonrandom X inactivation.

Diseases associated with single-gene non-Mendelian inheritance-

Although disorders resulting from single-gene defects that demonstrate Mendelian inheritance are perhaps better
understood, it is now clear that a significant number of single-gene diseases also exhibit distinctly non-Mendelian
patterns of inheritance. Among these are such disorders that result from triplet repeat expansions within or near
specific genes (e.g., Huntington disease and fragile-X syndrome); a collection of neurodegenerative disorders, such
as Leber hereditary optic neuropathy (LHON), that result from inherited mutations in the mitochondrial DNA; and
diseases that result from mutations in imprinted genes (e.g., Angelman syndrome and Prader-Willi syndrome)

Triplet repeat expansion

At least a dozen different disorders are now known to result from triplet repeat expansions in the human genome,
and these fall into two groups: (1) those that involve a polyglutamine tract within the encoded protein product that
becomes longer upon expansion of a triplet repeat, an example of which is Huntington disease, and (2) those that have
unstable triplet repeats in noncoding portions of the gene that, upon expansion, interfere with appropriate expression
of the gene product, an example of which is fragile-X syndrome (seephotograph). Both groups of disorders exhibit a
distinctive pattern of non-Mendelian inheritance termed anticipation, in which, following the initial appearance of the
disorder in a given family, subsequent generations tend to show both increasing frequency and increasing severity of
the disorder.

This phenotypic anticipation is paralleled by increases in the relevant repeat

length as it is passed from one generation to the next, with increasing size
leading to increasing instability, until a “full expansion” mutation is achieved,
generally several generations following the initial appearance of the disorder
in the family. The full expansion mutation is then passed to subsequent
generations in a standard Mendelian fashion—for example, autosomal
dominant for Huntington disease and sex-linked for fragile-X syndrome.
The fragile X chromosomeThe right-hand member in each of these two pairs
of X chromosomes is a fragile X; the leader points to the fragile site at the tip
of the long arm. Males hemizygous for this chromosome exhibit the fragile-X syndrome of mild to moderate mental
retardation.
Mitochondrial DNA mutations

Disorders resulting from mutations in the mitochondrial genome demonstrate an alternative form of non-Mendelian
inheritance, termed maternal inheritance, in which the mutation and disorder are passed from mothers—never from
fathers—to all of their children. The mutations generally affect the function of the mitochondrion, compromising,
among other processes, the production of cellular adenosine triphosphate (ATP). Severity and even penetrance can
vary widely for disorders resulting from mutations in the mitochondrial DNA, generally believed to reflect the
combined effects of heteroplasmy (i.e., mixed populations of both normal and mutant mitochondrial DNA in a single
cell) and other confounding genetic or environmental factors. There are close to 50 mitochondrial genetic diseases
currently known.

Imprinted gene mutations
Some genetic disorders are now known to result from mutations in imprinted genes.  Genetic imprinting involves a
sex-specific process of chemical modification to the imprinted genes, so that they are expressed unequally, depending
on the sex of the parent of origin. So-called maternally imprinted genes are generally expressed only when inherited
from the father, and so-called paternally imprinted genes are generally expressed only when inherited from the
mother. The disease gene associated with Prader-Willi syndrome is maternally imprinted, so that although every child
inherits two copies of the gene (one maternal, one paternal), only the paternal copy is expressed. If the paternally
inherited copy carries a mutation, the child will be left with no functional copies of the gene expressed, and the
clinical traits of Prader-Willi syndrome will result. Similarly, the disease gene associated with Angelman syndrome is
paternally imprinted, so that although every child inherits two copies of the gene, only the maternal copy is
expressed. If the maternally inherited copy carries a mutation, the child again will be left with no functional copies of
the gene expressed, and the clinical traits of Angelman syndrome will result. Individuals who carry the mutation but
received it from the “wrong” parent can certainly pass it on to their children, although they will not exhibit clinical
features of the disorder.
Upon rare occasion, persons are identified with an imprinted gene disorder who show no family history and do not
appear to carry any mutation in the expected gene. These cases are now known to result from  uniparental disomy, a
phenomenon whereby a child is conceived who carries the normal complement of chromosomes but who has
inherited both copies of a given chromosome from the same parent, rather than one from each parent, as is the normal
fashion. If any key genes on that chromosome are imprinted in the parent of origin, the child may end up with no
expressed copies, and a genetic disorder may result. Similarly, other genes may be overexpressed in cases of
uniparental disomy, perhaps also leading to clinical complications. Finally, uniparental disomy can account for very
rare instances whereby two parents, only one of whom is a carrier of an autosomal recessive mutation, can
nonetheless have an affected child, in the circumstance that the child inherits two mutant copies from the carrier
parent.

Diseases caused by multifactorial inheritance

Genetic disorders that are multifactorial in origin represent probably the single largest class of inherited disorders
affecting the human population. By definition, these disorders involve the influence of multiple genes, generally
acting in concert with environmental factors. Such common conditions as cancer, heart disease, and diabetes are now
considered to be multifactorial disorders. Indeed, improvements in the tools used to study this class of disorders have
enabled the assignment of specific contributing gene loci to a number of common traits and disorders. Identification
and characterization of these contributing genetic factors may not only enable improved diagnostic and prognostic
indicators but may also identify potential targets for future therapeutic intervention.
The table lists some conditions associated with multifactorial inheritance. Because the genetic and environmental
factors that underlie multifactorial disorders are often unknown, the risks of recurrence are usually arrived at
empirically. In general, it can be said that risks of recurrence are not as great for multifactorial conditions as for single-
gene diseases and that the risks vary with the number of relatives affected and the closeness of their relationship.
Moreover, close relatives of more severely affected individuals (e.g., those with bilateral cleft lipand cleft palate) are
generally at greater risk than those related to persons with a less-severe form of the same condition (e.g.,
unilateral cleft lip).
Human disorders attributable to multifactorial
inheritance

alcoholism

Alzheimer disease

cancer

coronary heart disease

diabetes
 Human disorders attributable to multifactorial
inheritance

epilepsy

hypertension

obesity

schizophrenia

Genetics Of Cancer

Although at least 90 percent of all cancers are sporadic, meaning that they do not seem to run in families, nearly 10
percent of cancers are now recognized as familial, and some are actually inherited in an apparently autosomal
dominant manner. Cancer may therefore be considered a multifactorial disease, resulting from the combined
influence of many genetic factors acting in concert with environmental insults (e.g., ultraviolet radiation, cigarette
smoke, and viruses).
Cancers, both familial and sporadic, generally arise from alterations in one or more of three classes of genes:
oncogenes, tumour suppressor genes, and genes whose products participate in genome surveillance—for example, in
DNA damage repair. All these functions are described in the article cancer. For familial cancers, affected members
inherit one mutant copy of a gene that falls into one of the latter two classes. That mutation alone is not sufficient to
cause cancer, but it predisposes individuals to the disease because they are now either more sensitive to spontaneous
somatic mutations, as in the case of altered tumour suppressor genes, or are more prone to experience mutations, as in
the case of impaired DNA repair enzymes. Of course, sporadic cancers can also arise from mutations in these same
classes of genes, but because all of the mutations must arise in the individual de novo, as opposed to being inherited,
they generally appear only later in life, and they do not run in families.
Retinoblastoma, an aggressive tumour of the eye that typically occurs in childhood, offers perhaps one of the clearest
examples of the interplay between inherited and somatic mutations in the genesis of cancer. Current data suggest that
60 to 70 percent of all cases of retinoblastoma are sporadic, while the rest are inherited. The relevant gene,  RB, encodes
a protein that normally functions as a suppressor of cell cycleprogression and is considered a classic tumour
suppressor gene. Children who inherit one mutant copy of the RB gene are at nearly 100 percent risk to develop
retinoblastoma, because the probability that their one remaining functional RBgene will sustain a mutation in at least
one retinal cell is nearly assured. In contrast, children who inherit two functional copies of the RB gene must
experience two mutations at the RB locus in the same retinal cell in order to develop retinoblastoma; this is a very rare
event. This “two-hit” hypothesis of retinoblastoma formation has provided a foundation upon which most
subsequent theories of the genetic origins of familial cancer have been built.
Recent studies of both breast and colorectal cancers have revealed that, like retinoblastoma, these cancers are
predominantly sporadic, although a small proportion are clearly familial. Sporadic breast cancer generally appears
late in life, while the familial forms can present much earlier, often before age 40. For familial breast cancer, inherited
mutations in one of two specific genes, BRCA1 and BRCA2, account for at least half of the cases observed.
The BRCA1 and BRCA2 genes both encode protein products believed to function in the pathways responsible for
sensing and responding to DNA damage in cells. While a woman in the general population has about a 10 percent
lifetime risk of developing breast cancer, half of all women with BRCA1 or BRCA2 mutations will develop breast
cancer by age 50, and close to 90 percent will develop the disease by age 80. Women with BRCA1 mutations are also at
increased risk to develop ovarian tumours. As with retinoblastoma, both men and women who
carry BRCA1 or BRCA2 mutations, whether they are personally affected or not, can pass the mutated gene to their
offspring, although carrier daughters are much more likely than carrier sons to develop breast cancer.
Two forms of familial colorectal cancer, hereditary nonpolyposis colorectal cancer (HNPCC) and familial
adenomatous polyposis(FAP), have also been linked to predisposing mutations in specific genes. Persons with
familial HNPCC have inherited mutations in one or more of their DNA mismatch repair genes,
predominantly MSH2 or MLH1. Similarly, persons with FAP carry inherited mutations in their APC genes, the protein
product of which normally functions as a tumour suppressor. For individuals in both categories, the combination of
inherited and somatic mutations results in a nearly 100 percent lifetime risk of developing colorectal cancer.
Although most cancer cases are not familial, all are undoubtedly diseases of the genetic material of somatic cells.
Studies of large numbers of both familial and sporadic cancers have led to the conclusion that cancer is a disease of
successive mutations, acting in concert to deregulate normal cell growth, provide appropriate blood supply to the
growing tumour, and ultimately enable tumour cell movement beyond normal tissue boundaries to achieve
metastasis (i.e., the dissemination of cancer cells to other parts of the body).Many of the agents that cause cancer (e.g.,
X rays, certain chemicals) also cause mutations or chromosome abnormalities. For example, a large fraction of
sporadic tumours have been found to carry oncogenes, altered forms of normal genes (proto-oncogenes) that have
sustained a somatic “gain-of-function” mutation. An oncogene may be carried by a virus, or it can result from a
chromosomal rearrangement, as is the case in chronic myelogenous leukemia, a cancer of the white blood cells
characterized by the presence of the so-called Philadelphia chromosome in affected cells. The Philadelphia
chromosome arises from a translocation in which one half of the long arm of chromosome 22 becomes attached to the
end of the long arm of chromosome 9, creating the dominant oncogene BCR/abl at the junction point. The specific
function of the BCR/abl fusion protein is not entirely clear. Another example is Burkitt lymphoma, in which a
rearrangement between chromosomes places the myc gene from chromosome 8 under the influence of regulatory
sequences that normally control expression of immunoglobulin genes. This deregulation of myc, a protein involved in
mediating cell cycle progression, is thought to be one of the major steps in the formation of Burkitt lymphoma.

Cognitive And Behavioral Genetics

Mental activities, expressed in human behaviour, are intimately related to physical activities in the brain and nervous
system. In 1929 British physician Sir Archibald Garrod emphasized this when he wrote:
Each one of us differs from his fellows, not only in bodily structure and the proteins which enter into his composite, but apart
from, or rather in consequence of, such individualities, men differ in mental outlook, character and ability. Since that time, many
investigators have sought to analyze the molecular and cellular components of behaviour in order to relate genes to
such abstractions as intellect, temperament, and the emotions. Because the brain is ultimately responsible for
behavioral development, neurobiologists have attempted to understand the unusual precision by which this organ’s
various regions are interconnected and the intricate chemical signals that, under genetic control, organize its
complicated nerve fibre circuits.Some of the most powerful experiments to dissect the “nature versus nurture” aspects
of human intelligence and behaviour have involved studies of twins, both monozygotic (identical) and dizygotic
(fraternal). Cognitive or behavioral characteristics that are entirely under genetic control would be predicted to be the
same, or concordant, in monozygotic twins, who share identical genes regardless of their upbringing. These same
characteristics would be predicted to be less concordant in dizygotic twins, who share, on average, only half of their
genes. Comparison of the concordance rates among monozygotic and dizygotic twins monitored for different traits
allows an estimate of the heritability of those traits—that is, the proportion of population variation for a given trait
that can be attributed to genes. A heritability value of 1.0 implies a purely genetic basis for a trait, and a value of 0.0
implies a purely environmental basis. Intelligence, measured as IQ, has a heritability value of 0.5, indicating that both
genetics and environment play major roles in determining this trait. In contrast, schizophrenia has a value of 0.7, and
both autism and bipolar disorder have heritability values of 1.0. Clearly, genetics play a large role in determining not
only how our bodies look and function but also how we think and feel.

Genetic Damage From Environmental Agents

We are exposed to many agents, both natural and man-made, that can cause genetic damage. Among these agents are
viruses; compounds produced by plants, fungi, and bacteria; industrial chemicals; products of combustion; alcohol;
ultraviolet and ionizing radiation; and even the oxygen that we breathe. Many of these agents have long been
unavoidable, and consequently human beings have evolved defenses to minimize the damage that they cause and
ways to repair the damage that cannot be avoided.

Viruses
Viruses survive by injecting their genetic material into living cells with the consequence that the biochemical
machinery of the host cell is subverted from serving its own needs to serving the needs of the virus. During this
process the viral genome often integrates itself into the genome of the host cell. This integration, or insertion, can
occur either in the intergenic regions that make up the vast majority of human genomes, or it can occur in the middle
of an important regulatory sequence or even in the region coding for a protein—i.e., a gene. In either of the latter two
scenarios, the regulation or function of the interrupted gene is lost. If that gene encodes a protein that normally
regulates cell division, the result may be unregulated cell growth and division. Alternatively, some viruses carry
dominant oncogenes in their genomes, which can transform an infected cell and start it on the path toward cancer.
Furthermore, viruses can cause mutations leading to cancer by the killing of the infected cell. Indeed, one of the
body’s defenses against viral infection involves recognizing and killing infected cells. The death of cells necessitates
their replacement by the division of uninfected cells, and the more cell division that occurs, the greater the likelihood
of a mutation arising from the small but finite infidelity in DNA replication. Among the viruses that can cause cancer
are Epstein-Barr virus, papilloma viruses, hepatitis B and C viruses, retroviruses (e.g., human immunodeficiency
virus), and herpes virus.

Plants, fungi, and bacteria
During the ongoing struggle for survival, organisms have evolved toxic compounds as protection against predators or
simply to gain competitive advantage. At the same time, these organisms have evolved mechanisms that make
themselves immune to the effects of the toxins that they produce. Plants in particular utilize this strategy since they
are rooted in place and cannot escape from predators. One-third of the dry weight of some plants can be accounted for
by the toxic compounds that are collectively referred to as alkaloids. Aspergillus flavus, a fungus that grows on stored
grain and peanuts, produces a powerful carcinogen called aflatoxin that can cause liver cancer. Bacteria produce
many proteins that are toxic to the infected host, such as diphtheria toxin. They also produce proteins called
bacteriocins that are toxic to other bacteria. Toxins can cause mutations indirectly by causing cell death, which
necessitates replacement by cell division, thus enhancing the opportunity for mutation. Cyanobacteria that grow
in illuminated surface water produce several carcinogens, such as microcystin, saxitoxin, and cylindrospermopsin,
that can also cause liver cancer.

Industrial chemicals

Tens of thousands of different chemicals are routinely used in the production of plastics, fuels, food additives, and
even medicines. Many of these chemicals are mutagens, and some have been found to be carcinogenic (cancer-
producing) in rats or mice. A relatively easy and inexpensive test for mutagenicity, the Ames test, utilizes mutant
strains of the bacterium Salmonella typhimurium and can be completed in a few days. Testing for carcinogenesis, on the
other hand, is very time-consuming and expensive because the test substance must be administered to large numbers
of laboratory animals, usually mice, for months before the tissues can be examined for cancers. For this reason, the
number of known mutagens far exceeds the number of known carcinogens. Furthermore, animal tests for
carcinogenesis are not completely predictive of the effects of the test chemical on humans for several reasons. First, the
abilities of laboratory animals and humans to metabolize and excrete specific chemicals can differ greatly. In addition,
in order to avoid the need to test each chemical at a range of doses, each chemical is usually administered at the
maximum tolerated dose. At such high doses, toxicity and cell death occur, necessitating cell replacement by growth
and cell division; cell division, in turn, increases the opportunity for mutation and hence for cancer. Alternatively,
unusually high doses of a chemical may actually mask the carcinogenic potential of a compound because damaged
cells may die rather than survive in mutated form.

Combustion products
The burning of fossil fuels quite literally powers modern industrial societies. If the combustion of such fuels were
complete, the products would be carbon dioxide and water. However, combustion is rarely complete, as is evidenced
by the visible smoke issuing from chimneys and from the exhausts of diesel engines. Moreover, in addition to the
particulates that we can see, incomplete combustion produces a witch’s brew of volatile compounds that we do not
see; and some of these, such as the dibenzodioxins, are intensely mutagenic and have been demonstrated to cause
cancer in laboratory rodents. Epidemiological data indicate that dioxins are associated with increased risk of a variety
of human cancers. The healthconsequences of combustion are further increased by impurities in fossil fuels and in the
oxygen that supports their burning. For example, coal contains sulfur, mercury, lead, and other elements in addition
to carbon. During combustion, sulfur becomes sulfur dioxide and that, in turn, gives rise to sulfurous and sulfuric
acids. The mercury in the fuel is emitted as a vapour that is very toxic. Atmospheric nitrogen is oxidized at the high
temperature of combustion.
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The smoke from a cigarette, drawn directly into the lungs, imparts a large number of particulates, as well as a host of
volatile compounds, directly into the airways and alveoli. Some of the volatile compounds are toxic in their own right
and others, such as hydroquinones, slowly oxidize, producing genotoxic free radicals. As macrophages in the lungs
attempt to engulf and eliminate particulates, they cause the production of mutagenic substances. A large fraction of
lung cancers are attributable to cigarette smoking, which is also a risk factor for atherosclerosis, hypertension (high
blood pressure), heart attack, and stroke.
Alcohol

Moderate consumption of alcohol (ethanol) is well-tolerated and may even increase life span. However, alcohol is a
potentially toxic substance and one of its metabolites, acetaldehyde, is a mild mutagen. Hence, it is not surprising that
the chronic consumption of alcohol leads to liver cirrhosisand other untoward effects. Consumption of alcohol
during pregnancy can cause fetal alcohol syndrome, which is characterized by low birth weight, mental retardation,
and congenital heart disease.

Ultraviolet radiation
Due to human activities that result in the release of volatile halocarbon compounds, such as the refrigerant freon and
the solvent carbon tetrachloride, the chlorine content of the upper atmosphere is increasing, and chlorine catalyzes the
decomposition of ozone, which shields the Earth from ultraviolet radiation that is emitted from the Sun. The Earth’s
ozone shield has been progressively depleted, most markedly over the polar regions but also measurably so over the
densely populated regions of northern Europe, Australia, and New Zealand. One consequence has been an increase in
a variety of skin cancers, including melanoma, in those areas. Steps have been taken to stop the release of halocarbons,
but the depletion of the ozone layer will nonetheless persist and may worsen for at least several decades.
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Ultraviolet light, when acting on DNA, can lead to covalent linking of adjacent pyrimidine bases. Such pyrimidine
dimerization is mutagenic, but this damage can be repaired by an enzyme called photolyase, which utilizes the energy
of longer wavelengths of light to cleave the dimers. However, people with a defect in the gene coding for photolyase
develop xeroderma pigmentosum, a condition characterized by extreme sensitivity to sunlight. These individuals
develop multiple skin cancers on all areas of exposed skin, such as the head, neck, and arms.
Ultraviolet light can also be damaging because of photosensitization, the facilitation of photochemical processes. One
way that photosensitizers work is by absorbing a photon and then transferring the energy  inherent in that photon to
molecular oxygen, thus converting the less-active ground-state molecular oxygen into a very reactive excited state,
referred to as singlet oxygen, that can attack a variety of cellular compounds, including DNA. Diseases that have a
photosensitizing component include lupus and porphyrias. In addition to photosensitizers that occur naturally in
the human body, some foods and medicines (e.g., tetracycline) also act in this way, producing
painful inflammation and blistering of the skin following even modest exposure to the sun.

Ionizing radiation
X rays and gamma rays are sufficiently energetic to cleave water into hydrogen atoms and hydroxyl radicals and are
consequently referred to as ionizing radiation. Ionizing radiation and the products of the cleavage of water are able to
damage all biological macromolecules, including DNA, proteins, and polysaccharides, and they have long been
recognized as being mutagenic, carcinogenic, and lethal. People are routinely exposed to natural sources of ionizing
radiation, such as cosmic rays, and to radioisotopes, such as carbon-14 and radon. They are also exposed to X rays and
man-made radioisotopes used for diagnostic purposes, and some people have been exposed to radioactive
fallout from nuclear weapon tests and reactor accidents. Such exposures would be much more damaging were it not
for multiple mechanisms of DNA repair that have evolved to deal with simple errors in replication as well as with
damage from naturally occurring sources.

Molecular oxygen
Molecular oxygen (O2), although essential for life, must be counted among the environmental toxins and mutagens.
Because of its unusual electronic structure, O2 is most easily reduced not by electron pairs but rather by single
electrons added one at a time. As O 2 is converted into water, superoxide (O 2−), hydrogen peroxide (H2O2), and a
hydroxyl radical (HO∙) are produced as intermediates. O 2− can initiate free-radical oxidation of important metabolites,
inactivate certain enzymes, and cause release of iron from specific enzymes. The second intermediate, H 2O2, is a
strong oxidant and can give rise to an even more potent oxidant, namely HO∙, when it reacts with ferrous iron. Thus,
O2− and H2O2 can collaborate in the formation of the destructive HO∙ and can subsequently lead to DNA damage,
mutagenesis, and cell death. Breathing 100 percent oxygen causes damage to the alveoli, which leads to accumulation
of fluid in the lungs. Thus, paradoxically, prolonged exposure to hyperoxia causes death due to lack of oxygen.
Humans have evolved multiple defense systems to counter the toxicity and mutagenicity of O 2. Thus, O2− is rapidly
converted into O2 and H2O2 by a family of enzymes called superoxide dismutases. H 2O2, in turn, is eliminated by other
enzymes called catalases and peroxidases, which convert it into O2 and water.
A few genetic diseases are known to be related to oxygen radicals or to the enzymes that defend against
them. Chronic granulomatous disease (CGD) is caused by a defect in the ability of the phagocytic leukocytes to mount
the respiratory burst, part of the body’s defense against infection. Upon contacting microorganisms and engulfing
them, phagocytes greatly increase their consumption of O 2 (the respiratory burst) while releasing O2−, H2O2,
hypochlorite (HOCl), and other agents that kill the microbe. The reduction of O 2 to O2− is caused by a multicomponent
enzyme called nicotine adenine dinucleotide phosphate (NADPH) oxidase. A defect in any of the components of this
oxidase will lead to the absence of the respiratory burst, giving rise to the constant infections indicative of CGD.
Before the discovery and clinical application of antibiotics, people born with CGD died from infection during early
childhood.
Another such genetic disease is a familial form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig
disease, which is characterized by late-onset progressive paralysis due to the loss of motor neurons. Approximately 20
percent of cases of ALS have been shown to result from mutations affecting the enzyme  superoxide dismutase. The
disease is genetically dominant, so that the mutant enzyme causes the disease even when half of the superoxide
dismutase present in cells exists in the normal form. Interestingly, most of the mutant variants retain full catalytic
activity.

HORMONAL DISEASE -
The endocrine system is a network of glands that produce and release hormones that help control many important
body functions, including the body's ability to change calories into energy that powers cells and organs. The
endocrine system influences how your heart beats, how your bones and tissues grow, even your ability to make a
baby. It plays a vital role in whether or not you develop diabetes, thyroid disease, growth disorders, sexual
dysfunction, and a host of other hormone-related disorders.

Glands of the Endocrine System

Each gland of the endocrine system releases specific hormones into your bloodstream. These hormones travel
through your blood to other cells and help control or coordinate many body processes.

Endocrine glands include:

Adrenal glands: Two glands that sit on top of the kidneys that release the hormone cortisol.

Hypothalamus: A part of the lower middle brain that tells the pituitary gland when to release hormones.

Ovaries: The female reproductive organs that release eggs and produce sex hormones.

Islet cells in the pancreas: Cells in the pancreas control the release of the hormones insulin and glucagon.

Parathyroid: Four tiny glands in the neck that play a role in bone development.

Pineal gland: A gland found near the center of the brain that may be linked to sleep patterns.

Pituitary gland: A gland found at the base of brain behind the sinuses. It is often called the "master gland" because it
influences many other glands, especially the thyroid. Problems with the pituitary gland can affect bone growth, a
woman's menstrual cycles, and the release of breast milk.

Testes: The male reproductive glands that produce sperm and sex hormones.

Thymus: A gland in the upper chest that helps develop the body's immune system early in life.

Thyroid: A butterfly-shaped gland in the front of the neck that controls metabolism.

Even the slightest hiccup with the function of one or more of these glands can throw off the delicate balance of
hormones in your body and lead to an endocrine disorder, or endocrine disease.

Causes of Endocrine Disorders

Endocrine disorders are typically grouped into two categories:

Endocrine disease that results when a gland produces too much or too little of an endocrine hormone, called a
hormone imbalance.

Endocrine disease due to the development of lesions (such as nodules or tumors) in the endocrine system, which
may or may not affect hormone levels.

The endocrine's feedback system helps control the balance of hormones in the bloodstream. If your body has too
much or too little of a certain hormone, the feedback system signals the proper gland or glands to correct the
problem. A hormone imbalance may occur if this feedback system has trouble keeping the right level of hormones in
the bloodstream, or if your body doesn't clear them out of the bloodstream properly.
Increased or decreased levels of endocrine hormone may be caused by: A problem with the endocrine feedback system

Disease

Failure of a gland to stimulate another gland to release hormones (for example, a problem with the hypothalamus
can disrupt hormone production in the pituitary gland)

A genetic disorder, such as multiple endocrine neoplasia (MEN) or congenital hypothyroidism

Infection
Injury to an endocrine gland ,Tumor of an endocrine gland ,Most endocrine tumors and nodules (lumps) are
noncancerous. They usually do not spread to other parts of the body. However, a tumor or nodule on the gland may
interfere with the gland's hormone production.
Types of Endocrine Disorders
There are many different types of endocrine disorders. Diabetes is the most common endocrine disorder diagnosed
in the U.S.

Other endocrine disorders include:

Adrenal insufficiency. The adrenal gland releases too little of the hormone cortisol and sometimes, aldosterone.
Symptoms include fatigue, stomach upset, dehydration, and skin changes. Addison's disease is a type of adrenal
insufficiency.

Cushing's disease. Overproduction of a pituitary gland hormone leads to an overactive adrenal gland. A similar
condition called Cushing's syndrome may occur in people, particularly children, who take high doses of corticosteroid
medications.

Gigantism (acromegaly) and other growth hormone problems. If the pituitary gland produces too much growth
hormone, a child's bones and body parts may grow abnormally fast. If growth hormone levels are too low, a child
can stop growing in height.

Hyperthyroidism. The thyroid gland produces too much thyroid hormone, leading to weight loss, fast heart rate,
sweating, and nervousness. The most common cause for an overactive thyroid is an autoimmune disorder called
Grave's disease.

Hypothyroidism. The thyroid gland does not produce enough thyroid hormone, leading to fatigue, constipation, dry
skin, and depression. The underactive gland can cause slowed development in children. Some types of
hypothyroidism are present at birth.

Hypopituitarism. The pituitary gland releases little or no hormones. It may be caused by a number of different
diseases. Women with this condition may stop getting their periods.

Multiple endocrine neoplasia I and II (MEN I and MEN II). These rare, genetic conditions are passed down through
families. They cause tumors of the parathyroid, adrenal, and thyroid glands, leading to overproduction of hormones.

Polycystic ovary syndrome (PCOS). Overproduction of androgens interfere with the development of eggs and their
release from the female ovaries. PCOS is a leading cause of infertility.

Precocious puberty. Abnormally early puberty that occurs when glands tell the body to release sex hormones too
soon in life.

Testing for Endocrine Disorders

If you have an endocrine disorder, your doctor may refer you to a specialist called an endocrinologist. An
endocrinologist is specially trained in problems with the endocrine system.

The symptoms of an endocrine disorder vary widely and depend on the specific gland involved. However, most
people with endocrine disease complain of fatigue and weakness.

Blood and urine tests to check your hormone levels can help your doctors determine if you have an endocrine
disorder. Imaging tests may be done to help locate or pinpoint a nodule or tumor.

Treatment of endocrine disorders can be complicated, as a change in one hormone level can throw off another. Your
doctor or specialist may order routine blood work to check for problems or to determine if your medication or
treatment plan needs to be adjusted.

METABOLIC DISORDER-
Metabolic disease, any of the diseases or disorders that disrupt normal metabolism, the process of converting food
to energy on a cellular level. Thousands of enzymes participating in numerous interdependent metabolic pathways
carry out this process. Metabolic diseases affect the ability of the cell to perform critical biochemical reactions that
involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty
acids).

Metabolic diseases are typically hereditary, yet most persons affected by them may appear healthy for days, months,
or even years. The onset of symptoms usually occurs when the body’s metabolism comes under stress—for example,
after prolonged fasting or during a febrile illness. For some metabolic disorders, it is possible to obtain prenatal
diagnostic screening. Such analysis usually is offered to families who have previously had a child with a metabolic
disease or who are in a defined ethnic group. For example, testing for Tay-Sachs disease is relatively common in the
Ashkenazi Jewish population. Countries that perform screening for metabolic diseases at birth typically test for up to
10 different conditions. Tandem mass-spectrometry is a new technology that allows for the detection of multiple
abnormal metabolites almost simultaneously, making it possible to add approximately 30 disorders to the list of
conditions for which newborns may be tested. If an infant is known to have a metabolic disorder soon after birth,
appropriate therapy can be started early, which may result in a better prognosis. Some metabolic disorders respond
very well if treatment is introduced at an early age. However, others have no effective therapy and cause severe
problems, despite early diagnosis. In the future, gene therapy may prove successful in the treatment of some of
these diseases.

Metabolic diseases are quite rare individually, but they are relatively common when considered as a group. Specific
metabolic disorders have incidences ranging from approximately 1 in 500 (or even higher in isolated populations) to
fewer than 1 in 1,000,000. As a group, it has been estimated that metabolic disorders affect approximately 1 in 1,000
individuals.

The routine monitoring of blood pressure levels is an important part of assessing an individual's health. Blood
pressure provides information about the amount of blood in circulation and about heart function and thus is an
important indicator of disease.

human disease: Metabolic control

In essence, metabolism involves all the physical and chemical processes by which cells are produced and maintained.
Included under this broad umbrella are the regulation of fluid and electrolytes, the maintenance of plasma protein
levels adequate for the building and repair of cells,…The Origins Of Metabolic Disease

Metabolic pathways-

In 1908 British physician Sir Archibald Garrod postulated that four inherited conditions of lifelong duration—
alkaptonuria, pentosuria, albinism, and cystinuria—were caused by defects in specific biochemical pathways due to
the diminished activity or complete lack of a given enzyme. He called these disorders “inborn errors of metabolism.”
Although Garrod was incorrect in his categorization of cystinuria, his insights provided the field of biochemical
genetics with a solid foundation, and the list of inherited inborn errors of metabolism has rapidly grown. This article
is primarily concerned with these inherited metabolic diseases, although other disorders, including endocrine
diseases (e.g., diabetes mellitus and hypothyroidism) and malnutrition (e.g., marasmus and kwashiorkor), also affect
cellular metabolism.

Food is broken down in a series of steps by cellular enzymes (proteins that catalyze the conversion of compounds
called substrates) into products with a different biochemical structure. These products then become the substrate
for the next enzyme in a metabolic pathway. If an enzyme is missing or has diminished activity, the pathway
becomes blocked, and the formation of the final product is deficient, resulting in disease. Low activity of an enzyme
may result in the subsequent accumulation of the enzyme’s substrate, which may be toxic at high levels. In addition,
minor metabolic pathways that usually lie dormant may be activated when a substrate accumulates, possibly
forming atypical, potentially toxic, products. Each cell in the body contains thousands of metabolic pathways, all of
which are interlinked to some extent, so that a single blockage may affect numerous biochemical processes.

The consequences of metabolic imbalance may be severe; intellectual disability, seizures, decreased muscle tone,
organ failure, blindness, and deafness may occur, depending on which enzyme is dysfunctional. In recent years, it
has become apparent that even some conditions associated with multiple congenital anomalies (e.g., Smith-Lemli-
Opitz syndrome) have an underlying metabolic cause.

Genetic mutations-

The molecular blueprint for nearly all enzymes, structural proteins, cellular transport proteins, and other
constituents that are responsible for carrying out the complex reactions involved in metabolism is stored as
deoxyribonucleic acid (DNA) in the nucleus of the cell. A small amount of DNA of critical importance to metabolism
also is contained in cellular organelles called mitochondria. DNA is organized into smaller units, termed genes, which
direct the production of specific proteins or enzymes. In 1945 American geneticists George Beadle and Edward
Tatum proposed a central tenet of molecular biology, the “one gene-one enzyme” principle, which states that a
single gene directs the synthesis of a single enzyme. This principle has been refined to account for the fact that not
all gene products are enzymes and that some enzymes are composed of multiple structural units encoded by
different genes. Nevertheless, the one gene-one enzyme theory had immediate implications when applied to
Garrod’s initial theories regarding inborn errors of metabolism. Inherited metabolic diseases were postulated to
occur when a gene is mutated in such a way as to produce a defective enzyme with diminished or absent function. In
1948 methemoglobinuria became the first human genetic disease to be identified as being caused by an enzyme
defect. In 1949 American chemist Linus Pauling and colleagues demonstrated that a mutation causes a structural
alteration in a protein; hemoglobin (the protein in red blood cells that carries oxygen to the tissues of the body)
extracted from normal human red blood cells was shown to behave differently from hemoglobin taken from persons
with the hereditary disease sickle-cell anemia. Thus, it was determined that mutant genes that direct the formation
of abnormal proteins with altered function cause inborn errors of metabolism.

Inheritance-
The inheritance of inborn errors of metabolism is most often autosomal recessive, meaning that two mutant genes
are required to produce the signs and symptoms of disease. The parents of an affected child are most often
asymptomatic carriers, because 50 percent of normal enzyme activity is adequate to maintain sufficient health.
When two carriers of a deleterious trait produce offspring, however, there is a 25 percent chance of having an
affected child, a 25 percent chance of having a child without the mutant allele, and a 50 percent chance of having a
child who is also a carrier. In genetic terms, the carrier of an autosomal recessive condition has only one mutant
gene (heterozygous), while an affected individual has two mutant genes (homozygous). All human beings have
approximately six recessive mutant alleles in their genomes, but it is relatively rare for an individual to mate with
someone who carries a mutation in the same gene. However, in cases of parental consanguinity, there is an
increased risk of having a child with an autosomal recessive condition, because a common genetic background is
shared.

Unlike autosomal recessive diseases, autosomal dominant diseases are expressed when only one mutant gene is
present. These disorders show a strong family history, unless the condition arose from a new spontaneous mutation
in an individual. A heterozygous individual has a 50 percent chance of passing the disorder to his offspring.
Individuals with autosomal dominant disorders show a wide spectrum of disease severity, and carriers of a dominant
trait may even appear asymptomatic.

Genetic material in the nucleus is found packed into DNA-protein complexes called chromosomes. Females have two
X chromosomes, while males have an X and a Y chromosome. If a mutant gene is part of the X chromosome, the
resulting disease is called X-linked. All male offspring who inherit an X-linked mutation are affected, because the Y
chromosome of the XY pair does not have a compensating normal gene. Because the mutation is on the X
chromosome and males transmit only the Y chromosome to their sons during fertilization, fathers do not transmit
the disease to their sons. They can, however, transmit the carrier state (i.e., the mutant X chromosome) to their
daughters. A heterozygous female carrier, meanwhile, has a 50 percent chance of producing a carrier daughter or
affected son.

X-linked inheritance is complicated by the process of X chromosome inactivation (lyonization) in females. Although
females carry two X chromosomes, early in embryonic development one of the X chromosomes is inactivated in each
cell. The process of X chromosome inactivation is usually random, resulting in the formation of two cell lines in a
given female who carries an X-linked disease mutation; one cell line has an inactivated normal X chromosome, and
the other has an inactivated abnormal X chromosome. However, it is possible that a higher proportion of normal X
chromosomes will be inactivated in a given individual, with the resultant appearance of symptoms of disease in
various degrees. Such females are known as manifesting heterozygotes. Examples of X-linked disorders include
ornithine transcarbamylase deficiency (an enzyme deficiency resulting in high blood levels of ammonia and impaired
urea formation), X-linked adrenoleukodystrophy (a disorder that is characterized by progressive mental and physical
deterioration and adrenal insufficiency), and Lesch-Nyhan syndrome (a disorder of purine metabolism that is
characterized by the excretion of large amounts of uric acid in the urine, neurological disturbances, and self-
mutilation).

The transmission of genes that are located in mitochondria (i.e., not contained in the nucleus of the cell) is termed
maternal (mitochondrial) inheritance. Mitochondrial DNA (mtDNA), although much smaller than nuclear DNA, is
critical in cellular metabolism. Most of the energy required by a cell to drive its metabolism is produced in
mitochondria by proteins in a series of electron donor-acceptor reactions that make up the electron-transport, or
respiratory, chain. Mitochondria are located in the cytoplasm of the ova and are inherited from the mother.
Spermatozoa also have mitochondria, but these do not become incorporated into the developing embryo. When a
cell divides, the mitochondria are randomly distributed to daughter cells. Each mitochondrion contains 2 to 10
copies of mtDNA, and each cell contains numerous mitochondria. In a given cell of a person with a mitochondrial
disorder, the number of normal mitochondria may be greater than the number of abnormal mitochondria, and the
cell may function well. On the other hand, if a cell contains a significant percentage of abnormal mitochondria, this
cell and any tissue containing many such cells will exhibit impaired function. Affected children may demonstrate a
spectrum of abnormalities, from appearing normal or mildly affected to being severely compromised, depending on
the degree of mitochondrial dysfunction and the extent of tissue involvement.

Disorders Of Amino Acid Metabolism-

Twenty amino acids, including nine that cannot be synthesized in humans and must be obtained through food, are
involved in metabolism. Amino acids are the building blocks of proteins; some also function as or are synthesized
into important molecules in the body such as neurotransmitters, hormones, pigments, and oxygen-carrying
molecules. Each amino acid is further broken down into ammonia, carbon dioxide, and water. Disorders that affect
the metabolism of amino acids include phenylketonuria, tyrosinemia, homocystinuria, non-ketotic hyperglycinemia,
and maple syrup urine disease. These disorders are autosomal recessive, and all may be diagnosed by analyzing
amino acid concentrations in body fluids. (Maple syrup urine disease also features the production of organic acids
and is discussed in the section Organic acidemias.)

Phenylketonuria (PKU) is caused by decreased activity of phenylalanine hydroxylase (PAH), an enzyme that converts
the amino acid phenylalanine to tyrosine, a precursor of several important hormones and skin, hair, and eye
pigments. Decreased PAH activity results in accumulation of phenylalanine and a decreased amount of tyrosine and
other metabolites. Persistent high levels of phenylalanine in the blood in turn result in progressive developmental
delay, a small head circumference, behaviour disturbances, and seizures. Due to a decreased amount of the pigment
melanin, persons with PKU tend to have lighter features, such as blond hair and blue eyes, than other family
members who do not have the disease. Treatment with special formulas and with foods low in phenylalanine and
protein can reduce phenylalanine levels to normal and maintain normal intelligence. However, rare cases of PKU that
result from impaired metabolism of biopterin, an essential cofactor in the phenylalanine hydroxylase reaction, may
not consistently respond to therapy.

Classic (hepatorenal or type I) tyrosinemia is caused by a deficiency of fumarylacetoacetate hydrolase (FAH), the
last enzyme in tyrosine catabolism. Features of classic tyrosinemia include severe liver disease, unsatisfactory weight
gain, peripheral nerve disease, and kidney defects. Approximately 40 percent of persons with the disorder develop
liver cancer by the age of 5 if untreated. Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione
(NTBC), a potent inhibitor of the tyrosine catabolic pathway, prevents the production of toxic metabolites. Although
this leads to improvement of liver, kidney, and neurological symptoms, the occurrence of liver cancer may not be
prevented. Liver transplantation may be required for severe liver disease or if cancer develops. A benign, transient
neonatal form of tyrosinemia, responsive to protein restriction and vitamin C therapy, also exists.
Homocystinuria is caused by a defect in cystathionine beta-synthase (or β-synthase), an enzyme that participates in
the metabolism of methionine, which leads to an accumulation of homocysteine. Symptoms include a pronounced
flush of the cheeks, a tall, thin frame, lens dislocation, vascular disease, and thinning of the bones (osteoporosis).
Intellectual disability and psychiatric disorders also may be present. Approximately 50 percent of persons with
homocystinuria are responsive to treatment with vitamin B6 (pyridoxine), and these individuals tend to have a better
intellectual prognosis. Therapy with folic acid, betaine (a medication that removes extra homocysteine from the
body), aspirin, and dietary restriction of protein and methionine also may be of benefit.

Non-ketotic hyperglycinemia is characterized by seizures, low muscle tone, hiccups, breath holding, and severe
developmental impairment. It is caused by elevated levels of the neurotransmitter glycine in the central nervous
system, which in turn are caused by a defect in the enzyme system responsible for cleaving the amino acid glycine.
Drugs that block the action of glycine (e.g., dextromethorphan), a low-protein diet, and glycine-scavenging
medications (e.g., sodium benzoate) may ease symptoms, but there is no cure for this severe condition.

Urea cycle defects-

Liver cells play a critical role in disposing of nitrogenous waste by forming the compound urea (the primary solid
component of urine) through the action of the urea cycle. When an amino acid is degraded, the ammonia nitrogen at
one end of the molecule is split off, incorporated into urea, and excreted in the urine. A defect in any of the enzymes
of the urea cycle leads to a toxic accumulation of ammonia in the blood. This, in turn, causes poor feeding, vomiting,
lethargy, and possibly coma in the first two or three days of life (except in the case of arginase deficiency, which
presents later in childhood).

Urea cycle defects are autosomal recessive, meaning they are passed on to offspring only when both parents carry
the defect. One exception is ornithine transcarbamylase (OTC) deficiency, which is X-linked (and therefore causes
severe disease in males who inherit the mutant X chromosome). However, OTC deficiency can also affect females
who are “manifesting heterozygotes” (see the section Inheritance), presenting with severe disease during infancy or
later in life during times of metabolic stress—for instance, during viral illness or childbirth. Emergency management
of urea cycle disorders includes intravenous ammonia-scavenging medications and hemodialysis to decrease the
blood ammonia level. Long-term therapy consists of a low-protein diet, the provision of nutrients deficient in these
disorders, and phenylbutyrate or benzoate (medications that rid the body of excess ammonia). Persons with urea
cycle disorders are at risk for recurrent crises with elevated ammonia levels, especially during times of infection;
untreated or repeated episodes of high ammonia levels may cause intellectual disability and developmental
impairment. Liver transplantation can cure some of these disorders.

Amino acid transport disorders

Energy is required to move many amino acids from the intestinal tract into the blood or to reclaim them from the
urine by special cells in the kidney. This transport of amino acids does not involve enzymes in metabolic pathways
but rather transport proteins embedded in cellular or intracellular organelle membranes. Mutant proteins with
decreased transport activities may prevent the absorption of dietary amino acids or cause their loss in the urine. For
example, in cystinuria there is increased excretion of cystine, ornithine, arginine, and lysine in urine, which results in
kidney stones. Cystinosis is characterized by the defective egress of cystine out of cellular organelles called
lysosomes owing to a defect in the transporter cystinosin; persons with this disorder develop corneal deposits and
kidney disease, and kidney transplantation may be necessary. Defective membrane transport of lysine, arginine, and
ornithine in the intestines causes lysinuric protein intolerance (LPI), a disorder characterized by protein intolerance,
diarrhea, unsatisfactory weight gain, osteoporosis, and rashes; late complications of LPI include kidney and lung
disease. Hartnup disease is a disorder of amino acid transport in the intestines and kidneys; ataxia, a photosensitive
rash, and mental abnormalities are the main symptoms.

Organic acidemias
Organic acids are carbon-based compounds that appear at abnormally elevated levels when metabolic pathways
involving specific enzymes are blocked. Organic acidemias are conditions characterized by the accumulation of
organic acids in body tissues and fluids, especially urine. The most common of these disorders are autosomal
recessive conditions that involve the metabolism of the branched-chain amino acids leucine, isoleucine, and valine.
Organic acidemias share many features, including increased acid in the blood (acidemia), low blood sugar
(hypoglycemia), low white blood cell count (neutropenia), poor growth, and varying degrees of mental impairment.
These disorders may manifest in infancy or later in childhood.

Propionic acidemia is caused by a deficiency of the enzyme propionyl-CoA carboxylase, which results in an
accumulation of propionic acid. Individuals with this disorder usually present with life-threatening illness early in
infancy. Acidemia, dehydration, low white blood cell count, low muscle tone, and lethargy progressing to coma are
typical features. The level of ammonia in the blood also may be high, because abnormal metabolites inhibit the urea
cycle from functioning properly. The main therapies for propionic acidemia are dietary restriction of branched-chain
amino acids, carnitine supplementation, and vigorous treatment of metabolic crises with intravenous fluids, glucose,
and bicarbonate.

Persons with the classic form of methylmalonic acidemia (MMA), caused by a defect in the enzyme methylmalonyl-
CoA mutase, have symptoms similar to individuals with propionic acidemia but may also develop the long-term
complication of kidney failure. A combined liver-kidney transplant may be beneficial in some patients with severe
kidney disease. One form of classic MMA responds to treatment with vitamin B12. Rarer forms are caused by defects
in the processing of vitamin B12 and often present later in childhood with progressive neurological
impairment.Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acid metabolism that leads to
the accumulation of leucine, isoleucine, valine and their corresponding oxoacids in body fluids—one result being a
characteristic maple syrup smell to the urine of some patients. The disorder is common in the Mennonites of
Pennsylvania. The classic form of MSUD presents in infancy with lethargy and progressive neurological deterioration
characterized by seizures and coma. Unlike most organic acidemias, prominent acidemia is rare. Treatment involves
restricting proteins and feeding with formulas deficient in the branched-chain amino acids. Persons with MSUD may
have intellectual disability despite therapy, but early and careful treatment can result in normal intellectual
development. Milder forms of MSUD may be treated with simple protein restriction or administration of thiamin
(vitamin B1).

Disorders Of Carbohydrate Metabolism-

The metabolism of the carbohydrates galactose, fructose, and glucose is intricately linked through interactions
between different enzymatic pathways, and disorders that affect these pathways may have symptoms ranging from
mild to severe or even life-threatening. Clinical features include various combinations of hypoglycemia (low blood
sugar), liver enlargement, and muscle pain. Most of these disorders can be treated, or at least controlled, with
specific dietary interventions.

Galactose and fructose disorders-

Galactosemia usually is caused by a defective component of the second major step in the metabolism of the sugar
galactose. When galactose is ingested, as in milk, galactose-1-phosphate accumulates. Therefore, the clinical
manifestations of galactosemia begin when milk feeding is started. If the feeding is not stopped, infants with the
disorder will develop lethargy, jaundice, progressive liver dysfunction, kidney disease, and weight loss. They are also
susceptible to severe bacterial infections, especially by Escherichia coli. Cataracts develop if the diet remains
galactose-rich. Intellectual disability occurs in most infants with galactosemia if the disorder is left untreated or if
treatment is delayed. Therapy is by exclusion of galactose from the diet and results in the reversal of most
symptoms. Most children have normal intelligence, although they may have learning difficulties and a degree of
intellectual disability despite early therapy. Hereditary fructose intolerance (HFI) is caused by a deficiency of the
liver enzyme fructose-1-phosphate aldolase. Symptoms of HFI appear after the ingestion of fructose and thus
present later in life than do those of galactosemia. Fructose is present in fruits, table sugar (sucrose), and infant
formulas containing sucrose. Symptoms may include failure to gain weight satisfactorily, vomiting, hypoglycemia,
liver dysfunction, and kidney defects. Older children with HFI tend to avoid sweet foods and may have teeth notable
for the absence of caries. Children with the disorder do very well if they avoid dietary fructose and sucrose.
Fructose 1,6-diphosphatase deficiency is associated with an impaired ability to form glucose from other substrates (a
process called gluconeogenesis). Symptoms include severe hypoglycemia, intolerance to fasting, and enlargement of
the liver. Rapid treatment of hypoglycemic episodes with intravenous fluids containing glucose and the avoidance of
fasting are the mainstays of therapy. Some patients require continuous overnight drip feeds or a bedtime dose of
cornstarch in order to control their tendency to develop hypoglycemia.

Glycogen storage disorders-

The brain, red blood cells, and inner portion of the adrenal gland (adrenal medulla) depend on a constant supply of
glucose for their metabolic functions. This supply begins in the small intestine, where transport proteins mediate the
uptake of glucose into cells lining the gut. Glucose subsequently passes into the bloodstream and then the liver,
where it is stored as glycogen. In times of starvation or fasting or when the body requires a sudden energy supply,
glycogen is broken down into glucose, which is then released into the blood. Muscle tissue also has its own glycogen
stores, which may be degraded during exercise. If enzymes responsible for glycogen degradation are blocked so that
glycogen remains in the liver or muscle, a number of conditions known as glycogen storage disorders (GSD) can arise.
Depending upon which enzyme is affected, these conditions may affect the liver, muscles, or both. In GSD type I (von
Gierke disease), the last step in glucose release from the liver is defective, leading to hypoglycemia. Therapy consists
of supplying continuous glucose to the digestive tract (e.g., by continuous drip feedings) during infancy and early
childhood. As the child grows, an improvement in symptoms tends to occur. Adequate glucose is supplied by
frequent feedings of carbohydrates and slow-release glucose (uncooked cornstarch) before bedtime. Liver
transplantation may also be curative, but this drastic measure is reserved for the small percentage of patients who
do not respond to the usual treatment or who develop liver cancer. For the muscular forms of the disease,
avoidance of strenuous exercise is the usual therapy. Defects in earlier steps in glycogen breakdown in the liver
cause GSD types III, IV, VI, and IX, which usually lead to milder versions of type I disease. Pompe disease (GSD type II)
is discussed in the section Lysosomal storage disorders.

In addition to glycogen degradation, glucose may be manufactured from amino acids and pyruvate in the process of
gluconeogenesis. Key enzymes in the gluconeogenic pathway include carboxylase, phosphoenolpyruvate
carboxykinase, and fructose-1,6-diphosphatase. Persons with defects in these enzymes develop conditions including
fasting hypoglycemia, lactic acidemia, and liver enlargement. Thus, gluconeogenesis disorders may be difficult to
distinguish from glycogen storage disorders at first presentation.

Congenital disorders of glycosylation

Congenital disorders of glycosylation (CDG; formerly known as carbohydrate-deficient glycoprotein syndrome) are
recently described diseases that affect the brain and many other organs. The primary biochemical defects of CDG are
in the N-glycosylation pathway that occurs in the cytoplasm and endoplasmic reticulum, cellular organelles involved
in the synthesis of proteins and lipids. A defect in a mannose-processing enzyme, phosphomannomutase 2, causes
the most common form of CDG (type I). Other enzymatic defects have been identified, but the biochemical bases of
some CDG subtypes have not yet been determined. The classic form of CDG (type Ia) is characterized by low muscle
tone in infancy, severe developmental delay, and brain abnormalities. Children with type Ia also have inverted
nipples and an unusual distribution of fat, especially in the suprapubic region and buttocks. Other features include
hypoglycemia, seizures, stroke-like episodes, retinal damage, impaired heart contractility, vomiting, liver disease,
diarrhea, and a bleeding tendency. No effective therapy exists for CDG, except for the rare type Ib disease
(phosphomannose isomerase deficiency), in which oral administration of mannose may reverse symptoms in some
cases.

Disorders Of Lipid Metabolism

Lipids are large, water-insoluble molecules that have a variety of biological functions, including storing energy and
serving as components of cellular membranes and lipoproteins. Cells that line the small intestine absorb dietary
lipids and process them into lipoprotein particles that enter the circulation via the lymphatic system for eventual
uptake by the liver. Triglycerides, cholesterol, and fat-soluble vitamins are transported through the blood by these
lipoprotein particles. Enzyme defects in tissue lipid disorders.,Encyclopædia Britannica, Inc.

Lipoprotein disorders
The major classes of lipoproteins are chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density
lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Disorders that affect lipid
metabolism may be caused by defects in the structural proteins of lipoprotein particles, in the cell receptors that
recognize the various types of lipoproteins, or in the enzymes that break down fats. As a result of such defects, lipids
may become deposited in the walls of blood vessels, which can lead to atherosclerosis (a disease characterized by
abnormal thickening and hardening of the walls of the arteries).

Familial hypercholesterolemia is an autosomal dominant disease that is caused by the deficiency of the LDL receptor
on the surface of cells in the liver and other organs. As a result, cholesterol is not moved into the cells. Under normal
conditions, when enough cholesterol is present in the cell, feedback mechanisms signal enzymes to cease cholesterol
synthesis. In familial hypercholesterolemia, these enzymes are relieved of feedback inhibition, thus inducing the
production of still more cholesterol. The disease is characterized by early coronary vascular disease, strokes, and
fatty deposits on the tendons. Blood cholesterol levels are very high from birth, and LDL cholesterol is also elevated.
Treatment is by a low-cholesterol diet and drugs that inhibit cholesterol synthesis or increase its excretion in the
gastrointestinal tract.If a person with familial hypercholesterolemia is homozygous for the condition, severe vascular
disease starts in early childhood, and heart attacks are usual by the age of 20. Similar symptoms are present in
familial dysbetalipoproteinemia (hyperlipoproteinemia type III), which may be inherited as an autosomal recessive or
autosomal dominant condition (that is, if the trait has been inherited from both parents). In this disorder, which
manifests in adulthood, increased blood cholesterol and triglycerides are present due to an abnormality of a
constituent of lipoproteins called apoprotein E. Treatment is similar to that required for familial
hypercholesterolemia.A deficiency of microsomal transfer protein causes abetalipoproteinemia, an autosomal
recessive condition characterized by the virtual absence of VLDL and LDL. Triglycerides accumulate in the
gastrointestinal tract and liver, and there are low blood levels of cholesterol, HDL cholesterol, and triglycerides.
Persons with abetalipoproteinemia have severe fat malabsorption and develop neurological symptoms including
unsteady gait, retinal defects, and nerve damage due to the deficiency of vitamin E.

Fatty acid oxidation defects

During prolonged starvation, the metabolism of fats stored in adipose tissue is needed for energy production. After
the glycogen stores have been depleted, both gluconeogenesis and the production of ketone bodies by liver fatty
acid beta-oxidation (or β-oxidation) are essential for providing energy for the brain. The oxidation of fatty acids for
energy occurs in the mitochondria of liver cells and requires a carrier molecule, carnitine, which is synthesized in the
body and is also obtained from the dietary intake of animal products such as meat, milk, and eggs. Some fatty acid
oxidation disorders arise through dysfunction of carnitine transport enzymes, although most of these conditions are
caused by fat-degrading enzymes directly involved in the beta-oxidation cycle itself. In individuals with inherited
disorders of carnitine transport, a deficiency of carnitine may cause severe brain, liver, and heart damage. Treatment
with carnitine is partially effective. Fatty acid oxidation disorders are relatively common and as a group may account
for approximately 5 to 10 percent of cases of sudden infant death syndrome (SIDS). The disorders commonly
manifest with hypoglycemia, liver disease, decreased muscle tone, and heart failure (cardiomyopathy).Children with
medium-chain acyl-CoA dehydrogenase deficiency (MCAD) appear completely normal, unless they fast for a
prolonged period or are faced by other metabolically stressful conditions, such as a severe viral illness. During
periods of metabolic stress, affected individuals may develop hypoglycemia, lethargy, vomiting, seizures, and liver
dysfunction. Intravenous hydration and glucose must be given in a timely fashion, otherwise the disease can be fatal.
However, if hydration and nutrition are monitored closely, children with MCAD lead a relatively normal life. Therapy
consists of carnitine administration and avoidance of excessive fat intake. Other fatty acid oxidation disorders may
respond to similar therapy, but in general, their prognosis is not as good.Long-chain 3-hydroxy-acyl-CoA
dehydrogenase (LCHAD) deficiency may present with heart failure, hypoglycemia, multi-organ system failure, and
retinal pigmentary changes. A fetus with LCHAD deficiency can induce liver disease during pregnancy in a mother
who is a heterozygous carrier for the condition. This appears to be due to a combination of the metabolic demands
of pregnancy, the lack of enzyme activity in the fetus, and the reduced activity of the enzyme in the mother, causing
enough of an imbalance in the usual energy pathways to result in the storage of fat in the maternal liver.

Mitochondrial Disorders
The mitochondrial respiratory chain consists of five multi-subunit protein complexes that produce the majority of
energy driving cellular reactions. Dysfunction of the respiratory chain leads to decreased energy production and to
an increase in the production of toxic reactive oxygen species. In addition, damaged mitochondria release apoptotic
factors, which act as signals to induce cell death. Respiratory chain proteins are formed by the concerted action of
both nuclear and mitochondrial genes. Therefore, mitochondrial disorders may be inherited in either a Mendelian
(autosomal recessive, autosomal dominant, or X-linked) or maternal (mitochondrial) fashion, because mutations may
occur in either the nuclear or mitochondrial genome.

The signs and symptoms of mitochondrial disorders are dependent on the severity of the mutation, the percentage
of dysfunctional mitochondria, and the energy requirements of the affected tissues. Patients with mitochondrial
disorders may present with a bewildering array of symptoms, because any tissue in the body may be affected at any
point in an individual’s lifetime. However, prominent involvement of the nervous and muscular systems is common
because these tissues are highly dependent on mitochondrial metabolism. Patients often have biochemical markers
of underlying disease (for example, an elevated blood lactate level or unusual organic acids in the urine), but some
patients have completely normal metabolic screens. Often the diagnosis of mitochondrial disorders requires
demonstration of respiratory chain dysfunction by the measurement of complex activities in muscle tissue obtained
from a biopsy. So-called muscle ragged red fibres may be seen on microscopic examination and are suggestive of
mitochondrial disease, but often are not present and may be seen in other muscle disorders. Sometimes a diagnosis
can be made by identifying an mtDNA mutation through molecular diagnostic techniques. However, not all
mutations are known, and it is impractical to perform a complete analysis of an individual’s mtDNA. Furthermore,
because some mitochondrial disorders may be caused by mutations present in the nuclear DNA, screening of nuclear
genes that code for mitochondrial respiratory gene subunits ultimately may be necessary to pinpoint the underlying
cause of a patient’s symptoms; however, such an exhaustive search is not practical.

Defective mitochondrial membrane ion transporters, transmembrane carrier proteins, and intramitochondrial metal
homeostasis may also cause mitochondrial disorders. Neurodegenerative disorders including Friedreich ataxia and
Wilson disease have been associated with aberrant mitochondrial metal metabolism; impaired iron homeostasis is
present in Friedreich ataxia, while copper metabolism is abnormal in Wilson disease. The respiratory chain is
affected secondarily in these conditions. Mitochondrial respiratory chain dysfunction also has been theorized to play
a role in more common neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington
disease, and amyotrophic lateral sclerosis (ALS, or Lou Gehrig disease), as well as in normal aging. However, evidence
of the role of mitochondrial dysfunction in these conditions and in normal aging is inconclusive. There is no proven
therapy for patients with respiratory chain disorders, though various dietary supplements and cofactors have been
tried, and experiments have begun in the area of gene therapy.

Lysosomal Storage Disorders

Lysosomes are cytoplasmic organelles in which a variety of macromolecules are degraded by different acid hydrolase
enzymes. Lysosomal enzymes are coded for by nuclear DNA and are targeted to lysosomes by specific recognition
markers. If a lysosomal enzyme is absent or has reduced activity or if enzymes are not correctly targeted to
lysosomes, the macromolecules normally degraded by lysosomes will accumulate, causing abnormal storage of
various complex compounds including glycolipids, glycosaminoglycans, oligosaccharides, and glycoproteins.
Lysosomal storage disorders are autosomal recessive, except for Fabry disease and Hunter syndrome, which are X-
linked. Abnormal macromolecule storage leads to a variety of signs and symptoms, depending on where the storage
occurs. Some diseases (e.g., Gaucher disease type I) usually affect only peripheral tissues such as the liver, spleen, or
bone, others affect only the central nervous system (e.g., Tay-Sachs disease), while yet others affect both brain and
systemic organs (e.g., Niemann-Pick disease).

Characteristics of many lysosomal storage disorders include coarsening of facial features, eye abnormalities,
enlarged liver and spleen, and bone disease. As a group, these conditions cause severe neurological impairment,
often starting in infancy. However, each disease often has a spectrum of severity depending on the degree of
enzymatic compromise. For example, although Tay-Sachs disease is often fatal in early childhood, some forms do not
present until adulthood. Most lysosomal storage disorders have no therapy, except for supportive care. The difficulty
with most therapies is that they do not enter the brain, because of the presence of the so-called blood-brain barrier.
Bone marrow transplantation has been attempted in individuals with lysosomal storage disorders, but overall results
have been disappointing. Successful therapy for disorders without central nervous system involvement has been
accomplished; Gaucher disease type I, for example, is responsive to enzyme replacement therapy, that is, frequent
intravenous infusions of the specific enzyme that is missing in the disorder, and encouraging results have been
reported in Fabry disease and Pompe disease (GSD type II).

Peroxisomal Disorders
Peroxisomes are cytoplasmic organelles that play a central role in the catabolism of very-long-chain fatty acids and
other compounds through the process of beta-oxidation. They also are critical in the biosynthesis of important
cellular membrane constituents (plasmalogens), cholesterol, and bile acids. Unlike mitochondria, peroxisomes do
not contain DNA, therefore all of the components of their enzyme systems and membrane proteins are coded for by
the nucleus. Most peroxisomal disorders exhibit autosomal recessive inheritance, with the exception of the X-linked
form of adrenoleukodystrophy. They usually present with severe neurological compromise, but other organ systems
—for example, bone and kidneys—may also be affected. No specific treatment exists for these disorders, and nearly
all are lethal early in their course. Some disorders feature a reduced number or complete absence of peroxisomes,
which results in severely depressed activity of peroxisomal functions, affecting the functions of numerous enzymes.
Such disorders include Zellweger (cerebrohepatorenal) syndrome, neonatal adrenoleukodystrophy, hyperpipecolic
acidemia, and infantile Refsum disease. Patients may have severely decreased muscle tone (hypotonia), cerebral
malformations, seizures, and an enlarged liver in infancy. Many develop eye abnormalities, in particular a defect in
retinal pigment. Patients with Zellweger syndrome also may have small kidney cysts and cranial abnormalities.

In other disorders peroxisomes appear normal, with decreased activity of only a single enzyme. One example is X-
linked adrenoleukodystrophy (X-ALD), an insidious disorder in which affected individuals show normal early
development. Between the ages of 4 and 8, behaviour problems including hyperactivity, aggressiveness, or poor
school performance appear in affected boys. Children often lose speech, memory skills, and the ability to walk, and
seizures occur late in the course of the disease. The skin may have a brownish hue due to adrenal insufficiency.
Other forms of X-ALD may not include neurological disease, or neurological complications may be mild
(adrenomyeloneuropathy). Classic severe X-ALD and adrenomyeloneuropathy may coexist in the same family.
Lorenzo’s oil (named after the patient who inspired its development), a mixture of trioleate and trierucate oils,
improves or completely corrects the elevation of very-long-chain fatty acids in blood, but it does not have an effect
on the neurological progression of the disease because it does not cross the blood-brain barrier. Some success has
been reported in patients treated by bone marrow transplantation early in the course of disease.

Purine And Pyrimidine Disorders

Purines and pyrimidines are essential building blocks of DNA, RNA, and compounds involved in cellular energy
transfer and biosynthetic reactions (e.g., adenosine triphosphate, ATP). Purine and pyrimidine disorders have a wide
spectrum of signs and symptoms, including autism, kidney stones, susceptibility to infections, and severe intellectual
disability. Symptoms may present from infancy to old age. Most metabolic screening tests do not detect disorders of
purine or pyrimidine metabolism; hence, they must be specifically sought out by having specialized analyses
performed.

Adenosine deaminase (ADA) deficiency results in the accumulation of 2′-deoxyadenosine in the circulating white
blood cells (lymphocytes). This, in turn, causes a decreased number of lymphocytes and a drastically increased
susceptibility to infection (severe combined immunodeficiency, SCID). Bone marrow transplantation may be curative,
and gene therapy has shown promise, but enzyme replacement therapy is the standard treatment. Lesch-Nyhan
syndrome is an X-linked condition caused by a deficiency in the enzyme hypoxanthine-guanine
phosphoribosyltransferase. The nervous system is affected, resulting in writhing movements in the first year of life,
after a period of normal development. A particularly troublesome feature is the occurrence of self-mutilation.
Intellectual disability is also common. Most individuals with Lesch-Nyhan syndrome excrete a large amount of uric
acid in their urine, leading to gout, kidney stones, and possible kidney failure. A high fluid intake and the drug
allopurinol are helpful in treating the joint and kidney problems, but have no effect on the severe intellectual
disability. Physical restraint and extraction of the teeth are the only successful therapies for the self-injurious
behaviour.

Porphyrias
Porphyrins are intermediate molecules in the biosynthetic pathway of heme, a complex molecule that carries oxygen
in red blood cells (as part of hemoglobin) and takes part in liver detoxification reactions. Porphyrins display
fluorescence when exposed to ultraviolet light. Disorders of heme biosynthesis, the porphyrias, present with
neurological symptoms, intermittent abdominal pain, nausea, and vomiting. They are distinguished by a dark or red
appearance of the urine. Porphyrias that primarily affect red blood cells tend to cause photosensitivity and blistering
skin rashes, while those that affect the liver are more commonly associated with gastrointestinal symptoms. Unlike
most metabolic diseases, many of the porphyrias are autosomal dominant conditions. Many patients with enzyme
defects in the heme biosynthetic pathway remain asymptomatic, which is unusual for inborn errors of metabolism.

Vitamins
Although deficiency diseases have been described in laboratory animals and humans deprived of single vitamins, in
human experience multiple deficiencies are usually present simultaneously. The eight B-complex vitamins function in
coordination in numerous enzyme systems and metabolic pathways; thus, a deficiency of one may affect the
functioning of others.

Vitamin A

Vitamin A deficiency is the leading cause of preventable blindness in children and is a major problem in the
developing world, especially in Africa and Southeast Asia; in the poorest countries hundreds of thousands of children
become blind each year due to a deficiency of the vitamin. Even a mild deficiency can impair immune function,
thereby reducing resistance to disease. Night blindness is an early sign of vitamin A deficiency, followed by abnormal
dryness of the eye and ultimately scarring of the cornea, a condition known as xerophthalmia. Other symptoms
include dry skin, hardening of epithelial cells elsewhere in the body (such as mucous membranes), and impaired
growth and development. In many areas where vitamin A deficiency is endemic, the incidence is being reduced by
giving children a single large dose of vitamin A every six months. A genetically modified form of rice containing beta-
carotene, a precursor of vitamin A, has the potential to reduce greatly the incidence of vitamin A deficiency, but the
use of this so-called golden rice is controversial.

Vitamin D

Vitamin D (also known as vitamin D hormone) is synthesized in the body in a series of steps, starting in the skin by
the action of sunlight’s ultraviolet rays on a precursor compound; thus, without adequate food sources of vitamin D,
a deficiency of the vitamin can occur when exposure to sunlight is limited. Lack of vitamin D in children causes
rickets, a disease characterized by inadequate mineralization of bone, growth retardation, and skeletal deformities
such as bowed legs. The adult form of rickets, known as osteomalacia, results in weak muscles as well as weak
bones. Inadequate vitamin D may also contribute to the thinning of bones seen in osteoporosis. Individuals with
limited sun exposure (including women who completely cover their bodies for religious reasons), elderly or
homebound persons, and those with dark skin, particularly those who live in northern latitudes, are at risk of vitamin
D deficiency. Vitamin D is found in very few foods naturally; thus fortification of milk and other foods (e.g.,
margarine, cereals, and breads) with the vitamin has helped protect those populations in which sun exposure is
inadequate. Supplemental vitamin D also may help protect against bone fractures in the elderly, who make and
activate vitamin D less efficiently even if exposed to sunlight.

Vitamin E

Vitamin E deficiency is rare in humans, although it may develop in premature infants and in people with impaired fat
absorption or metabolism. In the former, fragility of red blood cells (hemolysis) is seen; in the latter, where
deficiency is more prolonged, neuromuscular dysfunction involving the spinal cord and retina may result in loss of
reflexes, impaired balance and coordination, muscle weakness, and visual disturbances. No specific metabolic
function has been established for vitamin E; however, it is an important part of the antioxidant system that inhibits
lipid peroxidation; i.e., it protects cells and their membranes against the damaging effects of free radicals (reactive
oxygen and nitrogen species) that are produced metabolically or enter the body from the environment. The
requirement for vitamin E is increased with increasing consumption of polyunsaturated fatty acids. People who
smoke or are subjected to air pollution may also need more of the vitamin to protect against oxidative damage to
the lungs.
Vitamin K

Vitamin K is necessary for the formation of prothrombin and other blood-clotting factors in the liver, and it also plays
a role in bone metabolism. A form of the vitamin is produced by bacteria in the colon and can be utilized to some
degree. Vitamin K deficiency causes impaired clotting of the blood and internal bleeding, even without injury. Due to
poor transport of vitamin K across the placenta, newborn infants in developed countries are routinely given the
vitamin intramuscularly or orally within six hours of birth to protect against a condition known as hemorrhagic
disease of the newborn. Vitamin K deficiency is rare in adults, except in syndromes with poor fat absorption, in liver
disease, or during treatment with certain anticoagulant drugs, which interfere with vitamin K metabolism. Bleeding
due to vitamin K deficiency may be seen in patients whose gut bacteria have been killed by antibiotics.

Thiamin

Prolonged deficiency of thiamin (vitamin B1) results in beriberi, a disease that has been endemic in populations
where white rice has been the staple. Thiamin deficiency is still seen in areas where white rice or flour constitutes
the bulk of the diet and thiamin lost in milling is not replaced through enrichment. Symptoms of the form known as
dry beriberi include loss of appetite, confusion and other mental symptoms, muscle weakness, painful calf muscles,
poor coordination, tingling and paralysis. In wet beriberi there is edema and the possibility of an enlarged heart and
heart failure. Thiamin deficiency can also occur in populations eating large quantities of raw fish harbouring
intestinal microbes that contain the enzyme thiaminase. In the developed world, thiamin deficiency is linked
primarily to chronic alcoholism with poor diet, manifesting as Wernicke-Korsakoff syndrome, a condition with rapid
eye movements, loss of muscle coordination, mental confusion, and memory loss.

Riboflavin

Riboflavin (vitamin B2) deficiency, known as ariboflavinosis, is unlikely without the simultaneous deficiency of other
nutrients. After several months of riboflavin deprivation, symptoms include cracks in the skin at the corners of the
mouth, fissures of the lips, and an inflamed, magenta-coloured tongue. Because riboflavin is readily destroyed by
ultraviolet light, jaundiced infants who are treated with light therapy are administered the vitamin. Milk, milk
products, and cereals, major sources of riboflavin in the diet, are packaged to prevent exposure to light.

Niacin

Symptoms of pellagra develop about two months after niacin is withdrawn from the diet. Pellagra is characterized by
the so-called three Ds—diarrhea, dermatitis, and dementia—and, if it is allowed to progress untreated, death
ensues. Pellagra was common in areas of the southern United States in the early 1900s and still occurs in parts of
India, China, and Africa, affecting people who subsist primarily on corn. The niacin in corn and other cereal grains is
largely in bound form, unable to be absorbed well. Soaking corn in lime water, as practiced by Native American
populations for centuries, frees bound niacin and thus protects against pellagra. In addition, unlike other cereals,
corn is low in the amino acid tryptophan, which can be converted in part to niacin. Sufficient high-quality protein
(containing tryptophan) in the diet can protect against niacin deficiency even if intake of niacin itself is inadequate.

Vitamin B6

Vitamin B6 (pyridoxine and related compounds) is essential in protein metabolism, the synthesis of
neurotransmitters, and other critical functions in the body. Deficiency symptoms include dermatitis, microcytic
hypochromic anemia (small, pale red blood cells), impaired immune function, depression, confusion, and
convulsions. Although full-blown vitamin B6 deficiency is rare, marginal inadequacy is more widespread, especially
among the elderly, who may have a reduced ability to absorb the vitamin. People with alcoholism, especially those
with the liver diseases cirrhosis and hepatitis, are at risk of deficiency. A number of drugs, including the tuberculosis
drug isoniazid, interfere with vitamin B6 metabolism.

Folic acid

Vitamin B12 and folic acid (folate) are two B vitamins with many closely related functions, notably participation in
DNA synthesis. As a result, people with deficiencies of either vitamin show many of the same symptoms, such as
weakness and fatigue due to megaloblastic anemia, a condition in which red blood cells, lacking sufficient DNA for
cell division, are large and immature. Deficiency of folic acid also causes disruption of cell division along the
gastrointestinal tract, which results in persistent diarrhea, and impaired synthesis of white blood cells and platelets.
Inadequate intake of the vitamin in early pregnancy may cause neural tube defects in the fetus. Thus, women
capable of becoming pregnant are advised to take 400 micrograms (μg) of folic acid daily from supplements, fortified
foods (such as fortified cereals), or both—in addition to consuming foods rich in folic acid such as fresh fruits and
vegetables (especially leafy greens) and legumes. The cancer drug methotrexate interferes with folic acid
metabolism, causing side effects such as hair loss and diarrhea. Folic acid deficiency may also result from heavy use
of alcohol, which interferes with absorption of the vitamin.

Vitamin B12

Deficiency of vitamin B12 (cobalamin), like folic acid, results in megaloblastic anemia (large, immature red blood
cells), due to interference with normal DNA synthesis. Additionally, vitamin B12 maintains the myelin sheath that
protects nerve fibres; therefore, an untreated deficiency of the vitamin can result in nerve degeneration and
eventually paralysis. Large amounts of folic acid (over 1,000 μg per day) may conceal, and possibly even exacerbate,
an underlying vitamin B12 deficiency. Only animal foods are reliable sources of vitamin B12. Vegans, who eat no
foods of animal origin, are at risk of vitamin B12 deficiency and must obtain the vitamin through fortified food or a
supplement. For people who regularly eat animal products, deficiency of the vitamin is unlikely, unless there is a
defect in absorption. In order to be absorbed, vitamin B12 must be bound to intrinsic factor, a substance secreted by
the stomach. If intrinsic factor is absent (due to an autoimmune disorder known as pernicious anemia) or if there is
insufficient production of hydrochloric acid by the stomach, absorption of the vitamin will be limited. Pernicious
anemia, which occurs most often in the elderly, can be treated by injections or massive oral doses (1,000 μg) of
vitamin B12.

Pantothenic acid

Pantothenic acid is so widespread in foods that deficiency is unlikely under normal circumstances. Deficiency has
been seen only in individuals fed semisynthetic diets deficient in the vitamin or in subjects given a pantothenic acid
antagonist. Symptoms of deficiency include fatigue, irritability, sleep disturbances, abdominal distress, and
neurological symptoms such as tingling in the hands. Deficiency of the vitamin was suspected during World War II
when prisoners of war in Asia who exhibited “burning feet” syndrome, characterized by numbness and tingling in the
toes and other neurological symptoms, responded only to the administration of pantothenic acid.

Biotin
Deficiency of biotin is rare, and this may be due in part to synthesis of the vitamin by bacteria in the colon, although
the importance of this source is unclear. Biotin deficiency has been observed in people who regularly eat large
quantities of raw egg white, which contains a glycoprotein (avidin) that binds biotin and prevents its absorption. A
rare genetic defect that renders some infants unable to absorb a form of biotin in food can be treated with a
supplement of the vitamin. Long-term use of certain anticonvulsant drugs may also impair biotin absorption.
Symptoms of deficiency include skin rash, hair loss, and eventually neurological abnormalities.

Vitamin C
Vitamin C, also known as ascorbic acid, functions as a water-soluble antioxidant and as a cofactor in various enzyme
systems, such as those involved in the synthesis of connective tissue components and neurotransmitters. Symptoms
of scurvy, a disease caused by vitamin C deficiency, include pinpoint hemorrhages (petechiae) under the skin,
bleeding gums, joint pain, and impaired wound healing. Although rare in developed countries, scurvy is seen
occasionally in people consuming restricted diets, particularly those containing few fruits and vegetables, or in
infants fed boiled cow’s milk and no source of vitamin C. Scurvy can be prevented with relatively small quantities of
vitamin C (10 milligrams [mg] per day), although recommended intakes, which aim to provide sufficient antioxidant
protection, are closer to 100 mg per day. Disease states, environmental toxins, drugs, and other stresses can
increase an individual’s vitamin C needs. Smokers, for example, may require an additional 35 mg of the vitamin daily
to maintain vitamin C levels comparable to nonsmokers.

Minerals Iron
Iron deficiency is the most common of all nutritional deficiencies, with much of the world’s population being
deficient in the mineral to some degree. Young children and premenopausal women are the most vulnerable. The
main function of iron is in the formation of hemoglobin, the red pigment of the blood that carries oxygen from the
lungs to other tissues. Since each millilitre of blood contains 0.5 mg of iron (as a component of hemoglobin),
bleeding can drain the body’s iron reserves. When iron stores are depleted a condition arises known as microcytic
hypochromic anemia, characterized by small red blood cells that contain less hemoglobin than normal. Symptoms of
severe iron deficiency anemia include fatigue, weakness, apathy, pale skin, difficulty breathing on exertion, and low
resistance to cold temperatures. During childhood, iron deficiency can affect behaviour and learning ability as well as
growth and development. Severe anemia increases the risk of pregnancy complications and maternal death. Iron
deficiency anemia is most common during late infancy and early childhood, when iron stores present from birth are
exhausted and milk, which is poor in iron, is a primary food; during the adolescent growth spurt; and in women
during the childbearing years, because of blood loss during menstruation and the additional iron needs of
pregnancy. Intestinal blood loss and subsequent iron deficiency anemia in adults may also stem from ulcers,
hemorrhoids, tumours, or chronic use of certain drugs such as aspirin. In developing countries, blood loss due to
hookworm and other infections, coupled with inadequate dietary iron intake, exacerbates iron deficiency in both
children and adults.

Iodine

Iodine deficiency disorders are the most common cause of preventable brain damage, which affects an estimated 50
million people worldwide. During pregnancy, severe iodine deficiency may impair fetal development, resulting in
cretinism (irreversible mental retardation with short stature and developmental abnormalities) as well as in
miscarriage and stillbirth. Other more pervasive consequences of chronic iodine deficiency include lesser cognitive
and neuromuscular deficits. The ocean is a dependable source of iodine, but away from coastal areas iodine in food
is variable and largely reflects the amount in the soil. In chronic iodine deficiency the thyroid gland enlarges as it
attempts to trap more iodide (the form in which iodine functions in the body) from the blood for synthesis of thyroid
hormones, and it eventually becomes a visible lump at the front of the neck known as a goitre. Some foods, such as
cassava, millet, sweet potato, certain beans, and members of the cabbage family, contain substances known as
goitrogens that interfere with thyroid hormone synthesis; these substances, which are destroyed by cooking, can be
a significant factor in persons with coexisting iodine deficiency who rely on goitrogenic foods as staples. Since a
strategy of universal iodization of salt was adopted in 1993, there has been remarkable progress in improving iodine
status worldwide. Nonetheless, millions of people living in iodine-deficient areas, primarily in Central Africa,
Southeast and Central Asia, and even in central and eastern Europe, remain at risk.

Zinc

A constituent of numerous enzymes, zinc plays a structural role in proteins and regulates gene expression. Zinc
deficiency in humans was first reported in the 1960s in Egypt and Iran, where children and adolescent boys with
stunted growth and undeveloped genitalia responded to treatment with zinc. Deficiency of the mineral was
attributed to the regional diet, which was low in meat and high in legumes, unleavened breads, and whole-grain
foods that contain fibre, phytic acid, and other factors that inhibit zinc absorption. Also contributing to zinc
deficiency was the practice of clay eating, which interferes with the absorption of zinc, iron, and other minerals.
Severe zinc deficiency has also been described in patients fed intravenous solutions inadequate in zinc and in the
inherited zinc-responsive syndrome known as acrodermatitis enteropathica. Symptoms of zinc deficiency may
include skin lesions, diarrhea, increased susceptibility to infections, night blindness, reduced taste and smell acuity,
poor appetite, hair loss, slow wound healing, low sperm count, and impotence. Zinc is highest in protein-rich foods,
especially red meat and shellfish, and zinc status may be low in protein-energy malnutrition. Even in developed
countries, young children, pregnant women, the elderly, strict vegetarians, people with alcoholism, and those with
malabsorption syndromes are vulnerable to zinc deficiency.

Calcium

Almost all the calcium in the body is in the bones and teeth, the skeleton serving as a reservoir for calcium needed in
the blood and elsewhere. During childhood and adolescence, adequate calcium intake is critical for bone growth and
calcification. A low calcium intake during childhood, and especially during the adolescent growth spurt, may
predispose one to osteoporosis, a disease characterized by reduced bone mass, later in life. As bones lose density,
they become fragile and unable to withstand ordinary strains; the resulting fractures, particularly of the hip, may
cause incapacitation and even death. Osteoporosis is particularly common in postmenopausal women in industrial
societies. Not a calcium-deficiency disease per se, osteoporosis is strongly influenced by heredity; risk of the disease
can be lessened by ensuring adequate calcium intake throughout life and engaging in regular weight-bearing
exercise. Sufficient calcium intake in the immediate postmenopausal years does appear to slow bone loss, although
not to the same extent as do bone-conserving drugs.

Fluoride

Fluoride also contributes to the mineralization of bones and teeth and protects against tooth decay. Epidemiological
studies in the United States in the 1930s and 1940s revealed an inverse relationship between the natural fluoride
content of waters and the rate of dental caries. In areas where fluoride levels in the drinking water are low,
prescription fluoride supplements are recommended for children older than six months of age; dentists also may
apply fluoride rinses or gels periodically to their patients’ teeth. Fluoridated toothpastes are an important source of
fluoride for children and also for adults, who continue to benefit from fluoride intake.bad breathLearn what causes
bad breath and how to prevent it.

Sodium

Sodium is usually provided in ample amounts by food, even without added table salt (sodium chloride).
Furthermore, the body’s sodium-conservation mechanisms are highly developed, and thus sodium deficiency is rare,
even for those on low-sodium diets. Sodium depletion may occur during prolonged heavy sweating, vomiting, or
diarrhea or in the case of kidney disease. Symptoms of hyponatremia, or low blood sodium, include muscle cramps,
nausea, dizziness, weakness, and eventually shock and coma. After prolonged high-intensity exertion in the heat,
sodium balance can be restored by drinking beverages containing sodium and glucose (so-called sports drinks) and
by eating salted food. Drinking a litre of water containing two millilitres (one-third teaspoon) of table salt also should
suffice.Chloride is lost from the body under conditions that parallel those of sodium loss. Severe chloride depletion
results in a condition known as metabolic alkalosis (excess alkalinity in body fluids).

Potassium

Potassium is widely distributed in foods and is rarely deficient in the diet. However, some diuretics used in the
treatment of hypertension deplete potassium. The mineral is also lost during sustained vomiting or diarrhea or with
chronic use of laxatives. Symptoms of potassium deficiency include weakness, loss of appetite, muscle cramps, and
confusion. Severe hypokalemia (low blood potassium) may result in cardiac arrhythmias. Potassium-rich foods, such
as bananas or oranges, can help replace losses of the mineral, as can potassium chloride supplements, which should
be taken only under medical supervision.

Water deficiency (dehydration)

Water is the largest component of the body, accounting for more than half of body weight. To replace fluid losses,
adults generally need to consume 2 to 4 litres of fluid daily in cool climates, depending on degree of activity, and
from 8 to 16 litres a day in very hot climates. Dehydration may develop if water consumption fails to satisfy thirst; if
the thirst mechanism is not functioning properly, as during intense physical exercise; or if there is excessive fluid loss,
as with diarrhea or vomiting. By the time thirst is apparent, there is already some degree of dehydration, which is
defined as loss of fluid amounting to at least 1 to 2 percent of body weight. Symptoms can progress quickly if not
corrected: dry mouth, sunken eyes, poor skin turgor, cold hands and feet, weak and rapid pulse, rapid and shallow
breathing, confusion, exhaustion, and coma. Loss of fluid constituting more than 10 percent of body weight may be
fatal. The elderly (whose thirst sensation may be dulled), people who are ill, and those flying in airplanes are
especially vulnerable to dehydration. Infants and children with chronic undernutrition who develop gastroenteritis
may become severely dehydrated from diarrhea or vomiting. Treatment is with an intravenous or oral solution of
glucose and salts.